The outreach quarterly connecting science with society

ISSN 2517-7028
ISSUE 102

FEATURING RESEARCH FROM:

University of North Carolina, University of Texas at El Paso, Canadian Society for Molecular Biosciences (CSMB),
The Archbold Biological Station, North Carolina State University, McGill University, Vanderbilt University School
of Medicine, Canadian Blood Services, Université de Sherbrooke, University of Chicago, Roswell Park Cancer
Institute, University of British Columbia, University of Delaware, International Agency for the Prevention of
Blindness (IAPB), The UCLA Henry Samueli School of Engineering and Applied Sciences, University Hospital
Research Features 3
Carl Gustav Carus, University of California, Ludwig-Maximilians-Universitat, Brown University, Health Research
Alliance (HRA)
COLLABORATE

RESEARCH OUTREACH ISSUE 102

WELCOME
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ISSUE 102

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ENGAGE There are many overlaps between the fields of Health &
FEATURING RESEARCH FROM:
University of North Carolina, University of Texas at El Paso, Canadian Society for Molecular Biosciences (CSMB),
The Archbold Biological Station, North Carolina State University, McGill University, Vanderbilt University School
of Medicine, Canadian Blood Services, Université de Sherbrooke, University of Chicago, Roswell Park Cancer
Institute, University of British Columbia, University of Delaware, International Agency for the Prevention of
Blindness (IAPB), The UCLA Henry Samueli School of Engineering and Applied Sciences, University Hospital
Research Features 3
Carl Gustav Carus, University of California, Ludwig-Maximilians-Universitat, Brown University, Health Research
Alliance (HRA)

Medicine and Biology. In this issue of Research Outreach,

we feature researchers from both disciplines and hear from
thought leaders across the subjects.
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www.researchoutreach.org 3
CONTENTS
06 BUILDING INTERDISCIPLINARY
BRIDGES TO STUDY
INTERCELLULAR BRIDGES
Dr Amy Maddox
Uncovering the properties of
intercellular bridges within
multinucleated cells.
10 NOVEL 3D MICROSCOPE
PROVIDES UNPRECEDENTED
MOVING IMAGES OF
BIOLOGICAL PROCESSES
Dr Chunqiang Li
A novel 3D optical microscope
that uses a spectrally shaped
pulse laser.
14 CSMB: ENSURING A STRONG
FUTURE FOR SCIENCE
ND SCIENTISTS
Dr Philip Hieter
The Canadian Society for
Molecular Biosciences supports
fundamental research.
18 FLORIDA’S ARCHBOLD
BIOLOGICAL STATION
GIVES ONLINE ACCESS TO
UNUSUAL NATURAL HISTORY
COLLECTION
Dr Hilary Swain
Making data and images
of thousands of biological
specimens available online.
24 COMMUNICATING THE
LANGUAGE OF PLANTS
THROUGH INOSITOL
PHOSPHATES
Dr Imara Perera
Investigating signalling
molecules to understand their
role in plant communication.
28 CONTROLLING MAGNESIUM
FLUX: A CENTRAL ROLE FOR
THE PRL-CNNM COMPLEX
Professor Michel L. Tremblay
Investigating the role of a
newly discovered pathway in
controlling magnesium flux.
We identified a number of
‘neurobiological bricks’ that are central
for cognitive control mechanisms.
PROFESSOR CHRISTIAN BESTE
Page 68
4 www.researchoutreach.org
44
32 BLOOD, SKIN AND BONE:
THE COMPLEX CONTROL
OF BLOOD PRESSURE
Professor Raymond Harris
and Professor Ming-Zhi Zhang
Uncovering a novel role for
bone marrow-derived immune
cells in salt-sensitive high blood
pressure.
36 CANADIAN
BLOOD SERVICES: THE ROAD
TO REGAINING PUBLIC TRUST
Dr Graham Sher
Providing a safe, secure, cost
effective and accessible blood
supply for Canadians.
40 DISORDERED FAT STORAGE
ENHANCES DEVELOPMENT
OF TYPE 2 DIABETES
Professor André Carpentier
Exploring how obesity increases
the risk of type 2 diabetes
44 THE GENOMICS
OF CANCER
Dr Lixing Yang
Uncovering structural DNA
rearrangements.
48 REPROGRAMMING
THE IMMUNE SYSTEM
FOR PERSONALISED
IMMUNOTHERAPY
AGAINST CANCER
Dr Richard Koya
Using patients’ own immune
systems to target and kill
cancer cells.
52 INHIBITING CANCER
STEM CELL SURVIVAL IN
THE HOSTILE TUMOUR
ENVIRONMENT
Dr Shoukat Dedhar
The possibility of using a cancer
cell’s own physiology as a
weapon against it.
56 THE EPIGENETIC EFFECTS
OF ADVERSE EARLY-LIFE
EXPERIENCES
Dr Tania Roth
Exploring the impact of the
environment, particularly stress
factors, on individual genes.
36
18
60 IAPB: ENVISIONING THE
FUTURE OF UNIVERSAL
EYE CARE
Peter Ackland
Leading international efforts in
blindness prevention activities
and eye health.
64 A NEW TERAHERTZ MEDICAL
IMAGING TOOL COULD
PROVIDE EARLY DETECTION
OF CORNEAL DISEASE
Dr Warren Grundfest
and Dr Zachary Taylor
A promising method to
accurately detect and study
cornea-related diseases.
68 UNVEILING THE
NEUROBIOLOGICAL
PROCESSES BEHIND
COGNITIVE CONTROL
Prof Christian Beste
Understanding the neural
RESEARCH AREAS
Biology
40
underpinnings of human goal-
directed behaviour.
72 COMMUNITY
COLLABORATIONS
TARGETING BREAST CANCER
Dr Marion Kavanaugh-Lynch
Coaching for community and
academic partnership teams
conducting participatory
research.
76 DUAL ORIGINS OF TISSUE
MACROPHAGES
Professor Christian Schulz
Demonstrating that a large
proportion of the macrophage
population is derived during
embryonic development.
80 THE DANGERS OF SLEEP
DISORDERED BREATHING
IN PREGNANCY
Professor Ghada Bourjeily
Health & Medicine
76
Understanding sleep disordered
breathing (SDB) in pregnancy.
84 HRA: MAKING SCIENCE
OPEN, MANAGED
AND WELL-FUNDED
Dr Maryrose Franko
The number one place for
non-profit organisations
seeking to enhance return
on their investment in
biomedical research.
86 COMMUNICATION
Social media and the
rise of video
How video use is increasingly
important on social media.
www.researchoutreach.org 5
Biology ︱ Dr Amy Maddox
Building interdisciplinary
bridges to study
intercellular bridges
Dr Amy Shaub Maddox
from the University of North
Carolina is leading a diverse
team of researchers to uncover
the properties of intercellular
bridges within multinucleated
cells. Known as syncytia, cells
with interconnected nuclei can
be found in model organisms
such as Drosophila and
Caenorhabditis elegans as well
as more complex organisms,
including humans. Dr Maddox
has also placed significant
emphasis on outreach to a
variety of audiences throughout
the course of this research. The
imaginative techniques the
team is using are sure to inspire
successful collaborations within
the university community and
beyond.
6 www.researchoutreach.org
T
he building block of all life is the
cell. The architecture of a generic
animal cell is well understood: a
single nucleus resides in the cytoplasm,
surrounded by the cell membrane.
However, not all cells are generic. Both
simple and complex animals in fact
have some specialised cells with more
than one nucleus. A cell with multiple
interconnected nuclei is known as a
syncytium. One place in the body where
syncytia are found is the tissues that
generate sex cells (sperm and eggs). In
The syncytial germline of the nematode C.
elegans, with DNA (blue) and the syncytial
lining (magenta) labelled.
these syncytia, nuclei are connected to
a common cytoplasm via intercellular
bridges. The work of Dr Maddox and
her team of researchers at the University
of North Carolina focuses on the
composition, dynamics and regulation of
these bridges.
SYNCYTIA: WHAT? WHERE? AND
WHY?
To understand more about the work
of Dr Maddox and her colleagues, it is
necessary to understand more about
the syncytium. Though syncytia are
a little different from the commonly
taught norm, they are present
throughout the animal kingdom. From
the fruit fly, Drosophila, to humans,
many species feature syncytial cells
in their germline. The germline of a
multicellular organism is the population
of its bodily cells which allows it to
pass on genetic material via sexual
reproduction.
The structure of syncytia, including
the properties of the intercellular
bridges, has important consequences
for fertility. Intercellular bridges allow
for communication and coordination
among the nuclei that reside
there together,
incompletely
partitioned like
The structure of syncytia, including the
horses in barn stalls. properties of the intercellular bridges,
has important consequences for fertility
For example, in
various types of
syncytia, cytoplasm
must flow out of some stalls and into
others to enlarge them. When the
oocytes are fully enlarged, the bridges
collapse, thus achieving cellularisation.
If the bridges collapse prematurely, the
oocytes do not enlarge properly, and
are not viable. Thus, these intercellular
bridges must be stable. However,
Dr Maddox’s lab recently found that
in the gonad of the model organism
Caenorhabditis elegans, intercellular
bridges are surprisingly dynamic
throughout the germline, enlarging and
contracting multiple times over their
lifetime.
How syncytia form and are maintained
remains poorly understood, however,
research by Dr Maddox and others
has begun to unravel some of the
mysteries. For example, some of her
earlier work identified a protein called
anillin-2, which promotes the integrity
of syncytia and endows the intercellular
bridges with elasticity and stability.
Dr Maddox’s lab has now discovered
another pair of proteins that regulate
the stability of intercellular bridges.
Interestingly, one is implicated in a
human disease of brain vasculature, so
their discoveries of its mode of action
may help our understanding of that
condition.
STUDYING SYNCYTIA
The model organism for this study,
Caenorhabditis elegans, is a tiny
nematode worm with a history of
providing answers to some of the big
questions in modern science. In fact,
work with C. elegans has garnered
three different Nobel Prizes. Many
Amy (left) in the microscope room with
members of her lab.
characteristics of this worm make
it a powerful organism for syncytial
studies; not least the well understood
architecture of its simple body plan and
invariant lineage of its cells. Similarly to
other model organisms such as the fruit
fly, genomic modifications of C. elegans
can be conducted with relative ease.
By manipulating the genome of C.
elegans to introduce fluorescent protein
tags, the team is using quantitative
microscopy to gain unprecedented
insight into the make-up of intercellular
bridges. Quantitative microscopy
allows for automated analysis of two- or
three-dimensional images, meaning
vast amounts of data can be analysed
much more quickly
than via manual
measurement.
Quantitative analysis
is powerfully
combined with
high-resolution
light microscopy techniques housed
in the Maddox lab and within her
department’s shared equipment facility.
COLLABORATION ACROSS THE
CURRICULUM
The team of researchers led by Dr
Maddox share diverse geographical
and educational backgrounds and
the scope of the project allows for the
training and mentoring of individuals
at several stages of their education,
www.researchoutreach.org 7
from undergraduate students to post-
doctoral fellows. Amongst the lab
members involved in the “hands on”
research are Daniel B. Cortes, Kathryn
Rehain-Bell and Michael Werner. Dr
Maddox benefitted from the fact
that the other researchers involved
with this study are dedicated to and
experienced with educational outreach.
These activities ranged from interactive
sessions with elementary school
children to lab tours for prospective
undergraduates.
Using the project to engage multiple
audiences was very important to
Dr Maddox. Her outreach activities
sought out different groups within the
University of North Carolina as well
as individuals and groups in the local
community.
One of the groups Dr Maddox was keen
to involve with this project was the local
education sector. She approached this
aim in two ways. Firstly, each summer
a teacher is invited to participate with
the lab work for a 3-5 week internship.
Dr Maddox hopes the experience will
inspire these teachers to take their
experience back to the classroom
and relay their new knowledge and
enthusiasm to their pupils. Secondly,
Dr Maddox visits an elementary school
to teach children about embryonic
development. This classroom based
project was developed according to
established teaching goals and with the
school’s science specialist.
Dr Maddox also wanted to make the
most of the already-collegial campus
environment at the University of
North Carolina by creating innovative
opportunities for engagement. In
order to improve interdisciplinary
collaborations between the fields of
biology and mathematics, Dr Maddox
developed a module that allowed
students from these courses to work
alongside each other. In the module,
the students experience novel methods
of quantitative analysis and computer
modelling using data they collect in
the lab, studying intercellular bridges.
One of the most original pieces of
engagement proposed by Dr Maddox
was interdisciplinary speed-dating.
During these sessions, biologists briefly
present projects to mathematicians,
8 www.researchoutreach.org
C. elegans
hermaphrodite Behind the Bench
Dr Amy
Oogenic Maddox
germline
E: asm@unc.edu T: +1 919 843-3228 W: http://asmlab.web.unc.edu/
Research objectives
Dr Maddox and her team are
attempting to achieve the following:
understand intercellular bridge
composition, dynamics and regulation,
capture live images of cell dynamics
Intercellular using different C. elegans tissues,
bridges and also, conduct extensive outreach
activities within the University of North
Carolina and beyond.
Funding
• National Science Foundation (NSF)
• NIH’s National Institutes of General
Medical Sciences (NIGMS)
Intercellular Collaborators
bridge • Michael Werner, PhD
regulation
Q&A
Ste20 Kinase
GCK-1
CCM-3
What has been the most enjoyable
and challenging aspect of your
research?
It’s funny that you ask it like that,
but indeed the most challenging
non-muscle myosin II anillin aspects are the most enjoyable ones.
There are two classes of challenges:
Schematics of progressively magnified views of intercellular bridges (blue circles) logistical and scientific. Logistically,
in the C. elegans syncytial germline. it’s challenging to keep the lab funded
and keep the people happy, but
successes in both these realms have
Our outreach activities will strengthen
been incredibly rewarding. Scientifically,
our forays into mathematical biology
scientific research potential, not only
have really stretched me, but we’re
making headway, mostly thanks to the
during the funded period but for
fearlessness of trainees and generosity
of collaborators. This diversification
generations to come
of our research program will
doubtless propel us to new successes
and enjoyment.
physicists, computer scientists and future research. Dr Maddox is confident Were there any surprises for you due
statisticians interested in collaborations. that the proposed outreach activities to working with such a diverse team?
Several successful partnerships have “will strengthen scientific research I have actually been incredibly spoiled
emerged from these events, and still potential, not only during the funded to recruit people not only with
more participants benefit just from the period but for generations to come.” inner drive to study cell biology and
time spent building community. Scientifically, there are still many more development, but also with substantial
questions to be answered about the training to tackle those questions.
Both the scientific and public dynamics of intercellular bridges with In fact, all three of my current post-
graduate lab members were previously
engagement elements of this project such important consequences for so
provide numerous opportunities for many species.
Michael Daniel B.
Werner, Cortes,
PhD PhD
• Daniel B. Cortes, PhD
• Kathryn Rehain-Bell
The team acknowledges the valuable
collaboration of Jian Liu (NHLBI),
Francois Nedelec (EMBL), Adriana
Dawes (Ohio State U), Wanda
Strychalski (Case Western Reserve U),
and many colleagues at UNC.
Bio
Team members have expertise in cell
biology, high-resolution microscopy
and computer-aided image analysis.
Amy Maddox was trained in North
Carolina and San Diego and has served
as faculty in Montreal, Canada. Michael
E. Werner was trained in genetics and
developmental cell biology in Austria
trained to use C. elegans, our model
animal of choice. Since joining my
lab, Michael, Daniel and Katie have
diversified from each other by pursuing
the knowledge, technologies and skills
necessary to advance their projects
and their independent careers. I admire
their independence and inner drive, and
am grateful to be part of their journeys!
What has been the best thing about
working with other faculty members?
I really appreciate how my faculty
colleagues provide a stimulating, multi-
disciplinary environment, and express
genuine interest in my scientific success.
I am also grateful for their support of
my sometimes-wacky ideas to connect
people in new and different ways.
They have been my “guinea pigs,”
attending scientific speed dating events
and randomised lunch dates, and
they report enjoying these activities!
My most important colleague is my
husband, who is a professor in the same
department as I am. It is invaluable that
we understand and can contribute to
each other’s careers.
Do you expect that future work of
this nature will be conducted with C.
elegans?
Yes, we certainly have not exhausted
Kathryn
Rehain-Bell
and Chicago. Daniel B. Cortes was
trained in molecular and cell biology
at the University of California at Davis.
Kathryn Rehain-Bell was trained in
evolutionary developmental biology
at the College of William and Mary in
Virginia.
Contact
Amy Shaub Maddox, PhD
Assistant Professor of Biology
University of North Carolina at Chapel
Hill
CB 3280
408 Fordham Hall
Chapel Hill, NC 27599-3280
USA
the potential for this model animal
to reveal fundamental principles of
syncytial biology. Even as more cell
biologists are discovering the elegance
and accessibility of this tiny worm’s
oogenic (egg-making) syncytial gonad,
there are frontiers in the understanding
the spermatogenic gonad, and in
exploring the diversity of gonad
architecture throughout nematode
phylogeny and beyond.
How will a better understanding
of intercellular bridge stability be
useful for humans?
Since intercellular bridges are crucial
for animal fertility, our discoveries will,
in the long term, inform preventative
or therapeutic medicine. Furthermore,
findings of how multiple nuclei reside
in one cell are relevant to other tissues
(including heart muscle cells and certain
fungi) with syncytial architecture.
Importantly, “basic” research aimed
at defining the workings of the natural
world will always enrich humanity
by deepening our understanding in
general, and we can almost never
predict how and when our findings will
directly serve human health and society.
www.researchoutreach.org 9
 Fig. 1

Biology ︱ Dr Chunqiang Li
Prism pair

Novel 3D microscope provides

Femtosecond laser HWP Polarizer Mirror
Mirror

unprecedented moving images Pickoff mirror

of biological processes
L3 L2 AOM L1
3D stage Objective DM1

Dr Chunqiang Li and his team
of the University of Texas at El
Paso have developed a novel
three-dimensional (3D) optical
microscope that uses a spectrally
shaped pulse laser. Whilst
most prior microscopes used
scanning to achieve high speed
2D imaging, Dr Li’s approach
obtains the z-position from
a technique called ‘temporal
focusing’ that use ‘diffraction’
rings and clever mathematics to
infer the z-position.
3D defocusing imaging
of microbes.
D
r Li and his collaborative team
have achieved a breakthrough in
optical microscopy for 3D imaging
without raster scanning laser beams. He
expects to observe interaction between
living cells at the microscopic scale, in
three dimension (3D). Dr Li’s approach will
permit cellular and molecular activities like
protein motions, subcellular signalling,
and viral infection to be examined and
captured in real time.
The team have built on the work of
others in the field who have sought
to image the trajectory, in 3D, of tiny
‘particles’, molecules or cells for example,
at a precision of a nanometre, or one
billionth of a metre.
UNDERSTANDING 3D MICROSCOPY
Earlier microscopes relied broadly on
one of three techniques to capture
3D trajectory. The first uses a control
mechanism called ‘feed-back’ to track
the movement in all three dimensions
of a single particle using the scanning
of laser beams. The second technique
involves utilising the shape change of
an image illuminated with a focused
point of light, called the ‘point spread
function’ to calculate the z-position. The
final method uses the diffraction of light
of an image that has been defocused.
Unlike the previous method the resultant
image contains concentric rings and the
z-position can be determined with high
accuracy from the radius and centre of
the rings.
Sample
DM2
BP1
Imaging lens
Camera1
Schematic setup of the temporal focusing two-photon microscope.
THE TEAM AT EL PASO’S APPROACH
Dr Li and his team have developed a
microscope that is innovative in allowing
the tracking of more than one particle
using fluorescence. Fluorescent light
is detected from the target ‘particles’
by an optical technique often used
in microscopes called ‘two-photon
excitation’. In this,
Camera2
BP2
Imaging lens
BUILDING THE MICROSCOPE
Dr Li’s microscope uses a laser as its
illumination source, capable of delivering
pulses in the femtosecond range (i.e.,
10−15 or 0.000000000000001 seconds).
The ultrashort laser pulse is reduced
in power using optical components
Grating
AFG
colours overlap spatially at the objective
lens focal plane, they also overlap
temporally to achieve short laser pulses.
The subjects being examined are
fluorescently labelled so that they emit
light at certain wavelength after being
illuminated with the ultrafast laser pulse.
Dichroic beam

Dr Li demonstrated the power of his

the specimen is splitters are used
labelled to emit to separate the
light in a particular
colour when
invention and was able to track the high- emission light
from the excitation
excited by a laser speed motion of Cafeteria roenbergensis laser light. Images

as separate images that could be examined

beam. Shaped
ultrafast laser pulses
illuminate the scene
to be captured over
or combined into a 30 frames per second
a large volume, in
microscope terms,
of 100 µm, or millionths of a metre,
each side. The sample is deliberately
moved away from the focal plane of
the microscope objective lens to allow
defocused imaging, creating concentric
rings caused. This approach, called
‘temporal focusing’ can not only obtain
2D images of the specimen, but also
allows the z-position to be calculated
from the defocused rings. Time-lapse
images permit the progression of the
particles being tracked to be captured
and then viewed as a video or inspected
individually.
moving image
before being compressed by passing the
light through a pair of prisms. A special
component called grating splits the light
into separate colours and each colour
ray passes through a lens for collimation,
or make them travel in parallel paths like
railway tracks.
A device called an ‘acousto-optic
modulator’ can manipulate each
separated laser colour ray before it
passes through two further lenses that
relay the laser pulse to the objective lens.
When all the laser light with different
and videos are
captured by
cameras. Different
types of subjects
can be labelled
with difference
fluorescent agents to allow multiple
channel imaging.
WATCHING MARINE
ZOOPLANKTON
The operation of Dr Li and his team’s
microscope was tested using a fast-
moving marine zooplankton. They chose
Cafeteria roenbergensis, a D-shaped
biflagella single-celled organism. The
flagella are hair-like appendages that
permit the zooplankton to propel
themselves around the oceans.

10 www.researchoutreach.org www.researchoutreach.org 11

At around 10μm across, they feed
on bacteria and phytoplankton, are
significant predators of marine bacteria,
contributing to nutrient recycling, and
are important in the marine food chain.
For the experiment, two colours of
fluorescence agents were used to label
Cafeteria roenbergensis: green and
red, comprising tiny beads of 100nm in
diameter.
The laboratory grew cultures of Cafeteria
roenbergensis in culture medium,
with Escherichia coli bacteria as their
food source. For the experiment, small
quantities of Cafeteria roenbergensis
were extracted from the laboratory’s
stock and transferred to a medium
devoid of food. After four days of
starvation, the diluted fluorescent
beads were added to the culture. The
zooplankton ingested the beads as food
and could be used as targets in Dr Li’s
team’s microscope to track their motion.
They were kept in a darkened place
to preserve the fluorescence for the
experiment.
Time-lapse images were taken with
the two cameras, each camera capture
one of the fluorescent colours, green
or red. The techniques developed by
Dr Li meant that each image showed
the position of the organism in two-
dimensions and the defocused rings
around each image inferred the third
dimension. Using a mathematical model
permitted the team to calculate the
z-position of the two zooplankton being
12 www.researchoutreach.org
Dr Li’s novel approach could lead
to exciting discoveries in biology
and health as it waill be possible to
examine the interaction between tiny
organisms like viruses and their hosts
tracked, denoted by green and red
fluorescence, to add to the other two
dimensions filmed.
Dr Li demonstrated the power of his
invention and was able to track the high-
speed motion of Cafeteria roenbergensis
as separate frames that could be
examined or combined into a 30 frames
per second moving image.
IMPROVING THE MICROSCOPE
The team have shown that it isn’t
necessary to use a scanning laser to
capture wide-field 3D images on a
microscopic scale, instead they use
two-photon fluorescence as a method
and temporal focusing to reveal the
z-position of a target.
Dr Li states that the current frame
rate of 30 frames per second of their
Behind the Bench
Dr Chunqiang Li
E: cli@utep.edu T: +1 915 747 7537 W: http://science.utep.edu/photonics/
W: http://news.utep.edu/microscope-technology-will-enhance-array-of-studies/
Research Objectives
Dr Li and his team have developed a
high-speed temporal focusing two-
photon fluorescence microscope for
three-dimensional (3D) volumetric
imaging without laser beam scanning.
It will give scientists in biology and
chemistry a strong background in the
development and use of innovative and
contemporary instruments, significantly
enhancing their ability to conduct
cutting edge research. This will also
provide training for next generation
instrumentalists, who are currently
postdoctoral researchers or graduate
and undergraduate students.
Q&A
Your team’s approach to
determining the z-position using
the position of the rings in the
defocused region of the image is
novel. What drove you to select this
mechanism?
microscope is not an upper limit, but is Studying biological process in three
the result of the charged-couple-device dimensions is necessary as they
cameras he used. He has proposed happen in a 3D space. However,
that his team’s approach could achieve current optical microscopy can
millisecond resolution, and even higher obtain 2D images/videos. The third-
speed operation is a possibility for the dimension information requires extra
future. effort, such as scanning the object or
lens. This mechanical scanning is the
Dr Li’s novel approach could lead to bottle neck for achieving high speed
exciting discoveries in biology and health 3D imaging. Therefore, inventing a
sciences as it may be possible to examine fast way to conduct 3D imaging is
the interaction between tiny organisms very useful in many research fields.
like viruses and their hosts but it is not Defocused imaging can provide not
his only achievement. The microscope only 2D information, but also the
is not Dr Li’s only achievement from third dimension information from the
this research; he’s created complex level of defocusing. Therefore, it is my
mathematical models, utilising modelling vision to fully utilise the information
software, to generate noise reduction contained in such imaging setup.
algorithms and derive the z-position
from the temporal focusing rings with The acousto-optic modulator is an
high accuracy. integral part of your microscope
Funding
National Science Foundation (NSF)
Collaborators
• Wei Qian (Electrical and Computer
Engineering)
• Jorge Gardea-Torresdey (Chemistry)
• Chuan Xiao (Chemistry)
• Kyung-An Han (Biological Sciences)
Bio
Dr Chunqiang Li received a Doctor of
Philosophy in Electrical Engineering
from Princeton University in 2006 and,
from 2006 until 2010, he was a Post-
doctoral Fellow at Wellman Centre
and allows you some variability in the
design. How would this feature in a
commercialised microscope?
This acousto-optic modulator is used to
control the spectrum of our femtosecond
laser. It has been used in some products
in steering laser beams only. Our method
explores its novel use of shaping the
laser pulse in spectral domain. The
incorporation of this device in future
commercial microscope will expand
our ability to have better control of
laser beams, which opens many more
potential applications.
In your experiments, you used two
frequencies of light to track two
particles simultaneously. How could
this be achieved with many particles?
In many particles, it is necessary to
develop multi-frequency tracking, i.e.,
each particle is labelled with one-colour
label, and our microscope can visualise
them simultaneously.
Can you explain how the microscope
would operate if tracking the infection
of a cell with a virus?
The virus is stained with one dye at
one colour; and the cell is stained
for Photo-medicine in Massachusetts
at Harvard Medical School. Since
2010, Dr Li has worked within
the Department of Physics of the
University of Texas at El Paso, leading
the Bio-photonics Laboratory.
Contact
Chunqiang Li, PhD
Associate Professor
Physics Department
University of Texas at El Paso
El Paso, TX 79968
USA
with another dye at another colour.
Both species are visualised with our
microscope, and the laser can excite
both dyes simultaneously. Two CCD
cameras are used, one to detect the
first dye, and the other one to detect
the second dye. Therefore, there are
two detection channels, one for each
species. The final image/video is a mix
of signals from both channels.
You mentioned the limitations
caused by the cameras in use in the
microscope, particularly the frame
rate. You also suggested some ways
around the camera limitations. What
ideally would you like to achieve,
and how?
There is a trade-off between imaging
speed and signal-to-noise ratio in
detecting such week fluorescence
signals. If the fluorescent signal is
strong, the imaging speed can be
higher. Therefore, I would like to
use bright and robust fluorescence
molecules as the label to reduce the
image acquisition time. The ideal case
would be to achieve sub millisecond
time resolution to study fast molecular
dynamics in live animals.
www.researchoutreach.org 13
Thought Leader
CSMB: Ensuring a strong
future for science and
scientists
As scientists make fast and concerted advancements in life-saving technologies, the squeeze on funding could threaten
their momentum. That’s where Dr Philip Hieter, President of the Canadian Society for Molecular Biosciences (CSMB),
comes in. To get the ‘biggest bang for their buck’, the CSMB is leveraging its collective knowledge and talents by focusing
on the most pressing issues facing fundamental research, like funding. Through advocacy and education, they aim to
influence not only present and future scientists, but decision makers in the Canadian government and the world.
I
n 1957 the Canadian Biochemical
Society (CBS) was first conceived. After
merging with the Canadian Society of
Cellular and Molecular Biology in 1995
and the Genetics Society of Canada in
2010, it renamed itself the Canadian
Society for Molecular Biosciences (CSMB)
in 2011. While the society’s name and
make-up have changed over the years,
its basic premise has been to support
science.
And while science is making leaps
and bounds on its way to combatting
major diseases, it’s sometimes hard to
believe, given the state of funding for
fundamental research in Canada, after
a crippling decrease in financial support
over the past decade and a general lack
of understanding of the system’s needs.
Fortunately, CSMB and other
organisations have been working on
ways to ensure that scientists can do
what they do best, make amazing
discoveries. CSMB is a relatively small
organisation with a finite budget and
members who realise that to have the
biggest impact they need to broadcast
the exciting possibilities and their
importance both to government and to
the general population. They believe
that with advocacy and education,
the necessary funding and support
will follow. Dr Philip Hieter, President
of CSMB, spoke with us at Research
Outreach about the society and his
excitement about its future.
Hi Philip! Could you tell us what your
role involves as the President of
the Canadian Society for Molecular
Biosciences (CSMB)?
14 www.researchoutreach.org
During my time as CSMB President,
I will help guide the CSMB board
in identifying the pressing issues
confronting the basic scientific research
community, devising plans of action,
and working to enhance the support
Phil Hieter looking at
yeast colonies growing
on a Petri plate.
of science. I brought with me previous
experience in my role as President of
the Genetics Society of America (GSA)
a 5000-6000-member organisation
based in Washington, DC. The GSA, as
its name implies, is primarily focused on
The Michael Smith Laboratories Building at the University of British Columbia,
where scientists conduct fundamental research in molecular genetics,
bio-process engineering, bioinformatics, and genomics.
There is a beauty in discovery itself. I think society
is gratified by trying to understand nature,
understanding the world around us
the community of genetics researchers, system, which supports cutting edge efforts – and provided critical mass. I
whereas, CSMB has a broader mandate technology and approaches, is a critical became actively involved about the time
context for training the next generation the merged societies became the CSMB.
A key immediate issue is promoting of innovators, and for teaching science
a re-investment by government more broadly. How do you advocate the progression
into the scientific funding envelope of molecular bioscience? What is the
that is necessary to support science Can you tell us more about the CSMB’s value of basic science to society?
research and teaching in Canada at heritage and background? Why does it need to be supported by
an internationally competitive level. CSMB is an amalgam and evolution of governments?
Adequate support of fundamental three more focused societies. What Every basic discovery has the potential
discovery research is critical to the began as the Canadian Biochemical of affecting major applications in health,
realisation of long term societal benefits Society, became Biochemistry and agriculture, and industry. This is often
in health, agriculture, climate, and Molecular Biology before merging with a long-term progression, and federal
industry. We’ll also address standards the Cell and Molecular Biology Society, governments are the only bodies that
and practices that ensure success at all and finally with the Genetics Society take on that timeframe without short-
stages of scientific career development. of Canada in 2010. The unification of term economic return. Since we’re
The CSMB also strongly believes that biochemistry, cell biology, and genetics talking about scientific research that
a robust, research-based university helped to concentrate energies and leads to solutions in health treatment
www.researchoutreach.org 15

After DNA replication, chromosomes (light blue)
condense and undergo a series of coordinated
movements to achieve bipolar attachment
of sister centromeres on the mitotic spindle
(green) at metaphase (A and B). Once properly
attached, the replicated sister chromosomes are
coordinately pulled to opposite poles during
anaphase (C). Images courtesy of Dr Conly L
Rieder (conlyrieder@hotmail.com). The Hieter
laboratory studies chromosome biology in yeast
and human cancer.
and management, as well as other major
problems worldwide, it’s vital.
Under a previous administration, the
long-term recurring money available
for reaearch grants to basic scientists
declined significantly. This has caused
a devastating shortfall in the operating
budgets that fuel the day-to-day
operations of individual research
laboratories. It dramatically crippled our
pipeline for discovery and training at
the early stages in the broad continuum
of research from basic to applied, that
ultimately leads to direct applications. If
a government pulls funding from early
training and fundamental research, it
pays the price five, ten, twenty years
down the road.
That’s why we’re so excited about the
recommendations made in the Trudeau
government’s “Fundamental Review
of Science,” (April 2017), also known
as the Naylor report. It recommends a
large reinvestment in research operating
grants (back to 2007 levels), better
coordination across the federal funding
agencies, and financial support of open
competitions for early and middle career
16 www.researchoutreach.org
scientists. Using our ‘inclusive’ advocacy,
education programmes, website and
social media, we plan on broadcasting
this information to our members, the
broader scientific community, advocacy
organisations (lobbyists), and people at
every level in our community, including
decision-makers in government.
There is beauty in discovery itself. I think
society is gratified by trying to understand
nature, understanding the world around
us. But there are practical benefits that
are quite large and more than justify the
investment by governments. This truth
and awareness should help drive long-
term funding and support.
What are the main research interests and
key areas of focus current at the CSMB?
From a scientific standpoint, we try
to understand the basic mechanisms
of cells. Our members include
researchers in genetics, cell biology and
biochemistry, the perfect combination
for focusing on a gene or a pathway
to understand its function. Genetics
– finds mutants that define genes and
manipulates the genome to understand
the consequences gene disruption in
cells. Biochemistry – helps us understand
how gene products work at a structural
and molecular level. Cell biological
methods – akin to imaging, explore the
dynamics of gene function in cells. The
three together accurately define the
functions of genes.
Our last two presidents, Christian Baron
(University of Montreal) and Kristin Baetz
(University of Ottawa) helped revitalise
the CSMB. Christian upgraded our
website, our social media presence and
rallied the Board to achieve defined
goals in advocacy and training. Kristin
staged our 150th Anniversary of Science
meeting in Ottawa to encourage
interaction with MPs and instituted a
dual-track speaker programme with
lots of engaging crossover. Kristin
also worked tirelessly in advocacy
efforts through direct interaction with
government officals in Ottawa.
We will keep the momentum going and
continue to share the big picture of what
we do and how important it is to the
world. If we can’t support our scientists
and be internationally competitive, how
A win for one scientist is a win for the entire scientific
community and the world
will we develop our next generation of
scientists and solve the problems we
face? We simply can’t afford to allow
them to fail.
CSMB offer numerous awards to both
researchers and students, including
the New Investigator Award, the 2016
Video Challenge and the Graduate
Student PDF Poster Competition.
What are the benefits of having these
award schemes in place?
Every year, scientists make ground-
breaking discoveries and we feel that
recognising and celebrating their
excellence is invaluable, plus it is also
great fun! It’s important to remember
that a win for one scientist is a win for the
entire scientific community and the world.
Indeed, it is naturally quite a motivation
and encouragement to young scientists.
These awards also increase our visibility
and credibility which may help us
to influence the approval of ideas
and policies to support science, for
example, as in the recommended in the
Naylor Report. This historic document
addresses the state of science in Canada
and where it needs to go – a rigorous
accounting, and a clear roadmap for
the future. The CSMB and Canadian
scientific community is also encouraged
by the installation of the Canadian
Minister of Science, Kirsty Duncan, and
the Chief Science Advisor, Mona Nemer.
The society runs various petitions
seeking public support. What impact
do these petitions have and what
topics are you currently petitioning for
or against?
CSMB explores serious issues and makes
strong recommendations in the form of
petitions. It can be difficult to measure the
impact of our petitions, but we imagine
they do have an effect. We’re proud of our
role in arguing against the introduction
of a detrimental grant review process
at the Canadian Institutes of Health
Research (CIHR) that was eventually
overturned. Thousands of people signed
our petitions, and in coordination with the
efforts of many others, we saw the return
of the gold standard face-to-face peer
review mechanism for determining the
best grants.
In my own laboratory, CIHR grants
made possible our basic studies of
genes and pathways in yeast as a
model system for understanding the
corresponding human genes that are
mutated and cause the progression
of human cancer. Even though we do
basic studies on chromosome biology
in yeast, there’s a strong relevance
of what we discover in yeast to an
understanding of cancer biology. My
research has been funded by federal
health research agencies over the past
30 years, and we have close interactions
with both basic and clinician scientists.
CSMB petitions have advocated for
a balance between fundamental and
applied research to ensure a healthy
sustainable research ecosystem vital to
fundamental discoveries and innovation.
These advocacy efforts will continue to
be a top priority for the society in the
years to come.
Finally, where do you see molecular
biosciences going over the next ten
years or so? Are there any areas that
you are particularly excited about?
We’re all excited about CRISPR,
molecular biosciences’ new method for
making very specific directed changes to
the genome of essentially any organism.
This new ‘precision genetics’ technology
has broad applications in all areas of
boiology. Coupling next-generation
Thought Leader
DNA sequencing of whole genomes
with our access to large numbers of
people with genetic variants that cause
disease, we will be able to determine, for
example, the particular gene mutations
that cause each of the various sub-types
of cancer and be able to rationally
prescribe effective drugs, based on an
understanding of the specific biological
mechanisms at play. These technological
breakthroughs are not just going to
impact major diseases like cancer.
Hundreds of new disease genes that
cause rare human diseases are being
discovered every year. These dicoveries
provide a molecular diagnostic for
DNA testing for them, and open up
research avenues for developing novel
treatments. CSMB will continue to do
everything we can to help scientists keep
making phenomenal strides.
• If you would like to find out more
information and the work of the CSMB,
please visit their website at www.
csmb-scbm.ca/index.aspx.
Contact
Canadian Society for Molecular
Biosciences 
c/o Rofail Conference and
Management Services (RCMS)
17 Dossetter Way
Ottawa, ON K1G 4S3
Canada
E: contact@csmb-scbm.ca
T: +1 (613) 421 7229
W: http://www.csmb-scbm.ca/
index.aspx
www.researchoutreach.org 17
Biology ︱ Dr Hilary Swain
Florida’s Archbold Biological
Station gives online access
to unusual natural history
collection
F
The Archbold Biological Station, a world-renowned ecological field station ounded in 1941 by Richard
based in Florida, USA, is uploading its natural history collection onto Archbold, a biological explorer,
the Internet for the first time. The diverse collection, containing 270,000 the Archbold Biological Station
specimens of more than 10,000 species will provide researchers and (Archbold) is an internationally renowned,
students around the world, with access to this rich source of ecological not-for-profit biological field station
data. This highly collaborative project, which involves making data and located in central Florida. Archbold
images of thousands of biological specimens available online, is funded by manages nearly 20,000 acres of land, is
NSF and is being led by Dr Hilary Swain and Dr Mark Deyrup. dedicated to research and conservation
programs, and conducts scientific studies
at more than 50 locations throughout
the headwaters of the Everglades – a
2.6-million-acre watershed in south-
central Florida encompassing those
lands and waters that drain south to the
Everglades and onto the coasts. The
region is one of the most important
biodiversity “hot spots” in North
America. The endangered Florida scrub
is of special interest, being a harsh and
stressful habitat that is home to many
plants and animals found nowhere else
on Earth. Through its research, education
and outreach programs, Archbold aims to
conserve this biodiversity, and maintain
vital ecosystem processes that support
Florida’s natural environment and its
people. The research addresses many
of the most important issues facing our
world today, such as: climate change,
species and land conservation, water
quality, and sustainable food production.
The Station is also home to the
Archbold Natural History collection – a
diverse record of life taken largely from
the habitats of the ancient Lake Wales
Ridge, a 100-mile-long north-south
sand ridge running up the interior of
the Florida Peninsula. The 75-year-
old collection has grown through the
years, and currently contains more than
18 www.researchoutreach.org
Future museum specimens being wrangled from a dead oak;
the ecological data will be included on the specimen labels.
Photo by Dustin Angell.
270,000 specimens and over 10,000
different species. Although smaller
than the vast collections at some
universities and at large museums, the
Archbold collection is valuable in that
it is representative of in-depth and very
rich regional collections, with a nearly
complete local diversity rarely captured
elsewhere. “We all believe that natural
areas teem with biodiversity,” says
Archbold entomologist Dr Mark
Deyrup. “Here is proof. For example,
more than 1,500 species of beetles
live on this single site.” Overall, it is
one of the largest collections for any
North American site and includes a
wide variety of arthropods, plants, The chemical ecology of the
Bella Moth (Utetheisa bella) has
mammals, birds, fish, reptiles and been studied at Archbold for
amphibians. It also houses specimens many years. Specimens in the
of threatened and endangered plants collection serve as archived
vouchers, tying together field
and animals, giving scientists a unique research and publications.
opportunity to study these rare species.
And it includes specimens of many
newly arriving species, some of which Natural History collection with a much at the Station have been diligently
are invasive, thus tracking changes in wider audience, putting Archbold on photographing specimens, and adding
Florida’s diversity over time. Now, with the global stage. label information of the flora and fauna
National Science Foundation (NSF) into a searchable database. Significant
Collections in Support of Biological DIGITAL COLLECTION portions of the collection have been
Research (CSBR) funding, Dr Hilary During the last couple of years, a databased and now, for the first time,
Swain and colleagues, aim to share the team of scientists led by Dr Swain are being made available online
www.researchoutreach.org 19
 Left: Museum specimens can reflect major
ecological events. Tiny beetles were found in the
hidden rotten heart of oaks split by Hurricane
Irma on September 10, 2017. Photo by Dustin
Angell.

Above: Tiny beetles (sesame seed for reference)

found in rotten oak include six species never seen
before in 75 years of beetle study at Archbold.

In particular, the online arthropod

collection is outstanding, as the
Archbold Natural History collection is
best known for its pinned collection
of 250,000 insects, including 137,450
preserved specimens of ants; this
encompasses the largest collection
of Florida ants in the world. Currently
a total of 9,718 ant specimen records
– representing 236 species of ants –
have been uploaded online to SCAN, SCAN, representing a total of 902 The lands and waters that form the headwaters of the Evergaldes are notable for extensive natural areas
that have never been cultivated or strongly disturbed. Here Archbold scientists study species of plants
including detailed drawings completed insect species. This ecological dataset and animals that have been in residence for thousands of years. Figure by Archbold Biological Station.
by Dr Deyrup (see example opposite). is an important resource for biologists,

The online arthropod collection in

Over the years, the arthropod as it can answer questions like: Which
collection has served as the basis for bees visit which flowers and when? At

particular is absolutely outstanding, as many scientific papers, contributing

to numerous studies requiring insect
the Archbold Natural History collection identification, and was the main source
for the Dr Deyrup’s 2016 book Ants of
is best known for its pinned collection of Florida. The book is a natural history
the community level, this information
is now available to allow researchers to
model the stunningly complex network
of relationships among flowers and
insects at a single site.

250,000 insects
through several national collection
portals. This will allow scientists,
school children and the general public
from all over the world access to this
unique collection. To do this, Archbold
researchers are working with partner
organisation Integrated Digitized
Biocollections (iDigBio), an organisation
funded by NSF that is making data
and images of millions of biological
specimens available in electronic
format for the research community,
government agencies, students,
educators, and the general public.
Assisted by iDigBio, Archbold staff
has currently uploaded approximately
30,000 records of plants, birds and
arthropods to online portals hosted
by the Symbiota Virtual Biota software
package. To date these include 24,000
records of pinned insects available on
the Symbiota Collection of Arthropods
Network (SCAN), 1,474 records of bird
skins available on the Consortium of
Small Vertebrate Collections (CSVcoll),
and 4,795 herbarium records of pressed
plants available on the North American
Network of Small Herbaria (NANSH).
and identification guide for all 239
species of Florida ants.
The collection also includes specimens
of insects that were captured feeding
on nectar and pollen of local flowers.
This record of ‘flower-insect visitor
interactions’ was begun in 1983. It
includes more than 5,000 specimens
of bees and wasps, 1,500 flies, 200
Lepidoptera (butterflies and moths)
and 500 beetles, with labels that record
the species of flower being visited by
the insect, the location, and the date
of capture. So far, a total of 10,868
flower-insect visitor specimens have
been uploaded to the online database
WIDENING ACCESS
The online collection will be a huge
resource for scientists around the
world, providing them with easy access
to the data they need to conduct
their research. Plant specimens, for
example have been used by scientists
studying flowering times, which can
be affected by climate change. The
vertebrate collection provides a vital
resource for scientists wishing to study
the variation, growth patterns, life
histories, and population dynamics of
animals. The database will also be of
Temnothorax smithi. Multiple specimens in collections allow scientists to determine which features are
huge interest to schools and children. characteristic of a species and which are variable. After examining many specimens of this ant species in
Archbold has been dedicated to the Archbold collection Mark Deyrup drew this generalised diagnostic image.

20 www.researchoutreach.org www.researchoutreach.org 21

educational outreach for many years. It
shares its knowledge and habitats with
students of many ages, from age seven
through to adult learners. It provides
environmental education resources
to local schools, as well as access
to the site for school field visits and
summer camps. It hosts an estimated
2,000 3rd-5th grade and middle school
children annually, and nearly 50,000
school visitors have benefitted from its
outreach program in the last few years.
Undergraduate and graduate university
students regularly visit the Station
and use Archbold research to conduct
field courses or carry out independent
field studies. Archbold also provides
unique 6-12-month internships, longer
than most internships offered by other
organisations, where students receive
•Data collection websites to visit: http://symbiota.org (Symbiota Virtual Biota software package), http://symbiota4.acis.ufl.edu/
scan/portal/ (Symbiota Collection of Arthropods Network (SCAN)), http://csvcoll.org/portal/ (Consortium of Small Vertebrate
Collections (CSVcoll)), and http://www.nansh.org/portal/ (North American Network of Small Herbaria (NANSH)).
Behind the Bench
Dr Hilary Swain
E: hswain@archbold-station.org T: +1 863 465 2571 (Use EXTN 251) W: http://www.archbold-station.org
Research Objectives
Dr Swain, Dr Deyrup and their
collaborators’ aim is to increase digital
access to the Archbold Collection,
enabling studies of biodiversity
in ways that would be difficult to
replicate elsewhere, and enhancing
its conservation value as a critical
repository for species of the globally
threatened Florida scrub. In addition,
this project aims to offer students and
research interns more opportunities
for use of the collection as a source for
research ideas and study specimens, as
well as provide new mentoring for this
next generation of field station users in
the importance of collections.
Funding
National Science Foundation (NSF)
22 www.researchoutreach.org
The 75-year-old collection has been
expanded over many years, and currently
contains more than 270,000 specimens
and over 10,000 different species
training, participate in research projects
and, most importantly, are required to
conduct independent research projects
of their own design.
The online Archbold collection will
make the Station and its work even
more accessible to learners and the
younger generation. Not only will it be
a source of ideas and specimen data for
children and undergraduates/graduates
from around the world, it will fuel the
Collaborators
Co-Project Investigators: Dr Mark
Deyrup, Dr Reed Bowman, Dr Eric
S Menges, Dr Betsie B Rothermel,
Stephanie Leon and Stephanie Koontz.
Research Interns: Gabrielle LaTora,
Carly Tolle, Ryan Huether, Dylan Ricke,
Katherine Beigel and Trevor Young.
Graduate Students: Tram Nguyen
and Young Ha Suh from the Cornell
Lab of Ornithology who aided in the
digitisation of bird specimens.
Nancy Deyrup is a volunteer in
the entomology program who
singlehandedly digitised the majority
of the insect-flower database. Dr Butch
Norden, volunteer, organised the
amphibian and reptile collection for
digitisation.
minds of the younger generation.
“This is a giant trove of information for
them,” says one Archbold researcher.
“Advances in computer analyses and
graphics will allow the next generation
of scientists to swim joyously in floods
of data that would drown members of
our own generation.” Scientists hope
that learning to understand and value
complexities of the natural world will
inspire conservation of rare habitats
such as Florida scrub.
Bio
Hilary Swain has been the Executive
Director of Archbold since 1995,
directing activities at Archbold
Biological Station and the MacArthur
Agro-ecology Research Center
(MAERC). She works with a staff of
50 involved in long-term research,
environmental monitoring, science
education for students and the public.
Contact
Hilary M. Swain, PhD, Executive
Director Archbold Biological Station
123 Main Dr Venus, FL, 33960 USA
Q&A
This collections grant is an amazing
project to be involved with! What
are the major benefits this grant will
bring?
Swain: First and foremost, the major
benefit of the grant is to enable and
enhance more scientific research. As
anticipated by our funder, the National
Science Foundation, we already see
that having Archbold’s collection
online is shining a light on these data
for scientists around the world, not just
those who visit Archbold. Whether
scientific interests lie in identifying
new species, cataloguing biodiversity,
highlighting the arrival of new
species, noting changes in the timing
of flowering, or building complex
networking analyses for insect flower
visitors, this collection is a treasure
trove of ecological information just
waiting for scientific discovery and
synthesis. Archbold is one of many
biological field stations around the
world that are important to scientists
because although their collections
are relatively small, they are extremely
important representatives of regional
biodiversity.
Leon: One major benefit of this grant
is demonstrating the importance of
natural history collections, and how
they can be used outside of a museum
setting. More importantly, the fruits of
this grant can demonstrate how a well-
curated, regional, on-site collection
can provide useful data not only for
taxonomy and systematics, but also for
ecology and conservation.
Deyrup: Natural history collections are
currently cascading onto the Internet,
escaping from their reputation as
mouldering mortuaries to present their
true aspect as enormous and dynamic
sources of original information.
Why is it important that a record of
life in the Florida Scrub habitat is
made and preserved?
Swain: Since scientists first visited the
Florida scrub and started collecting
specimens of its plants and animals, it
has always been recognised as one of
the most threatened ecosystems in the
USA. Like nowhere else on Earth, there
has always been a scientific race to
ensure we capture and catalogue all its
precious life and unique adaptations.
Deyrup: As we consider our own
survival in a world of increasing
Dr Mark Deyrup and Stephanie Leon
environmental stress, we could benefit
from examining the information and
morphology associated with organisms
inured to a land of infertile sand, and
swept with fires, floods and droughts.
Leon: The Florida scrub is a unique
habitat with diverse flora and fauna.
It is important to show how such a
harsh habitat can support so much
biodiversity. This natural history record
will also show why conservation of
natural areas is important.
How will researchers use this data?
What scientific questions could be
answered?
Leon: Our data is useful at many
levels. It can inform scientists who
are interested in the distribution of a
particular species, it provides a record
of rare and endangered species,
it can aid taxonomic revisions and
descriptions of new species, and it also
provides useful ecological information
on plant-insect interactions, primarily
pollination. Those interested in
pollination ecology can find our “flower
visitor” dataset online, download it,
and use it to create intricate networks
to illustrate the complexity of these
relationships.
Deyrup: As data and images of
expertly prepared natural history
collections go online they become a
kind of universally accessible museum
– with the added feature that every
scientist can rearrange the “exhibits” to
further their individual goals.
How will school children benefit
from accessing the database?
Swain: Children are natural observers.
Their curiosity especially draws them
into the spectacular photography of
our plants, birds, and the bugs in the
online databases. Their faces watch
with awe as a small bug looms large on
the screen: they see the spectacular
colours and intriguing shapes. Here
lies inspiration for a future structural
engineer, computer modeller, fashion
designer, or budding ecologist.
Hopefully it will also draw them into the
natural world where they can use their
sharp and laser-focused eyes to be
further intrigued by nature.
Leon: Children will learn about the
diversity found in the Florida scrub. It
might encourage exploration, not only
of the scrub, but of different natural
Q&A with Dr Hilary Swain,
habitats. It might also supplement
their learning, research projects, and
general interest of biodiversity. Many
children that visit Archbold are given
tours of the Arthropod collection; they
learn about the vast diversity of insect
species collected at Archbold. This
might entice some to start their own
personal collections.
How will the archive further
conservation efforts in Florida?
Swain: Biodiversity is in flux worldwide,
and nowhere more than in rapidly
changing and threatened ecosystems
like the Florida scrub. Apart from
the obvious conservation question,
“What is out there”, we can use a
collection like Archbold’s to inform
conservation in many different ways.
How is biodiversity responding to
changing environmental conditions
over time? What new and potentially
invasive species are arriving? How
does conservation management, such
as prescribed fire, benefit species
of concern? Are we inadvertently
overlooking ecosystem components
that are more critical for conservation
than we realise, such as Mark
Deyrup’s long-term fascination with
documenting all the insects supported
by recently burned, dying, dead, and
decomposing wood.
Leon: Our goal is to demonstrate that
natural history collections can function
jointly with ecological research and
conservation efforts. In order to do this,
we have to showcase the biodiversity
of this unique habitat, and how this
biodiversity might be changing over
time. Rare, endangered plants are an
example of how we can use historical
records to track changes in their
distributions, and also track the history
of invasives, to aid in conservation and/
or restoration efforts.
Deyrup: Florida has an exploding
human population and amazing
numbers of invasive species, combined
with impending effects of climate
change on a vulnerable landscape.
Collection records give a baseline
of species diversity and distribution,
allowing targeting of conservation.
As the richness of Florida’s natural
heritage becomes easily visible through
natural history archives it should inspire
the next generation of conservationists.
www.researchoutreach.org 23
Biology ︱ Dr Imara Perera
Communicating the language
of plants through inositol
phosphates
Organisms require a variety
of signalling pathways to
communicate with and
respond to their environment.
Components such as signalling
molecules function as the
communicators of cellular
language. Dr Imara Perera and
her colleagues are investigating
one group of signalling
molecules, inositol phosphates
and their derivatives, to
understand its role in plant
communication.
Examples of data collected in studies on inositol phosphates and
pyrophosphates. Arabidopsis plants growing in a 96-well plate can be
grown under low energy conditions and analysed for inositol phosphate
changes in response to changing energy conditions.
24 www.researchoutreach.org
A
ll organisms interact with
and respond to their internal
and external environmental
conditions. Acting on these responses
requires a language comprised of
cellular words which interpret and
relay information within the organism.
One category of words, or signalling
molecules, are the myo-inositol
phosphates (InsPs) which have been
implicated in a variety of processes
within the cell. And much like words,
these molecules vary in the number
and position of letters (in this case
phosphates) with each combination
meaning different things in eukaryotic
cellular communication.
One particular group of these signalling
molecules are characterised by
diphosphate (PP) or triphosphate (PPP)
chains. These inositol pyrophosphates
(PPx-InsPs) have been implicated in
cellular metabolic processes given the
similarity of its structure to a molecule
called adenosine triphosphate (ATP),
sometimes referred to as the energy
currency of cells. Dr Imara Perera, Dr
Glenda Gillaspy and colleagues: Dr Joel
Ducoste and Dr Cranos Williams are
interested in the function of this group
of signalling molecules in eukaryotic
organisms such as plants.
INOSITOL HEXAKISPHOSPHATE
– A PRECURSOR TO INOSITOL
PYROPHOSPHATES
Inositol phosphates comprise an inositol
ring and varying numbers and positions
of phosphates attached to it, each
communicating unique messages in
the cell. A fully phosphorylated form
is inositol hexakisphosphate (InsP6),
a potential signalling molecule and a
precursor to the aforementioned group
of inositol phostphates PPx-InsPs that
Perera and colleagues are studying.
Inositol hexakisphosphate acts as
a storage compound of inositol,
phosphorus and minerals and is found
in large quantities in seeds. This large
quantity of InsP6 is later hydrolysed
during germination and has led
researchers to believe that as a PPx-
InsPs precursor, it is likely that plants
also synthesise this unique group of
signalling molecules. However, very little
attention has been paid to the presence
of PPx-InsPs in plants which is why
Dr Imera Perera and colleagues have
stepped in. This coupled with PPx-InsPs
role in ATP homeostasis make them an
interesting group of signalling molecules
to study.
Schematic showing how Arabidopsis seedlings By tagging important proteins with fluorescent markers,
are grown to facilitate labelling of inositol the authors can visualise where in the cell enzymes that
phosphates, that can be detected in the break down inositol pyrophosphates reside.
laboratory with high performance liquid
chromatography and radioisotope detection.
INOSITOL PYROPHOSPHATE
SYNTHESIS AND FUNCTIONALITY
One avenue of research is
understanding the enzymes which
synthesise PPx-InsPs molecules.
In fact, synthesis of InsPs and PPx-
InsPs molecules is carried out by two
evolutionary-conserved InsPs kinases.
These kinases catalyse the addition of
pyrophosphates at distinct positions
on the inositol ring. The first class are
delineated IP6Ks (but KCS1 in yeast and
absent in plants) and the second class
are VIPs (or PPIP5K in humans) which The authors utilise plant mutants that cannot make normal amounts of inositol phosphates (on right),
is conserved across eukaryotes. It is and compare responses to those from native, or so-called wildtype plants (on left).
these InsPs kinases which phosphorylate
InsP6 produces derivatives such as
inositol pyrophosphates InsP7 and InsP8. Using a variety of techniques, Dr Perera with elevated levels of InsP7 and InsP8.
Previous research has established InsP7 and her colleagues identified the One hypothesis for this is that a block
and InsP8 as important molecules in presence of these derivatives in higher in transportation of InsP6 provides a
metabolic programming as their energy- plant tissue. This was further supported larger pool for VIP kinases to access and
rich pyrophosphate moieties make them by the fact that Arabidopsis and maize thus produce InsP7 and InsP8. They also
comparable to ATP. However, they have seeds with a mutation in the InsP6 identified two similar Arabidopsis genes,
not been widely studied in plants. transporter protein produced plants AtVIP1 and AtVIP2 which functioned
to restore InsP7 synthesis in yeast,
These inositol pyrophosphates (PPx-InsPs) have clearly demonstrating that plants can
been implicated in cellular metabolic processes
synthesis pyrophosphates. What’s more
is researchers found that AtVIP1 and
given the similarity of its structure to a molecule AtVIP2 were differentially expressed in
called adenosine triphosphate (ATP), sometimes different plant tissue, alluding to distinct
functional roles.
referred to as the energy currency of cells
www.researchoutreach.org 25
 An example of radio-labelled inositol phosphate
separation allows the authors to quantify these
important signalling molecules.
But what function do inositol
pyrophosphates play in plant signalling
pathways and processes? Drs Perera,
Gillaspy, Ducoste and Williams are
exploring functions of PPx-InsPs, drawing
from a variety of studies. New work by
others has linked PPX-InsPs to phosphate
sensing (Wild et al., 2017; Puga et al 2017;
Jung et al 2018), a key process that allows
plants to regulate growth in sync with
phosphate, one of the most important
nutrients in the soil environment.
Previous studies have found that
InsP7 levels change in some non-plant
organisms in response to limiting
phosphate (Azevedo and Saiardi 2016).
PPx-InsPs have also been implicated
in Jasmonic acid signalling and plant
defense responses (Laha et al., 2015). As
mentioned above, the similarity of PPx-
InsPs to the energy currency molecule
ATP implies that they are involved in
processes involving energy homeostasis,
a crucial function in all organisms.
FURTHER AVENUES
However, there are still unanswered
and unexplored trajectories in this line
of research. Genetics and biochemical
approaches aside, Dr Perera and
colleagues hope to use computational
Inositol Pyrophosphate Synthesis
plasma
membrane PtdIns PtdInsP
myo-Inositol
Lipid
Independent
Pathway
InsP5
IPK1
P P P
P
P
P P
P InsP7
P
InsP6
MRP5
Storage
26 www.researchoutreach.org
Behind the Bench
Dr Imara Perera Dr Gillaspy
E: iperera@ncsu.edu T: +1 919 5 5 6985 W: http://pmb.cals.ncsu.edu/people/people-table/dr-imara-perera/
Research Objectives • Dr Joel Ducoste (North Carolina State Dr Gillaspy is Professor and Head of
Dr Perera and her colleagues’ aim University) Biochemistry at Virginia Tech. Glenda
with this project is to understand how • Dr Cranos Williams (North Carolina and Imara share common interests and
inositol phosphates are used to sense State University) a productive collaboration on inositol
the energy and nutrient status of plant phosphate signaling in plants.
cells, and how they signal this status so Bio
that the plant can use this information. Dr Perera is a Research Professor in Contact
the Department of Plant and Microbial Dr Imara Y. Perera
Phosphorous in undigested InsP6 seeds Funding
National Science Foundation (NSF)
Biology at North Carolina State
University. She received her PhD in
Research Professor
Department of Plant Biology
from non-ruminant animals has led to Collaborators
Plant Biology from the University of
Illinois at Urbana-Champaign.
North Carolina State University
Campus Box 7612
pollution of watersheds across the • Dr Glenda Gillaspy (Virginia Tech)
• Dr Pablo Sobrado (Virginia Tech)
Raleigh NC 27695
USA
United States
Q&A
environment. Non-ruminant animals do utilising known biochemical and
methods, such as kinetic modelling, to researchers can understand the potential not possess these enzymes in their gut, biological data, and by estimating key
predict how InsP synthesis is modulated behaviour of this pathway as well as key and thus they cannot breakdown InsP6. As parameters. Our initial PPx-InsP model
and identify key regulatory steps in components in the signalling pathway. How reliable are comparisons to a result, undigested InsP6 is excreted into uses biochemical data from a variety
the pathway. This system is based off similar pathways in eukaryotic the environment. This along with excess of eukaryotic enzymes and makes use
differential equations which represent Given the genetic conservation of organisms? unused phosphate from fertiliser ends up of observed changes in PPx-InsPs in
major reactions involved in the PPx-InsP proteins implicated in the InsPs signalling Although pathways are conserved in agricultural run-off and causes pollution plant mutants. By fitting the observed
pathway. By simulating these reactions, pathway, further research by Dr Perera between eukaryotic organisms, there of fresh water sources. Experimental data to the model, we can predict novel
they can compare these to observations and her colleagues will allow these are significant changes between plants approaches to reclaim or phosphate regulatory components.
seen in mutants where loss of function findings to form the basis of insights into and animals, in specific components from run-off are a focus of several
occurs. By utilising this methodology, other eukaryotes, such as humans. In of the InsP pathway, as well as how interdisciplinary research teams. How did you create InsP7 mutants in
other words, understanding how InsPs they are generated and regulated. yeast?
play a role in signalling in plants, may be For example, one key difference in Is it likely that VIP genes vary amongst We did not create these mutants but
used to understand this pathway in other inositol pyrophosphate synthesis is different plant species? were able to make use of mutants
PtdInsP2 DAG PtdOH multicellular organisms. that plants only contain the VIP class To our knowledge, VIP genes are created by other researchers in the
of enzymes whereas animals and yeast conserved in their DNA sequence field. The VIP mutants used in our
PLC Lipid Dependent On a bigger scale, research on this have two different types of enzymes across different plant species. As small study were obtained from Dr John
Pathway
signalling pathway has the potential (IP6K and VIPs). Additionally, InsP6 differences in VIP gene sequences are York of Vanderbilt University. The York
InsP3 to understand plant metabolism in is highly abundant and the major present, we cannot rule out the possibility laboratory created these mutants by
IPK2
the context of agricultural production. phosphate store in plant seeds, and that some plants encode VIP enzymes inserting DNA to disrupt key genes in
IPK2 In addition to this, phosphorous in no analogous situation occurs in most with different properties. Thus, it is PPx-InsP synthesis and degradation
5PP-Ins(1,2,3,4,6)P5 undigested InsP6 seeds from non- other eukaryotes. possible that there are species-specific pathways. We introduced the plant
ruminant animals has led to pollution of differences as well as gene duplication. VIP genes into these yeast mutants
P
P
P
P
1,5PP-Ins(2,3,4,6)P4 watersheds across the United States. Why can’t some animals digest to demonstrate that biochemical
P VIP1, VIP2 P
Better understanding of the signalling InsP6 in seeds? And what are What is kinetic modelling and how can complementation takes place. Showing
P P
P pathway may produce a solution to this the repercussions of phosphate it reveal key components in the PPx- that the plant VIP genes restore InsP7
VIP1, VIP2 P
P
P P P toxicity issue. Research of this kind will pollution? InsP signalling pathways? synthesis in the yeast mutants indicates
P P
P P therefore allow for the understanding of The phosphate bound up in the InsP6 Kinetic models of signalling networks that the plant VIP genes function
P
P P VIP1, VIP2 InsP8 signalling pathways at the cellular level molecule is most easily liberated by are a mechanistic description of the in a similar manner as do the yeast
P
P but also the environmental level with specific enzymes present in plants, key reactions that take place within the VIP genes.
which these molecules interact. ruminant animals, and microbes in our cell. Scientists can build kinetic models
1PP-Ins(2,3,4,5,6)P5
www.researchoutreach.org 27
Health & Medicine ︱ Professor Michel L. Tremblay
Controlling
magnesium flux:
a central role for the PRL-CNNM complex
Magnesium is an essential
metal ion for human health.
However, its ability to act as a
supplementary therapy against
disease is a poorly understood
area of science. Professor
Michel L. Tremblay and his
team at McGill University in
Montreal, Canada, are looking
to change this though, and are
currently investigating the role of
the newly discovered pathway,
PRL-CNNM, in controlling
magnesium’s mechanism of
action. This breakthrough
discovery has implications for
our understanding of cancer,
metabolism, circadian rhythm
and infectious disease.
The PRL-CNNM pathway could play a
substantial role in controlling the cellular
concentration of magnesium
28 www.researchoutreach.org
M
agnesium (Mg2+) is a metal
ion found in the earth, sea
and all living creatures, and is
essential to life. Present in every single
cell of the body, it serves many important
functions – especially in supporting
biochemical reactions. Notably, it’s
an intrinsic component of adenosine
triphosphate (Mg-ATP), the universal
energy store found in all forms of life.
Its most widely-understood function is
its ability to support the physiological
processes behind the metabolism of food
into energy. Magnesium contributes to
the creation of new proteins from amino
acids, the contraction and relaxation
of muscles, and the regulation of
neurotransmitters – chemical substances
that transfer messages throughout the
brain and nervous system. It also supports
gene maintenance, helping to hold
proper RNA and DNA structures.
Magnesium is an effective therapeutic
agent for a number of health conditions
including heart arrhythmia, migraines,
asthma and epilepsy. Due to its
significant role in sustaining the healthy
functioning of organisms, scientists have
been investigating its potential role
in disease for decades. Research has
particularly looked into the processes
that regulate magnesium’s presence
within the cells.
This is where Professor Michel L.
Tremblay comes in. Alongside his team,
he has uncovered one of the major
pathways that regulates magnesium’s
presence within the cells. His team’s
recent groundbreaking studies suggest
that a newly discovered pathway, reliant
on interactions between certain protein
phosphatase enzymes and magnesium
transporters, could play an essential
role in controlling the intra-cellular
concentration of magnesium which
has implications for countless cellular
processes and diseases.
PATHWAY TO PROGRESS
In recent studies Professor Tremblay
shows that the PRL-CNNM pathway
could play a role in controlling both the
cellular concentration of magnesium,
as well as the production of adenosine
triphosphate (ATP) – the organic
chemical that provides cellular processes
with the energy required to drive them.
The “PRL” and “CNNM” acronyms come
from the pathway’s reliance on two types
of proteins and the way they interact.
The first of these – the Phosphatase of
Regenerative Liver (PRL) proteins – come
in one of three forms, aptly named PRL-
1, PRL-2 and PRL-3. These PRL proteins
then interact individually with one of four
types of magnesium transporter, called
CNNM 1, 2, 3 and 4 proteins.
As yet, it is unclear whether these
interactions play a role in magnesium
transport, or if they simply act
as a magnesium sensor for cells.
Nonetheless, results currently show
that the more PRL-CNNM protein
complexes there are, the higher the level
of intracellular magnesium. Think of it
like three people (PRL proteins) getting a
choice of four cars (CNNM transporters)
to drive – driving these cars around
causes intracellular magnesium to
increase. Indeed, the central role of the
PRL-CNNM complex is supported by the
fact that it is evolutionarily conserved
across all chordates.
MAGNESIUM MUTATIONS
Mutating one of the PRL proteins in a
study using mice, Professor Tremblay
and his colleagues proved this
phenomena to be true – establishing
a decrease in intracellular magnesium
production when PRL-CNNM
interactions were inhibited. Through
their work, they also found that the PRL
enzymes and CNNM proteins worked
together and that their collaborative
function modulated magnesium levels
in cells.
PRL-CNNM: A CANCER-CAUSING
PATHWAY?
The implications of this research are
huge.The prominence of PRL gene
expression in almost all human cancers,
and the fact that PRL levels are higher
in metastatic (spreading) tumours
compared to non-metastatic tumours,
suggests PRL is involved in the process
whereby cancers spread.
Professor Tremblay and his team
therefore turned their attention towards
furthering understanding of this area,
investigating the influence of PRL
enzymes on cancer growth.
Again using mice as models, their
research found that – amazingly –
reducing the number of PRL proteins
in cancer cells significantly reduced
the rate of tumour
growth. In other
words: lower levels
The implications of Prof Tremblay’s area
of PRL enzymes, of work could be massive, especially
within the field of cancer research
lower levels of
cancer growth.
Not only that, but the team also
found that mutations in PRL or CNNM
genes reduce intracellular levels of
magnesium and lead to a decrease
in the metabolism of cancer cells –
preventing them from invading other
tissues. This could therefore explain
the oncogenic role of the PRL-CNNM
pathway, the outcomes of which could
be life-changing: should this process
occur similarly in humans, different
approaches to cancer prevention and
therapeutics may be developed.
THE COMPLEX AND THE CANCER
So far, Professor Tremblay and his team
have found an association between
the balance of intracellular magnesium
and the pro-oncogenic function of
PRL-2 enzymes, pinpointing CNNM
complexes as key PRL-binding partners.
Interestingly, the team uncovered that,
to ensure PRL is sufficiently present
in normal cells, a lower magnesium
concentration is needed for PRL-2
enzyme expression. Conversely, a
higher magnesium concentration
is needed to inhibit PRL-2 enzyme
expression – maintaining the balance
of magnesium concentration within the
cell. Think of it like balancing a see-
saw – you need one person to push up
and the other to pull down to create an
equilibrium.
However, cancer cells operate
differently. These cells rely on a higher
magnesium concentration to increase
the activity of the PRL-CNNM pathway,
ensuring their survival and replication.
It therefore makes sense that PRL
expression is often higher in metastatic
tumours – instances where cancer
spreads to surrounding tissue. Because
Figure 1 depicts magnesium atoms
(yellow balls) that are entering the
cells from the action of the two PRL
enzymes (green) associated with
two CNNMs transporter proteins
(pink/purple). This complex is
located at the cell membrane.
Once inside the cell, magnesium is
recruited by more than 300 proteins
(grey) to induce their building block
activities in active cells. A second
set of molecules that absolutely
requires magnesium, are the
nucleotides such as ATP (small stick
and ball structures) that need an
atom of magnesium to be an active
source of cellular energy.
of Prof Tremblay and his team’s findings,
the role of the PRL-CNNM pathway has
now been identified as a major part of
cancer’s ability to metastasise.
PRL-CNNM: OTHER IMPLICATIONS
Although the initial focus of the PRL-
CNNM complex research was on
cancer, the McGill University group have
since found it to have other important
metabolic functions. They demonstrate
that PRL-2
deficient mice
have an abnormal
physiology,
leading to growth
retardation, altered
body composition
and higher mortality rates after birth.
Some of these effects appeared to be
sex-dependent – especially in brown
adipocytes important for maintaining
body temperature – due to PRL being
found at higher levels in females than
in males. It is possible that female
hormones may have a positive effect
on PRL gene expression, increasing the
amount of available PRL.
PRL-2 deficient mice also showed
alterations in their circadian rhythm –
the internal clock system that regulates
energy expenditure, sleep pattern and
metabolism. The importance of this
mechanism was recently highlighted
www.researchoutreach.org 29
 Behind the Bench
Mg2+
Mg2+

Cell membrane open closed

Professor Michel L Tremblay

Transcriptional regulation
Structural change CNNMs
Protein expression

Mg2+
Mg2+ Mg2+ E: Michel.tremblay@mcgill.ca T: +1 514 398 7290/8480
W: https://mcgillgcrc.com/research/members/tremblay
Mg2+ Effectors
CNNMs
Active Inactive
Research Objectives • Prof Alphonso Martinez de la Cruz Chair in Cancer Research, at McGill
PRL2 ex. ATP-Mg2+ ex. ATP Professor Tremblay’s research focuses (Center of Excellence Severo Ochoa, University. A graduate of the Université
24 hr on investigating Protein Tyrosine Bilbao) de Sherbrooke (MSc) and of McMaster
or
Phosphatases (PTPases), specifically • Prof Andreas Bikfalvi (University de University (PhD), he completed his
looking into their roles in a variety of Bordeaux) post-doctoral training at the National
cellular processes such as cell growth, • Professor Rita Tewari (University of Institutes of Health in Bethesda.

Metabolism
Prl2 Prl2
or Tumour differentiation, and cancer. Nottingham)
Cnnms Cnnms
Growth • Professor Daniella Bucella (New-York Contact
Funding University) Professor Michel L Tremblay
Canadian Institutes of Health Research • Professor Joost Hoenderop Department of Biochemistry
24 hr (CIHR) (Rabdoub University) Rosalind and Morris Goodman Cancer
Research Centre
Figure 2 presents a schematic model of the PRL and CNNM complex cellular function. On the left panel, circadian transcription factors induce the daily Collaborators Bio Cancer Research Building
synchrony in expression of both PRL and CNNM. When they bind to each other at the cellular surface, they induce a rise in intracellular magnesium. Similarly, • Dr Noriko Uetani (McGill University) Michel L Tremblay is a Professor, a 1160 Pine Avenue West
PRL and CNNM are expressed differentially in males and females depending on the energy needs of cells. The complex at the membrane promotes the entry
of magnesium to support increased metabolic activities in their respective tissues. • Dr Serge Hardy (McGill University) James McGill Professor and holder of Office: Room 617; Lab: Room 603
• Prof Jose Teodoro (McGill University) the Jeanne and Jean-Louis Lévesque Montreal, Quebec H3A 1A3, Canada
On the right panel, once evening arrives, a decrease in the need for magnesium occurs causing a reduction in the expression of both PRL and CNNM.
A consequent drop in magnesium concentration and a decrease in metabolism favour resting during the incoming night. In cancer, higher levels of
magnesium are needed to sustain the high-energy metabolism of cancer cells. This occurs either through a positive feedback mechanism that is initiated
when magnesium is required, thus inducing expression of the PRL enzymes and high magnesium entry or through an increased expression of PRL and CNNM

induced by various oncogenes that leads to high magnesium levels, increased cell metabolism and a strengthening of tumour and metastatic burdens.
by the award of the 2017 Nobel Prize
in Physiology or Medicine to Jeffrey
C. Hall, Michael Rosbash and Michael
W. Young for their discoveries of
molecular mechanisms controlling
the circadian rhythm. Not only that,
but another of Prof Tremblay’s studies
found evidence suggesting that the
PRL-CNNM pathway is involved in
energy metabolism – the chemical
process animals and humans use to turn
ingested food into energy.
Previous research had already
pinpointed magnesium as a regulator
of metabolic and circadian processes,
but in a recent report Prof Tremblay
identified that the PRL-CNNM proteins
were directly regulated by proteins
responsible for controlling circadian
rhythm. During the morning, higher
levels of PRL-CNNM complexes
are present, which increases the
concentration of intracellular
magnesium. This facilitates metabolic
output, awakening us and providing
us with an active start to the day. In
contrast, at the end of the day, the
intracellular magnesium concentration
depletes, allowing our “cellular furnace“
to cool down and encouraging us to
rest.
Lastly, but rather excitingly, the PRL-
CNNM complex has been seen to be
modulated by virus infection. Findings
from Profs Tremblay and Teodoro’s
McGill laboratories have suggested
that – in a similar way to cancer –
certain viruses rely on activating the
PRL-CNNM complex, to produce the
higher levels of magnesium required
for optimal viral reproduction. This
also seems to be true of many human
parasites, including the malarial agent,
which in collaboration with Dr Tewari
(University of Nottingham) suggests
a new possibility for fighting these
pathogens.
THE PATHWAY FORWARD
Prof Tremblay and his team’s research
provides vital evidence about the
newly-discovered PRL-CNNM protein
complex, and the biological importance
of controlling intracellular magnesium
concentrations. Their research will
inform further studies looking into the
role of magnesium, both metabolically
and therapeutically – within disease
prevention.
The implications for this area of work
are huge, especially within the field
of cancer research. Tumour growth
is associated with the PRL-CNNM
pathway and the flux control of
intracellular magnesium. Improving
understanding of this area, and
extending research insight from mice
to humans, will not only broaden our
knowledge of the molecular processes
involved in controlling magnesium
concentration, but it could also lead to
novel therapies both in oncology, and
against infectious disease.
One thing is for sure: magnesium’s role
has never looked so important.
Q&A
When and how did you first start
being interested in the role of
magnesium for the functioning and
potential malfunctioning of the
human body?
When we first identified that mice
engineered to lack functional PRL
genes had changes in their blood
magnesium concentration, and that
PRL proteins were binding to the
magnesium concentration regulator
CNNMs proteins.
What would you say were your most
noteworthy findings so far and how
might these be applied to human
studies in future?
• Cancer cells must increase their
magnesium intracellular levels to
maintain a high metabolic rate
through the PRL-CNNM complex.
• Many infectious agents may
target this complex – influencing
cell metabolism – to favour their
infectious cycle and replication.
• Magnesium controlling the beginning
of the daily circadian rhythm does this in
part by regulating this complex.
• Females and males have differences
in their levels of the complex, thus
affecting the metabolic output and
mechanism of using glucose differently
in males and females.
• The control of magnesium levels by the
complex likely explains the multiple
sites in cells affected by PRL. This is
because over 300 enzymes are known
to depend on magnesium to maintain
their activities.
In the mouse studies you conducted,
what evidence suggests that pathways
controlling the magnesium flux could
be involved in diseases and what
further research needs to be carried
out in order to ascertain that?
The most solid findings come from our
research showing that, by removing PRL
in tumour cells, cancer cells were less
invasive and oncogenic in the animal
model. When we examined these cancer
cells with PRL reductions, they had less
intra-cellular magnesium and were less
oncogenic.
You recently met with other
international scientists who are
also carrying out research in this
area, what were some of the most
prominent points you discussed?
The structure of the complex
– the existence of mutations in
the CNNM human population
and their association with kidney
hypomagnesonemia diseases. We
also discussed the role of the complex
in modulating infectious agents, as
well as how PRL-CNNM modulates
magnesium concentration, and how
the PRL-CNNM genes and proteins are
regulated.
What are your next steps in terms of
future investigation?
Developing novel inhibitor molecules
and identifying infectious agent
proteins that interact with this complex.
We also hope to identify how the
complex controls energy expenditure
and other cellular functions.

30 www.researchoutreach.org www.researchoutreach.org 31
Health & Medicine ︱ Professor Raymond Harris and Professor Ming-Zhi Zhang

Blood, skin and

Skin High-salt Kidney
diet

bone: the complex

Macrophage

T cells
? Arachidonic ?
VEGF-C Cytokines
acid

control of blood
NCC

Lymphangiogenesis COX-2

pressure
mPGES-1 EP4R

Na+ content PGE2 Na+ content

It is well-known that excessive salt intake can be a risk factor for high blood pressure. But how this effect is mediated The COX-2/mPGES-1/EP4 receptor pathway in macrophages maintains sodium
– and why some people are more susceptible than others – remains up for debate. Collaborators Professor Raymond homeostasis by influencing salt secretion in the kidney and extrarenal sodium storage.
Harris and Professor Ming-Zhi Zhang, at Vanderbilt University School of Medicine, have uncovered a novel role
for immune cells derived from bone marrow in salt-sensitive high blood pressure, hinting at potential new ways to
manage and treat the condition.

H
igh blood pressure (hypertension) Inhibition of the cyclooxygenase- on the bone marrow, the source of
may affect as many as a quarter prostaglandin pathway has already ‘haematopoietic’ cells: stem cells
of the developed world been linked experimentally to clinically responsible for making all other types
population, and is a significant risk factor significant salt-sensitive hypertension. of blood cells, including the white blood
for cardiovascular conditions such as cells of the immune system.
heart attacks and strokes. Although the Until recently, the action of the
causes of high blood pressure are many cyclooxygenase-prostaglandin pathway HYPERTENSION THROUGH
and complex, most cases are at least in maintaining stable blood pressure was TRANSPLANTATION
partially triggered by a high salt diet: thought to be limited to the kidneys – the Professors Harris and Zhang took
high levels of sodium pull water into the organs that, after all, play the major role laboratory mice with a normal,
blood stream, increasing the functioning cyclooxygenase-
pressure as it passes through the
blood vessels. Therefore, the
Previous paradigms about the prostaglandin pathway, which
could maintain normal blood
relationship between dietary salt development of salt-sensitive pressure regardless of the

hypertension are incomplete

and hypertension is an important
public health concern that needs
addressing.
A HEALTHY BALANCE
When our bodies function correctly, they
can counteract excess salt consumption
and maintain ‘homeostasis’ – a constant
balance of the chemicals, hormones,
and other parameters within the body.
A key mediator of salt homeostasis
is the cyclooxygenase-prostaglandin
pathway, which synthesises hormone-like
signalling molecules (prostaglandins)
responsible for a range of physiological
effects – including inflammation, dilation
of blood vessels, and the production
of blood-pressure-related hormones.
in maintaining our bodies’ salt and water
balance. High salt diets were known to
increase production of the pathway’s key,
rate-limiting enzyme, cyclooxygenase-2
(COX-2) in both kidney tissue and white
blood cells circulating in the kidney,
resulting in an excretion of excess
sodium.
The work of Professor Harris and
others, however, is beginning to
implicate a range of other tissues in salt
homeostasis, including the immune
system and even the skin. In particular,
Harris and Zhang’s research focuses
amount of salt ingested. They
then transplanted bone marrow
cells into these mice, in which
the gene for COX-2 had been switched
off. When the mice were then fed a high
salt diet, their blood pressure increased.
This showed that, without COX-2 in their
bone marrow – and therefore also in the
blood cells derived from it – the mice
were less able to deal with the excess
salt, despite having functional COX-2
molecules in other parts of their body
including the kidneys.
Professors Harris and Zhang concluded
that cells produced in the bone marrow
must play a hitherto-overlooked role
in maintaining salt balance and blood

32 www.researchoutreach.org www.researchoutreach.org 33

pressure through the cyclooxygenase-
prostaglandin pathway. Not only that,
but as Prof Harris points out: “Previous
paradigms about the development
of salt-sensitive hypertension are
incomplete.” When the experiment
was reversed, so that mice lacking in
COX-2 throughout their body were
transplanted with normal bone marrow,
their hypertension improved, confirming
the new findings.
Further investigations of the transplanted
mice found changes in the population
of at least two forms of white blood
cells, macrophages (which usually engulf
invading pathogens and debris) and
T cells (which recognise and attack
pathogens through specific antigens,
contributing to immunity), in their
kidneys and skin. Prof Harris suggests
that prostaglandins generated from
bone marrow-derived white blood cells
may partner with those from the kidney
to prevent hypertension caused by a
high salt diet.
Very similar results were found
when mice were transplanted with
macrophages lacking a key receptor
further on in the cyclooxygenase-
prostaglandin pathway, EP4, which
mediates prostaglandin signalling,
suggesting that disrupting either
prostaglandin production (by COX-
2) or reception (by EP4) in these cells
can cause salt-sensitive hypertension.
Overall, the study suggests an
unexpectedly important role for
white blood cells in salt homeostasis,
generated in the bone marrow but
acting at remote sites including the
kidneys and skin. However, according
to Harris and Zhang, the underlying
mechanisms appear to be complex and
multifactorial.
STOP POPPING THE PAINKILLERS
The cyclooxygenase-prostaglandin
pathway has many different roles in the
human body besides salt homeostasis,
for instance mediating inflammation
and pain. Some of the world’s most
popular painkillers – the non-steroidal
anti-inflammatory drugs (NSAIDs),
such as aspirin and ibuprofen – act
by blocking the action of COX-2 to
prevent inflammation triggered by
prostaglandins. Thus, side-effects of
regular NSAID use include both salt-
34 www.researchoutreach.org
Cells produced in the bone marrow
must play a hitherto-overlooked role in
maintaining salt balance and blood pressure
sensitive hypertension and peripheral
oedema, an associated swelling of the
extremities caused by a build-up of fluid
in the spaces between tissues of the
body. Harris and Zhang’s work shows
that these effects may be more complex
and widespread than previously thought.
Their results so far are tantalising,
suggesting a completely novel route to
hypertension in mammals. In a project
funded by the US National Institutes
of Health, they now propose to further
tease out the complex role of the
prostaglandins produced by COX-2
in cells derived in the bone marrow.
They want to find out exactly how the
pathway is triggered into action by the
presence of excess salt, how it relates to
Behind the Bench
Dr Raymond
C Harris
E: raymond.harris@Vanderbilt.Edu T: +1 615 322 2150 W: http://medicine.mc.vanderbilt.edu/nephrol_RaymondHarris
Research Objectives
Professors Harris and Zhang’s work
specifically focuses on understanding
the role of COX-2 and prostaglandins
in the kidney, studying the underlying
mechanisms of diabetic nephropathy
and determining mechanisms of
growth and repair in response to acute
and chronic injury.
Funding
National Institutes of Health (NIH)
National Institute of Diabetes Digestive
and Kidney Diseases (NIDDK)
Bio
Raymond Harris, MD is currently
the Ann and Roscoe R Robinson
Q&A
How does a high salt diet lead to
hypertension?
Although there continues to be
the occurrence of peripheral oedema, some controversy about the role of
and to quantify the relative roles of dietary science, most epidemiologic
macrophages in the different organs of evidence indicates an association with
the body in managing hypertension. hypertension. A significant percentage
of the population is “salt sensitive”,
In light of their findings so far, Harris and increased salt ingestion leads to
and Zhang propose to test whether either development or exacerbation of
hypertension linked specifically to hypertension.
NSAID use occurs through the inhibition
of the cyclooxygenase-prostaglandin How do the different organs
pathway in bone-marrow derived cells. now known to be involved in salt
homeostasis (for instance, kidneys,
They are also considering the possibility
of activating the EP4 receptor through bone marrow and skin) communicate
drugs, as a new treatment for salt-
sensitive hypertension. Their results may
with one another?
Our understanding of salt homeostasis
ultimately suggest ways to both treat and is rapidly changing. Although new
prevent this widespread, chronic medical studies now clearly show that salt can
condition. accumulate in both skin and muscle,
Ming-Zhi Zhang
Professor of Medicine and Director
of the Vanderbilt Center for Kidney
Diseases. Research in the Harris lab has
focused on understanding mechanisms
underlying the pathogenesis of both
acute and chronic kidney disease.
Ming-Zhi Zhang graduated from
XuZhou Medical University in China
and is an Associate Professor of
Medicine and Cancer Biology
in Division of Nephrology at
Vanderbilt. His research focuses on
cyclooxygenase-2/prostaglandin
signalling pathway in macrophage
polarisation and its role in regulation of
blood pressure homeostasis.
how these organs communicate with the
kidney, which is ultimately responsible
for salt and water homeostasis, remains
uncertain. However, there is increasing
evidence that increased salt ingestion
activates an inflammatory response in the
affected organs, which may be a major
predisposing factor for development of
salt-sensitive hypertension.
How can you be sure that your results
from mouse studies are applicable to
humans?
Ongoing clinical studies using sodium
MRI clearly show that humans also
It is well known that both non-selective
and COX-2 selective NSAIDs can
predispose to development of salt-
sensitive hypertension
Contact
Raymond C Harris MD
Ann and Roscoe Robinson Professor
of Medicine
Chief, Division of Nephrology and
Hypertension
C-3121 MCN
Vanderbilt University School
of Medicine
Nashville, Tennessee 37232
USA
accumulate sodium in skin and muscle,
and studies with COX-2 selective
inhibitors have shown a predisposition
for development or exacerbation of
salt-sensitive hypertension.
What do your results mean for the
use of NSAIDs?
It is well known that both non-selective
and COX-2 selective NSAIDs can
predispose to development of salt-
sensitive hypertension. These studies
provide a mechanistic understanding
of underlying mechanisms.
www.researchoutreach.org 35
Thought Leader

Canadian
Blood Services:
The road to regaining public trust
The need for blood is constant; so is the need for donations. Every day, all the
hospitals and clinics in Canada need blood and blood products to treat patients,
since most surgical interventions and a great number of medical procedures
require blood transfusions. This is where Canadian Blood Services comes in.
Canadian Blood Services is a non-profit charitable organisation with a mission
to manage the bloody supply for Canadians and provide a safe, secure, cost-
effective and accessible supply of quality blood, blood products and their
alternatives. We spoke with Canadian Blood Services’ CEO Dr Graham Sher
at Research Outreach, to discuss this and more, in greater detail.

I
n the 1980s, more than 2,000 people
in Canada were infected with HIV
and over 30,000 with hepatitis C
after they had been administered
tainted blood products. In the wake of
disaster, an inquiry led by Justice Horace
Krever exposed years of negligence,
bureaucratic inertia and at times
corruption at the Canadian Red Cross
Society, then in charge of the blood
donation system. In consequence of
Can you tell us what attracted you to
Canadian Blood Services and what
your role there involves?
When I was asked by the newly
founded Canadian Blood Services to
join the organisation as a vice-president
of medical, scientific and clinical
management back in 1998, I worked as
a physician and scientist on staff at the
Toronto Hospital and on faculty at the
University of Toronto. I had no plans to

Patients depend on us to manage a safe,

secure and cost-effective blood system

Krever’s recommendations, 1998 saw leave my research lab or teaching role,

the foundation of Canadian Blood
Services that replaced Canadian Red
Cross Society in managing national
blood supplies. It took nearly 20 years of
Canadian Blood Services’ leadership and
dedication to rebuild the Canadian blood
system, make it an international success
story, and regain the public trust.
We recently caught up with Dr Sher at
Research Outreach and talked with him
about the organisation’s role, his role
as CEO over the last 20 years and the
future of blood donation in Canada.
but the opportunity to move beyond
the individual patient level and have
a greater impact on the wider health-
care system, and ultimately, serve more
patients, was too appealing to pass up.
A few years later, in 2001, I became a
CEO. Since then, I have been leading
the organisation through a multi-
year transformation journey aimed at
redesigning the entire service delivery
model, introducing best business
practices, and growing a culture of
high performance.
As part of transforming the national
blood system, I have also led Canadian
Blood Services through a significant
expansion in its scope of services,
which led to the organisation assuming
a national leadership and coordinating
role for both organ and tissue donation
and transplantation in Canada, and the
development of Canada’s national cord
blood banking programme. Finally,
I co-founded and continue to actively
participate in an international alliance
of national blood system operators,
with the focus of benchmarking, best
practice sharing and global policy
advancement in our sector.
Can you give us an overview of what
Canadian Blood Services does and
what its aims are?
Canadian Blood Services manages
the national supply of blood, blood
products, stem cells and related
services for all provinces and territories
(except Quebec). We operate within
the larger health-care system of
transfusion and transplantation
medicine in Canada. Patients depend
on us to manage a safe, secure,
and cost-effective blood system.
The organisation collects, tests and
manufactures blood, blood products
and stem cells, and plays an integral
role in organ and tissue donation and
transplantation.
Our responsibilities also include:
running national patient registries for
organ donation and transplantation;
operating the OneMatch Stem Cell
and Marrow Network, which matches
donors to patients that require stem
cells transplants; as well as Canadian
Blood Services’ Cord Blood Bank.
Moreover, Canadian Blood Services is
involved in research and development
efforts focused on several areas of

36 www.researchoutreach.org www.researchoutreach.org 37

transfusion and transplantation science
and medicine. We draw in experts
from various disciplines who together
can bring innovative thinking to bear
on real problems.
Why was the decision made to centralise
Canada’s blood services in 1998?
What have been the organisation’s key
achievements in that period?
This decision was made in the wake
of the tainted blood tragedy, the
largest public health catastrophe in the
country’s history. Justice Horace Krever
led an inquiry into the scandal and
published his report in 1997. Following
one of his recommendations, Canadian
Blood Services was created and trusted
with a mission to ensure such a disaster
would never happen again.
Back in 1998, we inherited a fragmented
blood supply system plagued with
critical quality failures, badly ageing
facilities, and structural complexity.
When I became CEO, I recognised that
to transform the system in a long-term
and sustainable manner we needed
to move from crisis management to
strategic management. I set about
creating a business framework that
allowed us to plan for changes over
a long horizon and to move the
organisation to a much higher level of
operational stability and performance
success. Since then, the organisation
has integrated about a dozen regional,
disconnected supply chains into one
seamless national system.
Today, whether patients are in Victoria,
Iqaluit, St. John’s, or anywhere in
between, they can count on the same
high-quality product when they need
it, without geographical or financial
barriers. When new pathogens emerge,
like West Nile virus, SARS, H1N1, or
Zika, Canadian Blood Services is at the
forefront of an international community
of scientists working together to
protect patients at home and around
the globe.
Can you describe Canadian Blood
Services’ role in the national formulary
of plasma-derived medicine, and
synthetic alternatives? What are
the benefits and disadvantages
of this system?
As the steward of the public blood
38 www.researchoutreach.org
Dr Graham Sher,
CEO of Canadian
Blood Services since 2001
system, Canadian Blood Services is the
trusted supplier of plasma and plasma
protein products for patients in Canada.
We manage a pan-Canadian formulary
of approximately 45 brands of plasma
protein products, which we bulk-
purchase on behalf of provincial
governments. For the patient’s
standpoint, our product selection
process supports patients’ and
physicians’ involvement in decision-
making. It’s also cost-effective. Bulk-
buying and price negotiations bring
significant savings.
In addition to collecting plasma for
transfusion, we collect plasma to be
used as a raw material to produce
immune globulin (Ig), a critical,
lifesaving drug in very high demand.
It is our responsibility to ensure enough
plasma goes to manufacturing Ig for
Canadian patients.
We currently only collect enough
plasma to meet about 17% of the
demand for Ig. To meet patient needs,
we purchase the remainder of the
necessary product from the commercial
plasma industry. We plan to expand
plasma collections in Canada to ensure
a secure supply of plasma for Ig for
Canadian patients.
Can you tell us more about the
OneMatch Stem Cell and Marrow
Network?
Fewer than 25% of patients who need
stem cell transplants find a compatible
donor in their own family. The rest rely
on those who have volunteered to
donate stem cells to anyone in need.
Thanks to the OneMatch programme
we can now search more than 23 million
donors in more than 70 registries
in other countries when we need to
find a match. By making donor data
available worldwide, international
registries have significantly increased
the odds of finding a matching donor
for any patient anywhere in the world.
What role does Canadian Blood
Services have in improving the national
levels of blood and organ donation?
Improving the national inventory
of blood is ongoing. We help
We draw in experts from various disciplines who together can
bring innovative thinking to bear on real problems
hospitals improve blood utilisation
and surveillance and have found
that educating consumers, donors,
physicians and other health
professionals is key to managing
utilisation of blood and blood products.
Our work in organ donation and
transplantation may be less well known.
Let me name a few of our initiatives
aimed at improving matters in this
field. Through the Kidney Paired
Donation (KPD) programme, we
facilitate medically compatible kidney
transplants through chains of donor
exchanges from medically incompatible
pairs. The Highly Sensitized Patient
Kidney (HSP) programme improves
chances of a kidney transplant for
hard-to-match patients. The National
Organ Waitlist (NOW) is a real-time
data source for non-renal patients
throughout Canada.
We work with stakeholders, partners
and physician groups to evolve
knowledge, policy and technology.
This leads to increased donation and
transplantation rates, gives patients
the best possible chances to receive
transplants with optimal outcomes,
and gives families the opportunity
to honour their loved one’s wishes
to become an organ donor.
With more than 800 transplants
resulting from the KPD and HSP
programmes combined, many
Canadians have received transplants
that may never have otherwise occurred.
You are a haematologist by training,
and an expert in transfusion medicine.
How did you first become interested
in this field?
In short, while doing my undergraduate
medical training, I was interested in
neurology, and therefore, destined to
become a neurologist. I even did a PhD
degree (simultaneous with my medical
degree) in neuroscience. In my second-
to-last year of medical training, while
rotating through a general medical unit,
I become the responsible physician
looking after a young patient with
acute myeloid leukaemia. We managed
to get the patient into remission, and
ready her for a lifesaving bone marrow
transplant from her only sibling,
an older brother.
Back then, unrelated bone marrow
stem cell transplants had not become
standard of care, and so it was a related
transplant or nothing. Fortunately, this
patient’s brother was a perfect “6 out
of 6” match for her, so all was hopeful
and positive. Tragically, the day before
the planned bone marrow collection,
her brother (and donor) was killed in
a motor vehicle accident. As such,
no transplant option existed for this
patient, and she died some months
later after relapse of her leukaemia.
These two — she 16, he 19 — were
the only children of two remarkable
parents, who themselves had been
children survivors of the Holocaust in
Europe. The capacity of these parents
to deal with the enormity of the grief
and loss they experienced was the
most remarkable display of humanity
I had ever witnessed. It was profoundly
humbling and entirely remarkable,
in ways that defy description. Their
impact on me personally was so
significant, that I switched paths
and dedicated my future career
Thought Leader
to haematology rather than neurology.
And, as they say, the rest is history!
What challenges are likely to face
blood and organ service provision
in Canada during the next decade?
We need to increase the amount
of plasma we collect to ensure a
secure supply of plasma needed
to manufacture immune globulin (Ig),
a critical lifesaving drug, for Canadian
patients. We plan to do this within our
current voluntary, unpaid system.
We also need to recruit more blood
and organ donors. We are focused
on connecting with an ever-changing
population of donors; the population
in Canada is shifting to metropolitan
areas, and we need to go where the
people go to operate as efficiently
as possible and make blood donation
as convenient as possible for donors.
• For more information on the
Canadian Blood Services, their
ground-breaking research and blood
donation, please visit their website at
blood.ca/en.
Contact
Dr Graham Sher
Canadian Blood Services
1800 Alta Vista Drive
Ottawa
Ontario
K1G 4J5
Canada
E: feedback@blood.ca
T: +1 613 739 2300
F: +1 613 731 1411
W: blood.ca/en
www.researchoutreach.org 39
Health & Medicine ︱ Professor André Carpentier
Disordered fat storage
enhances development
of type 2 diabetes
Diabetes is a devastating, life-
changing condition. Professor
André Carpentier and his
colleagues from Université de
Sherbrooke are exploring how
obesity increases the risk of type
2 diabetes. After all, abnormal
fat storage can lead to insulin
resistance, which endangers
organ function. Through his
and his team’s research, Dr
Carpentier aims to develop
therapeutic measures which
reverse detrimental pre-diabetic
effects.
40 www.researchoutreach.org
I
n 2015, diabetes mellitus was the sixth
leading cause of death worldwide.
This chronic metabolic disorder results
in insufficient glucose uptake from the
blood, due to abnormal insulin activity.
Pancreatic cells secrete the hormone
insulin into the blood where it triggers
skeletal muscle, liver and fat cells to
absorb and store glucose. Irregular insulin
activity can lead to hyperglycaemia
(high blood glucose levels) which in the
long-term can cause kidney disease,
cardiovascular complications, foot ulcers
and eye damage.
Insufficient insulin activity arises from
either: i) an autoimmune response,
leading to a loss of pancreatic cells and
dangerously low insulin levels (type 1
diabetes), or ii) cells that become insulin
resistant and are unable to respond
to insulin signals with an inability of
pancreatic cells to compensate by
secreting enough insulin to counter this
insulin resistance (type 2 diabetes [T2D]).
Environmental factors such as obesity,
smoking or a high, low-quality fat and
carbohydrate diet all increase the risk of
T2D development.
Although preventable, T2D is much
more common, accounting for 90% of
all diabetes cases worldwide – a statistic
that is increasing rapidly. Globally, T2D
cases have quadrupled since 1980 and
currently 8% of the global population
suffer from it. Increasing incidence rates
are also costly, with direct medical costs
for T2D exceeding $825 billion globally.
Clearly, there is an urgent need for
therapeutic options to prevent T2D
progression at the pre-diabetes
stage, where blood glucose levels are
high, but do not cross the ‘diabetic’
threshold. Professor Carpentier and
Above: A healthy individual undergoing a study to measure brown adipose tissue (BAT) metabolic be applied to all skeletal muscle/
response to acute cold exposure using positron emission tomography coupled to computed
tomography (PET/CT), indirect calorimetry and various metabolic tracers administered intravenously
adipose tissues simultaneously,
limiting the measurement of whole
body DFA partitioning, and secondly,
his team are therefore researching how lower in obese individuals, compared isotopic tracers are invasive, making
obesity-related abnormal fat storage/ to healthy individuals. Consequently, it challenging to study internal organs
metabolism drives insulin resistance. lean tissues such as the heart, liver and such as the heart.
Through this research, the team skeletal muscles are overexposed to However, Professor Carpentier’s
have been able to explore innovative fatty acids, which leads to lipotoxicity, method of using non-invasive PET
measures to prevent T2D. organ dysfunction and insulin resistance. (Positron Emission Tomography)
imaging overcomes these limitations.
DIET-RELATED INSULIN RESISTANCE PET IMAGING PET is a sensitive imaging technique
Studies have shown that there is a strong To investigate altered fat distribution, which can detect tiny (picomolar) tracer
link between a diet high in saturated Professor Carpentier used an innovative concentrations. Professor Carpentier
fat and insulin resistance. Although molecular imaging tool to quantify performed a study in which healthy
the exact mechanisms are unknown, organ-specific DFA partitioning. subjects were orally administered the
evidence suggests that the disordered Previously, isotropic tracers have radioactively labelled tracer FTHA
storage of dietary fatty acids (DFA) been used to assess organ-specific (14-R,S-F-fluoro-6-thia-heptadecanoic
in white adipose acid), a long-chain
tissue (WAT) plays a
key role. WAT is an
Inspired by their promising results, fatty acid analogue.
Sequential, whole-
extremely Professor Carpentier and his colleagues body PET acquisition
are now exploring other mechanisms to
dynamic energy was then performed
store and over- over six hours.
nutrition can result
in adipose tissue
prevent development of type 2 diabetes During this period,
all tracer movements
remodelling. were recorded as
Adipocytes can then undergo drastic DFA uptake. Radioactively labelling a three-dimensional image to highlight
alterations in number, size and metabolic DFA enables detectors to track whole-body tracer partitioning.
activity. Despite adipose tissue movement and deposition location. Essentially, this allowed DFA fat storage
expansion, DFA storage efficiency per However, isotropic tracers have several in different tissues and organs to be
mass of adipose tissue is significantly limitations: firstly, this method cannot measured. Results showed that in healthy
www.researchoutreach.org 41
 Behind the Bench
Professeur André C Carpentier
E: Andre.Carpentier@USherbrooke.ca T: +1 819 564 5241 W: www.usherbrooke.ca/dep-medecine/
recherche/professeurs-ayant-des-activites-de-recherche/endocrinologie/pr-andre-carpentier/

Research Objectives Collaborators scientist in the Departments of Medicine,

Professor Carpentier’s research interests
include: 1) the role of postprandial fatty acid
metabolism in the development of type 2
diabetes and cardiovascular diseases; 2)
the investigation of brown adipose tissue
metabolism in diabetes; and 3) the anti-
diabetic mechanisms of bariatric surgery.
Funding
An axial view of the heart using PET/CT after intravenous injection of 11C-palmitate, a free fatty acid
• Canadian Institutes of Health Research
tracer. Incremental tracer uptake is depicted using a blue to red color scheme (low to high uptake)
(CIHR)
• Canadian Diabetes Association
men, DFA storage was high in the liver and pre-diabetic individuals for the liver
and heart. However, skeletal muscles and or skeletal muscle. However, Professor
subcutaneous adipose tissue storage Carpentier found that cardiac DFA
contained relatively low levels of DFA per uptake is significantly greater in pre-
• Éric Turcotte, MD, Université de
Sherbrooke
• Brigitte Guérin, PhD, Uni. de Sherbrooke
• Martin Lepage, PhD, Uni. de Sherbrooke
• Roger Lecomte, PhD, Uni. de Sherbrooke
• Denis Richard, PhD, Université Laval
• André Tchernof, PhD, Université Laval
• François Haman, PhD, University of
Ottawa
Bio
Professor Carpentier is the recipient of
the GSK Research Chair in Diabetes of
Université de Sherbrooke and professor,
endocrinologist-lipidologist and clinician
Faculty of Medicine at the Université de
Sherbrooke. He is also the director of
the university’s Centre de recherche sur
le diabète, l’obésité et les complications
cardiovasculaires.
Contact
Professeur André C Carpentier MD FRCPC
Chaire GSK sur le Diabète de l’Université
de Sherbrooke/GSK Chair in Diabetes of
Université de Sherbrooke
Département de médecine
Centre de recherche du CHUS
Université de Sherbrooke
Canada

volume of tissue.
Professor Carpentier also investigated
DFA partitioning in brown adipose
tissue (BAT). The function of BAT is
thermoregulation via thermogenesis –
heat generation by oxidation of fat stores
to raise body temperature. Subjects
were administered oral FTHA and
exposed to low temperatures of 18°C.
PET imaging results confirmed that BAT
does uptake DFA during cold exposure.
However, BAT DFA partitioning per
volume of tissue was around 83% lower
than the liver and 55% lower than in the
heart, contributing to only 0.3% of total
body DFA clearance.
DISORDERED FAT STORAGE
The team also explored organ-specific
DFA partitioning per volume of tissue
in pre-diabetic and obese (with normal
glucose levels) subjects. Interestingly,
results support the notion that a pre-
diabetic state results in ineffective
adipose DFA tissue storage, which is
strongly related to obesity. In terms of
lean organ partitioning, DFA storage
did not differ between healthy, obese
Professor Carpentier and his team have
greatly advanced our knowledge of how
abnormal fat distribution enhances the
risk of type 2 diabetes development
diabetic individuals. In both healthy and
obese individuals, 2–3% of DFAs are
stored in the heart. However, this rises
to 4% in pre-diabetic individuals, which
can lead to severe cardiac complications,
such as left ventricular dysfunction, and
potential heart failure. Although this
finding is alarming, Professor Carpentier
showed that by making lifestyle changes
leading to a modest reduction of body
fat, this can reverse DFA channelling
to the heart. Inspired by this promising
result, Professor Carpentier and his
colleagues are now exploring other
mechanisms to prevent T2D from
developing.
BARIATRIC SURGERY TO TREAT T2D
Bariatric surgery is where the stomach
is reduced in size by stapling and the
small intestine bypassed, limiting food
intake and intestinal fat absorption.
The team investigated the benefits of
bariatric surgery in terms of improved
WAT activity and reduced overexposure
of lean tissue to DFA in obese individuals
with and without T2D. Twelve months
following bariatric surgery, on average,
Coronal view of PET/CT acquisition after
intravenous injection of 18Fluorodeoxyglucose,
a glucose tracer, during acute cold exposure.
The bright yellow areas depict regions with
high glucose uptake, including the brain,
supraclavicular brown adipose tissues, the heart,
and the liver
an excess weight loss of 85% was
achieved. Furthermore, all T2D subjects
were in partial or complete remission
after three months following surgery.
This is due to improved insulin sensitivity
in accordance with increased weight loss,
better fatty acid handling by lean tissues,
and significant reduction of WAT cell size.
FUTURE RESEARCH
Overall, Professor Carpentier and
his team have greatly contributed
to advancing our knowledge of how
abnormal fat distribution enhances
the risk of T2D development and
how preventative mechanisms such
as bariatric surgery can reverse these
detrimental effects. However, several
questions remain unanswered. For
example, why is DFA channelling to
the heart increased in pre-diabetic
individuals and whether it could be
targeted to reduce the risk of heart
failure, and how exactly does lean tissue
lipotoxicity result in insulin resistance?
Q&A
How does excess fat cause
insulin resistance?
Many mechanisms have been described
including: 1) intracellular accumulation
of reactive fat metabolites such as
diacylglycerols and ceramides; 2)
mitochondrial fatty acid overload
with increased production of reactive
oxygen species (ROS); 3) endoplasmic
reticulum stress that also may lead
to exaggerated ROS production; 4)
changes in phosphorylation of the insulin
signalling pathways by activation of
cellular inflammation; and 5) activation
of Toll-like receptors, triggering cellular
inflammation pathways. In general,
saturated fats have more profound
effects on these pathways than
unsaturated fats.
What cardiac complications could
result from increased pre-diabetic
channelling of fatty acids to the heart?
We and others have observed higher
cardiac oxygen consumption, but
reduced glucose utilisation when fat
utilisation by the heart was increased.
This may lead to enhanced susceptibility
of the heart to lack oxygen when its
blood flow is hampered. It may also lead
to intracellular acidification, leading in
turn to chronic heart damage. In our
studies, whenever cardiac DFA uptake
was enhanced, we found reduced cardiac
pumping of the blood.
Why is PET imaging advantageous to
observe abnormal fat metabolism?
PET is the most sensitive imaging
modality to non-invasively detect labels
administered into the body. With proper
setup and expertise, one can design almost
any labelled molecule that can then be
detected by PET in any organ of the body.
Because PET is so sensitive, you can safely
administer very small amounts of these
labels that are chemically altered to suit the
needs of the investigations pursued. With
PET, you also are not limited to one organ or
tissue, but you can simultaneously study the
uptake and metabolism of your preferred
PET label in all tissues in the field of view
of your scanner. That makes PET an ideal
tool for multi-organ integrative metabolic
studies.
Could diet-induced thermogenesis help
to prevent type 2 diabetes?
This is an important question to which
we still do not have a definitive answer.
In animal experiments, there is a strong
body of evidence that brown adipose
tissues (BAT) may strongly increase energy
expenditure and reduce the metabolic
abnormalities leading to type 2 diabetes. In
rodents, there is also strong evidence that
BAT is an important effector of diet-induced
thermogenesis. In humans, we now know
that BAT can utilise DFA and, therefore, may
somewhat contribute to energy expenditure
occurring after meals. We however found
that, at least during cold exposure, the
relative contribution of BAT is small. There
are many limitations to current work,
however, including the fact that no one,
including our group, is able to precisely
quantify the total volume of BAT in the
body. Therefore, the precise contribution
of BAT thermogenesis may at the
moment be severely underestimated,
especially in individuals suffering from
obesity and type 2 diabetes. This is the
next outstanding question that needs to
be addressed in the field of human BAT
research.
What are your research goals over the
next five years?
In addition to quantifying more
accurately BAT thermogenesis in
individuals with obesity and type 2
diabetes, our major goals will be to
establish the mechanisms of enhanced
cardiac DFA uptake in men and women
with pre-diabetes and whether this
functional biomarker can be used to
successfully predict and monitor the
benefits of nutritional, pharmacological
and surgical interventions to treat type 2
diabetes.
The quantification of BAT thermogenesis
and DFA organ-specific partitioning may
serve as functional biomarkers leading
to more individualised preventive and
therapeutic approaches of people at risk
of suffering from type 2 diabetes and its
complications.

42 www.researchoutreach.org www.researchoutreach.org 43
Health & Medicine ︱ Dr Lixing Yang

The genomics
duplications, insertions, inversions or A DNA double helix
translocations of DNA within and
between chromosomes.

Recent advances in technology now

of cancer
make it cheaper, quicker and easier than
ever before to determine the entire
sequence of the DNA held in the cells
of an organism. This ‘whole genome
sequencing’ has revolutionised many
areas of biology – and cancer biology is
no exception. Dr Yang’s research focuses

Many cancers are associated
with changes to our genetic
material, DNA. These may be
small, single unit substitutions,
large rearrangements such as
deletions or duplications of
a part of the DNA sequence,
or various other forms of
mutations. Although the smaller
substitutions have been more
intensively studied, Dr Lixing
Yang, of the University of
Chicago, focuses on uncovering
changes at the larger end of the
spectrum. His work suggests
certain key variations may be
connected to particular forms of
the disease.
W
hen we hear the term ‘genetic
disease’, we probably think of
something like cystic fibrosis,
or Huntington’s Disease. But, increasingly,
cancers are also being linked to genetic
causes, whether an inherited trait found
in every cell of the body, or a change
occurring in just the cells of a tumour
itself.
REARRANGING THE GENOME
Genes are held on chromosomes,
aggregates of DNA and protein found
in almost every cell of the body. DNA is
the blueprint of most living organisms.
Our DNA is made up of a sequence of
paired sub-units known as nucleotides
or bases, denoted by the letters A,
C, G and T. DNA changes can be as
small as a single substitution: a T for
an A, say, or a C for a G; or they can
be as large as an entire portion of one
chromosome – thousands or millions of
As, Cs, Gs and Ts – being transferred
to another. The larger changes may
affect an order of magnitude more DNA
than single nucleotide variations, yet
the functional impact of such ‘genomic
rearrangements’ has until now been
largely unexplored.
Genomic (or ‘structural’) rearrangements
are commonly generated during
DNA replication, or when the cellular
machinery that repairs damaged DNA
is not functioning correctly. They may
take many forms and arise from multiple
different events, such as deletions,
on using whole genome data to discover
larger scale structural rearrangements
of our genetic material that may cause,
or contribute to, the development of
cancer, and to determine the relative
contributions of these different kinds of
rearrangements in different kinds
of cancers.
MEERKAT TO THE RESCUE
The human genome is over three billion
base pairs long – so searching for
genomic rearrangements in its sequence
is no easy matter. For this reason, Dr
Yang has developed a novel computer
program to facilitate his quest. The
algorithm, Meerkat, can both identify
more complex rearrangements than
available methods and ensure high levels
of accuracy in pinpointing the location
and nature of structural rearrangements
of the genome. Dr Yang has already
used Meerkat to catalogue structural
variations found in over a thousand
tumours from patients with dozens of
different types of cancer.

His research has shown that in tumours,

two forms of DNA damage – breaks
in both strands of the DNA double
helix and errors in DNA replication –
drive the majority of events leading to
genomic rearrangements. For deletion-
type structural changes, for instance,
around 20% result from complex errors
occurring when DNA is replicated.
Focusing on particular types of cancer,
Dr Yang has found that in patients with a
rare form of kidney cancer,
that 12% of these patients display
genomic rearrangements near a DNA
region known as a promoter, which
controls the activity of the TERT gene. In
glioblastoma multiforme, an aggressive
form of brain cancer, a more complex
picture is emerging: structural changes
of many different kinds can cause the
activation of several key oncogenes
functional consequence of highly
clustered genomic rearrangements in
cancer is the switching on of oncogenes.
A COMPLEX PICTURE
Dr Yang’s research highlights just
how intricate the interacting factors
influencing DNA changes can be,
with multiple mechanisms of mutation
sometimes acting to cause

Increasingly, cancers are being

chromophobe renal cell
carcinoma, one gene, known
as TERT, is sometimes
activated. TERT is
linked to genetic causes
involved in cell proliferation
and is essential to keep the
chromosomes stable after many cycles
of cell division. Dr Yang discovered
and inactivation of important tumour
suppressors. In fact, says Dr Yang,
his research has shown that the main
rearrangements within one
gene, while at the same time
multiple driving forces acting
on completely separate parts
of the genome can together
lead to an increased risk of cancer. It
seems common that a positive feedback
loop is present, where existing mutations

44 www.researchoutreach.org www.researchoutreach.org 45

The genome view of somatic alterations in a colorectal cancer patient. From the outer rings to the inner ones:
chromosomes 1 to Y, base substitutions, copy number changes (red - amplifications, blue - losses), intra-chromosomal
rearrangements, inter-chromosomal rearrangements
in genes involved in DNA replication or
repair result in an increased likelihood
of further mutations including large
structural rearrangements. Dr Yang has
shown that almost all cancer patients
have at least one alteration in a gene
involved in DNA replication or repair, and
almost half of these
are themselves the
result of structural
Almost all cancer patients have at least
rearrangements to one alteration in a gene involved in DNA
the genome.
replication or repair
While whole-
genome-sequencing data, which offers
unprecedented accuracy and resolution,
is the ‘holy grail’ for researchers trying
to identify DNA rearrangements, the
time and expense needed to generate
it remains a constraint. Much more
widely available are so-called ‘whole
exome sequences’ focusing only on
the DNA regions thought to code for
protein – known as ‘exons.’ The whole
46 www.researchoutreach.org
exome sequencing data are typically
only used to discover single base
substitutions. Dr Yang has also improved
his approach to scour exome data for
structural rearrangements to re-use the
vast amount of existing data, which has
yielded further valuable findings.
On the other hand, although the greatest
interest in structural rearrangements
so far has been in those within genes
themselves, there is growing evidence
that changes in DNA regions previously
considered ‘non-coding’ may also play
an important, though perhaps more
subtle, role. These changes might only
be picked up through the whole genome
Behind the Bench
Dr Lixing Yang
E: lixingyang@uchicago.edu
Research Objectives
The goal of Dr Yang’s research is to
understand the roles of genomic
rearrangements in human cancer
by development and application of
novel computational methods. In
particular, he focuses on analysis of
whole-genome sequencing data,
which offers unprecedented accuracy
and resolution in identifying such
rearrangements.
Funding
National Cancer Institute (NCI)
approach in which Dr Yang specialises.
Dr Yang is quick to point out that this
Q&A
is an emerging field, and an inexact How did you first become interested
science. “The rearrangements we in this area of cancer research?
observe” he comments, “are a snapshot Cancer is a disease caused mostly by
… of the alterations in cancer genomes.” genetic and epigenetic alterations.
His research group at the University Cancer research not only can help
of Chicago is, he millions of patients, but can also
says, “battling
on the frontiers
advance our understanding on many
fundamental processes of biology
of precision including organ development, various
medicine.” Precise signalling pathways, metabolism, cell–
characterisation of cell interactions, ageing, immunology,
the mechanisms and many others.
and nature of genomic rearrangements
is crucial: by understanding the genetic How do structural rearrangements
mechanisms underlying tumour of the genome cause cancer?
development, we come one step closer The best-known cases are gene fusions
to discovering new drug targets, and – two different genes normally far away
ultimately, to helping patients. are fused into one new gene and the
new gene performs a novel function in
the cells. There are certainly other ways
such as the relocation of regulatory
T: +1 773 834 2948 W: http://yanglab.me
Collaborators
• The Cancer Genome Atlas (TCGA)
Research Network
• International Cancer Genome
Consortium (ICGC)
Bio
Dr Yang completed his PhD in plant
genome evolution at the University
of Georgia. He joined the Park lab at
Harvard Medical School in 2010 before
starting his own research group at
the University of Chicago in January
2017, continuing his work on cancer
genomics.
elements altering the gene functions that
they target.
What are the easiest types of
rearrangements to identify? And the
hardest?
The type doesn’t matter too much; what
matters is where they are. There are a
lot of DNA fragments that have been
repeated many times in the human
genome and some copies are completely
identical. The ones in such regions are
the hardest to identify. The situation is
more like being given two pictures: The
Empire State Building and a random
single family house. Which one is easier
to identify?
Does your research suggest that many
cancers are heritable? Or that they
result from mutations occurring during
our lifetime? Or both?
There are certainly some inherited
variants which increase the risk of cancer,
Contact
Lixing Yang, PhD
Assistant Professor
Ben May Department for Cancer
Research
Department of Human Genetics
Institute for Genomics & Systems
Biology
Comprehensive Cancer Center
The University of Chicago
929 E. 57th Street, GCIS W432
Chicago, IL 60637
USA
but most cancers are not heritable.
There are damages occurring to DNA
all the time and the vast majority are
repaired. Only a very small number
accumulate during each cell cycle.
Over the years, more and more
mutations accumulate in different cells.
Once the mutations reach a certain
combination, cancer starts to develop.
How do you think your findings
could be translated into treatments
for cancer?
Many targeted therapies for cancer
block protein functions of fusion genes.
If we discover more rearrangement
events that are responsible for
tumourigenesis, some of the genes
involved in the rearrangements could
be good drug targets.
www.researchoutreach.org 47
Health & Medicine ︱ Dr Richard Koya
Reprogramming the immune
system for personalised
immunotherapy against cancer
For decades, researchers have
strived to understand how the
immune system recognises
and fights cancer, ultimately
aiming to exploit and augment
these processes to create more
effective cancer therapies.
Dr Richard Koya, Associate
Professor of Oncology,
Associate Director of the Center
for Immunotherapy, and Director
of the Vector Development &
Production Facility at Roswell
Park Cancer Institute is a
prominent researcher in this
area. He leads an international
team of researchers in
developing cutting edge
technologies to use patients’
own immune systems to target
and kill cancer cells.
48 www.researchoutreach.org
O
ur immune system is not
only critical in our defence
against bacteria, viruses and
other pathogens, but it also plays an
instrumental role in preventing and
fighting cancer. The immune response to
cancer is complex, involving antibodies
and a broad repertoire of white blood cell
types, including lymphocytes and other
leukocytes.
Cancer immunotherapy refers to any
strategy that uses the immune system to
fight cancer, and several breakthroughs
have brought immunotherapy to
the forefront of cancer treatment in
recent years. Immunotherapy offers
several advantages over conventional
chemotherapy, including reduced side
effects and the potential to suppress
cancer reoccurrence through the
While cancer vaccines represent an
enticing strategy, the presence of
immune resistance mechanisms in cancer
cells can limit their long-term efficacy
development of long-lasting immune
responses.
RECEIVING THE CANCER SIGNAL –
THE T CELL RECEPTOR
One class of white blood cells, known as
T cells, has long been known to play an
important role in the immune response to
cancer. T cells harbour signalling proteins
called T-cell receptors (TCR) on their
surfaces, a feature that distinguishes them
from other white blood cells. In a complex
process, TCRs recognise pathogen- or
tumour-specific proteins (known as
antigens) that are presented by other
immune cells and also cancer cells.
Several T cell subsets exist, each with their
own unique TCR and specialised function.
Cytotoxic T cells and T helper (Th) cells
are characterised by the presence of
a CD8 or CD4 receptor on their cell
surfaces, respectively. Cytotoxic T cells
become activated when they recognise
pathogens or tumour cells via their
TCR. This is followed by the release of
enzymes and toxic proteins that trigger
programmed cell death in target cells. Th
cells, as their name suggests, help other
immune cells by releasing important
chemical messengers called cytokines,
which refine and regulate immune
responses.
THE IMMUNE SYSTEM VS. CANCER
Continuous advances in the
understanding of cancer immunology
pave the way for significant clinical
translation of novel immunotherapeutic
strategies. Cancer vaccines were among
the first immunotherapies to emerge in
the early 1980s, with the FDA-approved
hepatitis B virus (HBV) vaccines developed
to prevent chronic HBV-induced liver
cancer. In simple terms, cancer vaccines
are created using specific tumour antigens
(TA) – stimulating the immune system to
mount a targeted anti-tumour response.
While cancer vaccines represent an
enticing strategy, the presence of immune
resistance mechanisms in cancer cells can
limit the long-term efficacy of vaccination.
Despite intense efforts in cancer vaccine
development, progress has been slow in
Patient A
Tumour
Human Tumour
MHC I
TCR
Cancer-specific T cell
T-cell receptor (TCR)-engineered T cells for metastatic cancer treatment
Take the TCR genes from one patient who beat cancer and use them to engineer a cancer-fighting immune system in other patients
Take the TCR genes from one patient who beat cancer and use them to
this area. To date, no cancer vaccines have
been approved for use in all individuals
by both the American Food and Drug
Administration (FDA) and the European
Medicines Agency (EMA).
ADOPTIVE CELLULAR THERAPY
While efforts to develop cancer vaccines
continue, researchers including Dr
Koya are continuously exploring other
strategies. One such strategy is based on
adoptive cell transfer (ACT). This is a form
of personalised immunotherapy whereby
a small number of T cells are taken from
a patient’s blood or tumour, sorted and
multiplied in vitro (in the laboratory), and
then reinfused into the same patient’s
blood – in a similar manner to a blood
transfusion. ACT usually follows a period
of pre-conditioning chemotherapy known
as lymphodepletion, where patients’
overall lymphocyte numbers are reduced
to maximise the chances of proliferation
of the newly infused T cells.
The potential of ACT was first
demonstrated by the National Cancer
Institute (US) following long-standing
Subcloning of
anti-cancer TCR into
a viral vector
Cancer-redirected T cell
observations that the presence of
tumour infiltrating lymphocytes (TILs)
is associated with improved clinical
outcomes in a broad range of cancers.
TILs refer to any white blood cells that
leave the bloodstream and migrate into a
tumour. While early ACT attempts using
in vitro-selected TILs seemed promising,
methods for isolating and processing TILs
are labour-intensive and only benefit a
subset of cancer patients.
TCR-ENGINEERED T CELL
IMMUNOTHERAPY – IT’S IN THE
GENES!
For more than a decade, Dr Koya has
focused on advancing ACT for highly
specific and sustained cancer treatment.
His research centres specifically on TCR-
Engineered T Cell Immunotherapy, using
genetic engineering to reprogramme or
‘re-educate T cells to deliver a lethal hit
on malignant cells in an extremely precise
and efficient way’.
Dr Koya’s group utilises viral DNA to
inject TA-specific TCRs into T cells. These
newly inserted receptors then target
Patient B
Harvest T cells
from new patient
these cells to the tumour in a highly
specific manner. This approach improves
ACT, because the engineered T cells
are superior in targeting tumours than
the in vitro-selected TILS used in earlier
ACT attempts. In other words, T cells are
reprogrammed specifically to destroy
cancer cells. By expanding these cells
under specialised laboratory conditions,
billions of highly active tumour-specific T
cells can be injected back into the patient,
targeting tumours with high efficiency and
specificity.
Engineered T cell ACT has the potential
to target any kind of cancer, but the
most widely studied cancer to date is
metastatic melanoma.
FROM LAB TO CLINIC
Previous studies performed under Dr
Koya’s guidance, and indeed by other
research groups, have revealed dramatic
clinical responses with ACT therapy using
TCR-engineered T cells in patients with
metastatic melanoma. However, while
response rates often exceed 50%, relapse
is eventually seen in most patients. Dr
www.researchoutreach.org 49
 TGFβ Blockade in TCR-Engineered T cell Cancer Immunotherapy

Clinical Trial: Roswell Park Cancer Institute

for Advanced Solid Tumors

Behind the Bench

Clinical Trial: Roswell Park Cancer Institute TGFβ blockade in TCR-engineered
TGFβT cell cancer immunotherapy
Blockade for advancedTsolid
in TCR-Engineered celltumours
Cancer Immunotherapy
Clinical grade (cGMP) production of the retrovirus vector and
for
Clinical grade (cGMP) production of Advanced
the Solid
retrovirus vector Tumors
and testing in human T cells
testing in human T cells Dr Richard Koya

NY-ESO1 TCR
NY-ESO1 TCR E: richard.koya@roswellpark.org T: +1 (716) 845 1300, ext. 6582 W: www.roswellpark.edu/richard-koya
Clinical grade (cGMP) production of the retrovirus vector and
W: http://tactivatherapeutics.com/ W: www.youtube.com/watch?v=VwUJHR-Wznc

tetramer
testing in human T cells
W: https://clinicaltrials.gov/ct2/show/NCT02650986?term=koya&rank=1

NY-ESO1 TCR
NY-ESO1 TCR

tetramer
LTR TCRα P2A TCRβ T2A dnTGFβRII LTR
Ψ
LTR TCRα P2A TCRβ T2A dnTGFβRII LTR
Ψ

dnTGFβRII dnTGFβRII Research Objectives • Dr Thinle Chodon, Director of Contact

dnTGFβRII dnTGFβRII
Dr Koya’s research focuses on Translational Research Operations at Richard C Koya, MD, PhD
developing innovative ways to the Center for Immunotherapy Associate Professor of Oncology and
Phase I/IIa
5. Phase Clinical
I/IIa Clinical Trial for
Trial for Advanced
Advanced StageStage NY-ESO1(+)
NY-ESO1(+) Cancer
Cancer (accruing (accruing patients)
patients) utilise the patients’ own immune Immunology
5. Phase I/IIa Clinical
T cells
Trial for Advanced Stage NY-ESO1(+) Cancer (accruing patients) system to target and kill cancer cells.
His approach is based on genetic
Bio
Dr Koya received his MD in 1991 and
Director of the Vector Development &
Production Facility
Leukapheresis Retrovirus engineering of a subset of immune completed his residence in Internal Associate Director of the Center for
Activation
 FDA Approved 5/17 cells called T lymphocytes, by utilising Medicine and fellowship in Clinical Immunotherapy
(OKT3+IL-2)T
Leukapheresis cells
LTR
Ψ
TCRα P2A TCRβ T2A dnTGFβRII LTR (IND 17410)
Retrovirus viral vectors to re-programme these Oncology at UFRGS, Brazil. He Roswell Park Cancer Institute

FDA Approved 5/17

RV-NYESO1-TCR/dnTGFβRII immune cells. received his PhD in Molecular Biology Center for Immunotherapy
Activation
 transduction & Pathology from Hokkaido University Elm and Carlton Streets, CCC-419
(OKT3+IL-2) release test
test Funding
(IND 17410)
Lot release in 2001. From 2001–2003 he pursued Buffalo, NY, 14263
LTR TCRα P2A TCRβ T2A dnTGFβRII LTR National Institutes of Health (NIH) a postdoctoral fellowship at USC, Los USA
Ψ
ACT (T cells) Angeles, before joining UCLA in 2003.
RV-NYESO1-TCR/dnTGFβRII Collaborators He became Associate Professor of
0 1 7
transduction 14 30 60 90 120 • Dr Kunle Odunsi, Deputy Director of Oncology at RPCI in 2013.
Roswell Park Cancer Institute
Cyclophosph.
conditioning PBMC collections
Lot release test
FDG PET or CT (screening, wk. 4, 12)
Tumour Biops./TIL harvest (screening, wk. 4,
upon progression)
R01 NCI/NIH CA164333 (PI: Richard Koya)

Koya’s group hypothesises that the highly

active TCR-engineered T cells eventually
succumb to the immunosuppressive
Cyclophosph.
TCR-engineering, because T cells are
also engineered to lose sensitivity to the
immunosuppressive effects of secreted
exhausted T cells, it is anticipated that
sustained immune responses can be
realised by the synergy of CD8TCR- and
Q&A
What has been the biggest technical
Are there likely to be undesired
effects or safety issues with
widespread use of ACT?
Do you anticipate that patients
can be resubjected to ACT after a
relapse?
tumour microenvironment – an
conditioning
TGF-β. If the hypothesis is correct, these PBMC collections
CD4TCR-engineered T cells. This idea challenge in your research to date? The main issue that sometimes Yes, and this is also a plan we
environment that is imposed largely specially engineered T cells should exhibit FDGtoPET
is likely or CT (screening,
be investigated in future wk. 4, 12) The biggest challenge in my research accompanies ACT is the widespread are pursuing. The point is that in
by the secretion of a clinical trials with ACT.
Tumour Biops./TIL harvest (screening, wk. 4, was to select among many candidates inflammation that can happen in certain early-phase clinical trials, the FDA
transforming growth
factor beta (TGF -β)
Dr Koya’s research uses genetic Another avenue under
upon progression)
investigation is the
the most efficient and more specific
TCR to target a Tumour Associated
patients with certain types of cancer,
a side effect called cytokine release
recommends a trial with a single dose
to first check for side-effects, as safety
by tumour R01 cells.NCI/NIH
This engineering to re-educate T cells to
CA164333 (PI: Richard Koya) combination of ACT Antigen that is in cancer but not in syndrome. This is much less common in is paramount.
hypothesis is supported with therapies that block normal tissues. TCR-based therapies, but much more
by Dr Koya’s previous deliver a lethal hit on malignant cells other cellular pathways prevalent with CAR-T cell, another Are there tumour types that ACT is
clinical trial experiences, used by cancer cells to Do you believe that future modality of ACT. unlikely to be effective against?
and is currently being tested in a new sustained efficacy in the microtumour evade the immune system. developments in immunotherapy Actually no. Any solid or liquid tumour
National Institutes of Health-funded environment, resulting in fewer cases of will one day completely replace can be targeted by ACT.
prospective clinical trial at Roswell Park relapse, and better patient outcomes. Immunotherapy is an exciting area, and conventional chemotherapeutic
Cancer Institute, led by Dr Koya. new approaches currently dominate approaches?

The trial will specifically address a novel

ACT approach based on an immune-
modulator-enhanced TCR-engineered T
cell transfer for metastatic cancer patients. Th cells are now known to promote the
This investigation takes TCR-engineered
T cell transfer one step further than
Previous clinical trials based on ACT have
mainly focused on the use of cytotoxic T
cells only. However, evidence is growing
for the efficacy of Th cells in ACT. Since
maintenance of cytotoxic T cell responses
against cancer cells, as well as rescuing
ongoing clinical trials in the pursuit of
effective, personalised cancer treatments.
I would not say replace completely
since some chemo-agents are also
There is no tumour type against which
These therapies might one day become useful to prime the cancer cells, ACT will be ineffective; any solid or
the standard of care for cancer patients. making them more susceptible to
immunotherapies. liquid tumour can be targeted by ACT

50 www.researchoutreach.org www.researchoutreach.org 51
Health & Medicine ︱ Dr Shoukat Dedhar
CAIX-Targeted Therapy is a Weapon used to Exterminate

Inhibiting cancer stem cell

CAIX-Targeted
Hypoxic,Therapy is a Weapon used
Treatment-Resistant to Cells
Cancer Exterminate
Hypoxic, Treatment-Resistant Cancer Cells
Hypoxic Tumour

survival in the hostile tumour

CAIX-Positive Cancer
CAIX-Positive
StemCancer
Cells
Hypoxic Tumour CAIX-Negative
CAIX-Negative
Cancer Cells
Stem Cells
Hypoxic Microenvironment Cancer Cells

environment
Hypoxic
(Cancer Stem CellMicroenvironment
Niche and CAIX-
(Cancer StemHypoxic
Positive Cell Niche and CAIX-
Cancer Cells) CAIX-Positive Cancer-
Positive Hypoxic Cancer Cells) CAIX-Positive Cancer-
Associated Fibroblasts
Blood Vessels Associated Fibroblasts
Blood Vessels

Wouldn’t it be great if a small
non-toxic molecule could
be used to treat cancer? By
investigating the possibility
of using a cancer cell’s own
physiology as a weapon against
it, Dr Shoukat Dedhar, at the
University of British Columbia,
is developing a new treatment
that could help prevent tumour
growth and metastasis.
E
very two minutes, someone in the
UK is told they have cancer, with
one out of every two people likely to
be diagnosed at some point in their lives.
The disease is the world’s second leading
cause of death, and was responsible for
nearly nine million global deaths back in
2015.
Current treatment methods involve the
removal of cancer cells either through
surgery or via radiation or toxic chemicals.
However, cancer cells are tricky, and it is
Inhibition of CAIX resulted
in significant depletion of cancer
stem cells within tumours
very difficult to eradicate every single one
of them. If the cancer has metastasised
(spread from the original tumour to
another part of the body), surgery can
rarely remove every cell, and treatments
that typically kill cancer cells are generally
toxic to normal cells as well. If even a few
cancerous cells remain, they can cause a
resurgence of the disease. Think of it like
an ant’s nest – you can get rid of nearly
all of them, but leaving just two or three
could be enough for the nest to reappear
down the line.
Dr Dedhar and his team are investigating
a new type of treatment, which takes
advantage of the unique physiology
of cancer cells. It aims to inhibit their
growth and ability to metastasise,
without damaging healthy body cells.
The results so far have proved very
encouraging.
A HOSTILE ENVIRONMENT
To understand how the new treatment
works, we must first understand the
inner workings of a tumour. Tumours
Chemotherapy
Chemotherapy
Radiotherapy
Radiotherapy
Tumour Recurrence
Tumour Recurrence
Metastasis
Metastasis
Resistance to
Resistance
Chemotherapy to
and Radiotherapy
Chemotherapy and Radiotherapy
are made up of millions of cells and,
as each one grows, the blood supply
required to nourish the rapidly dividing
cancer cells with oxygen and nutrients
becomes inadequate, causing regions
of the tumour to become hypoxic (low in
oxygen). Like normal body cells, cancer
cells cannot survive without oxygen, so
to overcome this, they stabilise a very
important protein called HIF-1α (hypoxia
inducible factor 1 alpha). This protein
mediates the activation of numerous
genes vital for the adaptation of cancer
cells to the hypoxic environment.
Through HIF-1α,
cancer cells in By targeting CAIX, we may be able to
Chemotherapy CAIX-
Chemotherapy
Radiotherapy CAIX-
Targeted
Radiotherapy Targeted
Therapy
Treatment Therapy
Treatment
Functionally Impairs/Kills
Functionally Impairs/Kills
• Hypoxic Cancer Cells
HypoxicStem
• Cancer Cancer Cells
Cells
Stem Cells Fibroblasts
• Cancer Associated
• Cancer Associated Fibroblasts
Tumour Regression
Tumour Regression
Inhibition of Metastasis
Inhibition of Metastasis
also removing waste products such as micro-environment present in hypoxic
carbon dioxide. However, the capillaries parts of the tumour, they will soon die.
are often leaky and deformed, so –
although they allow the tumour to grow ADAPT OR DIE
bigger and more quickly – the hypoxic As part of their adaptive response,
micro-environments inside the tumour cancer cells begin producing a cell
remain. membrane-bound protein called
carbonic anhydrase IX (CAIX). CAIX
To compound the problem, hypoxic converts carbon dioxide from outside
cancer cells alter the way they produce the cell into bicarbonate and protons.
energy and cellular building blocks, The bicarbonate is then transported
such as proteins and fats, to continue into the cell to reduce the intra-cellular
their growth in the absence of oxygen. acidity, providing a survival benefit for
This altered metabolism produces these cells. The protons remain outside
and contribute to
the acidification
of the micro-

overcome resistance to chemotherapy

hypoxic regions of environment.
the tumour begin Creating this
producing proteins
that trigger the
and radiotherapy, tumour recurrence acidic environment
causes cancer stem
growth of hundreds and metastasis cells to divide more
of capillaries rapidly, enhancing
from nearby blood vessels. These new acidic waste products that build up their ability to invade healthy tissue and
capillaries provide the tumour with inside and outside the cells. If cancer metastasise across the body.
additional oxygen and nutrients, whilst cells cannot adapt to the hostile, acidic

52 www.researchoutreach.org www.researchoutreach.org 53

AN ATTRACTIVE TARGET
Since cancer cells become absolutely
dependent on CAIX to reduce
acidification and thus promote their
survival, this requirement becomes
their “Achilles heel”, thus making CAIX
a promising target for cancer therapy.
CAIX is an attractive target for anti-
cancer therapies for several reasons.
First, it is only produced by cancer cells,
so could be inhibited with no harmful
effects to normal cells. Second, it is
critical for the survival of cancer stem
cells and their ability to invade healthy
tissue. And third, its position on the
outer surface of the cell membrane
makes it a relatively easy target for
drugs.
CAIX is produced in large amounts
by cancer cells that metastasise, and
Dr Dedhar has shown that if CAIX
expression is depleted, cancer stem
cells no longer function properly,
blocking metastasis. His study, and
others like it, have provided proof-
of-principle data that CAIX inhibition
could provide a therapeutic benefit in
treating cancer.
Dr Dedhar believes that by targeting
CAIX, we may be able to overcome
resistance to chemotherapy and
radiotherapy, tumour recurrence and
metastasis. He and his team have
developed a targeted small molecule
inhibitor of CAIX and have shown that
Behind the Bench
Dr Shoukat Dedhar
E: sdedhar@bccrc.ca T: +1 604 675 8029 W: www.bccrc.ca/
W: https://clinicaltrials.gov/ct2/show/NCT02215850
Research Objectives
Dr Dedhar’s research focuses on the role
of ILK signalling in cancer progression,
the molecular basis and targeting of
centrosome clustering in cancer cells, and
the therapeutic targeting of tumour hypoxia
effectors, Carbonic Anhydrases IX and XII.
Funding
The Canadian Institutes of Health Research
(CIHR)
54 www.researchoutreach.org
this inhibitor reduces tumour growth and
metastasis in models of human cancer.
Inhibition of CAIX in human breast
cancer cells in the laboratory prevented
breast cancer stem cells from dividing
and replenishing the cell population in
hypoxia. The team also tested the CAIX
inhibitor in a mouse model of breast
cancer, with CAIX inhibition resulting in a
significant depletion of tumorous cancer
stem cells. Combination treatment
using the inhibitor with paclitaxel (a
chemotherapy drug) was also found
to enhance tumour growth delay
and completely eradicate metastasis
of cancer cells to the lungs, when
compared to treatment with paclitaxel
alone.
Collaborators
• Dr Claudiu Supuran
• Welichem Biotech, Inc.
Bio
Dr Dedhar received his BSc (Hons) in
Biochemistry from the University in
Aberdeen, Scotland, and his PhD from the
University of British Columbia, Canada
in 1984. He carried out a Postdoctoral
Fellowship in the laboratory of Dr Erkki
The team have recently completed a
phase 1 safety clinical trial of the CAIX
inhibitor, with findings showing it to
be safe and well tolerated by patients.
They are now embarking on clinical
trials in which the CAIX inhibitor can be
combined with standard chemotherapy
regimens, and Dr Dedhar anticipates
significant, additive effects on tumour
growth – especially on recurrence and
metastasis. Through his team’s tireless
work, a cancer diagnosis might not be
the death sentence it once was.
Ruoslahti at the Burnham Institute, in La Jolla,
California, USA.
Contact
Shoukat Dedhar, PhD
BC Cancer Research Centre
Rm 3-110
675 West 10th Avenue
Vancouver, B.C.
V5Z 1L3
Canada
Q&A
How did you first become
interested in CAIX?
We were carrying out research
to identify causative genes in
breast cancer metastasis. We
discovered that a set of genes
were active in tumour cells
that had the capacity to form
metastases, but were silent in
tumours that did not have this
capacity. Interestingly, all of
these genes are activated by
hypoxia and HIF-1, and one
of the most active genes was
CAIX. We proved that CAIX
was indeed required for breast
cancer cells to metastasise
by depleting CAIX from the
cells with metastatic capacity:
this depletion resulted in
the almost complete loss of
metastatic ability.
Could the CAIX inhibitor be
used to treat any type of
cancer?
Yes, any type of cancer
that produces CAIX could
be inhibited by the CAIX
inhibitor. However, not all
cancers produce CAIX, since
some types of cancers are not
hypoxic. So, the CAIX inhibitor
will be used therapeutically
only in tumours that produce
CAIX. We will have to analyse
the patient tumours for CAIX
expression before embarking
on a therapeutic regime that
includes the CAIX inhibitor.
Could the CAIX inhibitor
be used on its own to treat
cancer without the need for
chemotherapy?
Since only a proportion of
cancer cells within a tumour
produce CAIX (the proportion
can vary from 20% to as much
as 80%), it is unlikely that CAIX
inhibitor monotherapy would
be effective in eradicating
the tumour. On the other
hand, while both radiation and
chemotherapy will effectively
kill the majority of tumour
cells, they are ineffective in
killing tumour cells within the
hypoxic niches which should
be killed by inhibitors such
as the CAIX inhibitor. Our
recent, unpublished work also
demonstrates that inhibiting
CAIX makes chemotherapy
agents such as temozolomide
and gemcitabine, more effective.
While we do not understand the
reason for this, it is likely that
inhibiting CAIX changes the
tumour physiology in such a way
as to make the tumour cells more
sensitive to the chemotherapy
agents.
Can you describe the mouse
breast cancer model that
was used to test the CAIX
inhibitor?
We have used several mouse
tumour models to test the CAIX
inhibitor. Our initial model was
transplantation of breast cancer
cells into the mammary fat pad
of the mouse. This results in the
formation of a breast tumour
within the mammary gland of
the mouse. Once the tumour
reached a reasonable size so
that it could be palpated, we
started administering the CAIX
inhibitor orally on a daily basis for
approximately 21 days. Control
mice received only the “vehicle”
used to dissolve the CAIX
inhibitor. Tumour volumes were
measured daily and the results
tabulated. We had also “tagged”
the tumour cells so that they
could be followed in the mouse
using an imaging instrument
called IVIS. This allowed us to
determine the extent of spread,
or “metastasis”, of the tumour in
the control and treated mice
What will the clinical trial of
the CAIX inhibitor involve?
Having completed the Phase
1 Safety trial with the CAIX
inhibitor, we can now embark
on clinical trials to test the
efficacy of the compound.
Our next trial will be a multi-
centre Phase 1b/Phase 2
trial in patients with CAIX-
positive pancreatic ductal
adenocarcinoma, or PDAC.
These cancers are very
difficult to treat with current
therapeutic regimes, and we
have found that PDAC patient
tumours are very hypoxic and
about 40–60% of the cells
produce CAIX. Furthermore,
our pre-clinical data in mouse
models of PDAC demonstrate
that adding the CAIX inhibitor
to the standard of care
therapeutic, gemcitabine,
results in substantial survival
benefit, with depletion of
cancer stem cells. Thus,
the clinical trial will involve
treatment of CAIX-positive
patients with a combination
of gemcitabine and CAIX
inhibitor. We will measure
a number of parameters,
including circulating drug
levels, and whether cancer
stem cells are depleted in
the tumours, but a major end
point will be to determine
whether there was any benefit
in progression-free survival.
Similar trials are in the planning
stages for “triple-negative“
breast cancer and glioblastoma
(brain cancer).
www.researchoutreach.org 55
Health & Medicine ︱ Dr Tania Roth
The epigenetic effects
of adverse early-life
experiences
L
Environmental factors interact with genetics in driving living organisms’ ife experiences and environmental Over the past few decades, a
development throughout life. Epigenetics is the field of study that factors play a substantial role in considerable body of research
explores this interaction, as well as its potential effects on individuals’ how individuals develop over has been investigating the way in
behaviour and health. Dr Tania Roth, working at the University of time, in terms of their behaviour, as well which environmental and genetic
Delaware in Newark, USA, carried out extensive research exploring the as their physical and mental health. factors interact with one another,
impact of the environment, particularly stress factors, on individual genes, However, different people who have resulting in different effects on
and how these changes might influence behaviour and psychological similar experiences might react to these individuals’ health, behaviour, and
development. Her findings indicate that adverse early-life experiences in entirely different ways and be affected psychological development.
can result in particular alterations in the brain that have consequences for differently. This is often thought to be due
gene expression and behaviour. to individual DNA and genetic factors. EPIGENETICS: HOW GENES AND
ENVIRONMENT INTERACT
Epigenetics is the field of research
that focuses on the biological changes
occurring in living organisms as a result
of genes interacting with environmental
factors and life experiences. A number
of factors can influence a human
being’s psychological development
and health over time, including prenatal
environment, parenting, and other stress
encountered throughout life. All these
different factors leave their marks on
an individual being’s genetic make-up
(DNA), in the form of chemical tags that
instruct genes on what to do. Studying
and observing these alterations could
help determine how stress factors can
affect different individuals’ physical and
mental health. Dr Tania Roth has been
investigating the epigenetic alterations
in the brain that can occur after early-life
adversities, such as maltreatment or
poor parenting.
BRAIN ALTERATIONS
AFTER ADVERSE EARLY-LIFE
EXPERIENCES
Dr Roth and her team of researchers
carried out experiments on rats to
test the epigenetic effects of early-life
adversity in the brain, as well as their
behavioural outcomes. By providing
scarce living resources, such as nesting
56 www.researchoutreach.org
DNA
Methylation
Histone
modifications
Epigenetic marking of the genome by DNA methylation (red) and histone modifications
(green and yellow), such as acetylation.
The pups of maltreated female rats
showed epigenetic alterations later in
life, which still occurred even if the pup
was placed with a foster mother
materials, they prompted rats to offer
poor caregiving to their neonate pups.
They then tested the rodents who
received maltreatment for any changes
or abnormalities in the brain.
The rats that received poor caregiving
presented a number of epigenetic
alterations, which varied according to
the rats’ sex. These alterations were
particularly pronounced in brain regions
known to be affected by child abuse and
neglect, such as the prefrontal cortex,
the amygdala and the hippocampus.
The prefrontal cortex is a region of
the brain associated with a number
of complex behaviours and cognitive
functions, while the amygdala is involved
in the experiencing of emotions. The
hippocampus has been found to play a
role in memory and emotion processing.
Dr Roth’s research suggested that infant–
caregiver interactions could mark genes
that have previously been found to play
a prominent role in psychiatric disorders.
Maltreatment appeared to cause
changes in methylation, the process by
which methyl groups are added to the
DNA, particularly in neurons. Methyl
groups are chemicals made up of a
single carbon and three hydrogen atoms.
The biochemical process of methylation
is involved in regulating the expression
of genes.
EPIGENETIC EFFECTS ON
BEHAVIOUR
Dr Roth’s research found that poor
caregiving for neonate rats did not
affect their behaviour as adolescents,
but significantly affected their behaviour
as adults. Female rats who were
www.researchoutreach.org 57
 Behind the Bench
Dr Tania Roth
E: troth@psych.udel.edu T: + 1 302 831 2787 W: http://rothlab.psych.udel.edu/

Research Objectives Bio Contact

Dr Roth’s work explores the impact of
the environment, specifically stress, on
our genes and how these epigenetic
changes influence our behaviour and
development.
Funding
• National Institutes for Health (NIH)
Collaborators
• Dr Mary Dozier, University of
Delaware
Dr Tania Roth is an Associate Professor Tania L. Roth, PhD
and Director of Graduate Education Associate Professor
in Psychological and Brain Sciences Psychological and Brain Sciences
at the University of Delaware, University of Delaware
where she teaches upper-level and 108 Wolf Hall
graduate courses in psychology Newark, DE 19716
and neuroscience. Her research USA
programme is focused on defining
epigenetic mechanisms responsible
for environmental influences on gene
activity, development of behaviour, and
psychiatric disorder.

Early life experiences can cause epigenetic changes that affect behaviour into adult life

Q&A time is very difficult. Identifying whether

maltreated as pups appeared to be
more anxious days before giving birth
and also displayed the same types of
adverse caregiving behaviour towards
their offspring that they received from
their caregivers in early-life. Moreover,
the pups of maltreated female rats also
showed epigenetic alterations later in
life, and some of these alterations still
occurred even if the pup was placed
with a foster mother who had not been
maltreated in early life.
As well as displaying these disruptions
in maternal behaviour, the maltreated
females also performed poorly in a series
of cognitive tasks. The male rats tested
during the study appeared to present
problems with extinguishing fear-related
or troubling memories.
PREVENTING OR REVERSING
EPIGENETIC STATES
Understanding the epigenetic alterations
that follow adverse early-life experiences
or environmental factors could help to
devise policies or treatments that could
either prevent or reverse these changes
in the brain.
The rats that received poor caregiving
presented a number of epigenetic
alterations, which varied according
to the rats’ sex
Dr Roth’s research has found that treating
adult animals with a drug that changes
methylation states can somehow
counteract or rescue the changes in
DNA methylation and gene expression
produced by the maltreatment. She is
now exploring the possibility that the
same pharmacological treatment that
could reverse these epigenetic states
might also be able to affect the maternal
behaviour of maltreated females,
leading them to display more nurturing
caregiving tendencies.
In future, a similar treatment could be
developed to counteract the effects of
poor caregiving on methylation states
earlier on in development, which might
change the behavioural trajectories
that follow mistreatment and prevent
the adult rats from replicating the same
dysfunctional behaviour while raising
their own pups.
A MEANINGFUL CONTRIBUTION
Dr Roth’s research has provided evidence
suggesting that maltreatment and other
adverse environmental factors in early
life can produce changes in methylation
processes within the brain, which
result in altered gene activity and adult
behaviour. Her work has substantially
contributed to the field of research
exploring epigenetics, providing further
empirical evidence of preventable and
potentially reversible epigenetic states.
If Dr Roth’s observations were found to
be similar in humans, her work could aid
the development of pharmacological
or behavioural treatments to prevent,
counteract and reverse some of the
behavioural and developmental effects
of adverse early-life experiences.
When did you first become
interested in the interaction of
environmental factors and genetics,
as well as the effect it might have on
human health and development?
During my graduate training I became
interested in understanding how an
experience or environmental factor
could get under the skin to influence
development and behaviour. I was
fascinated by the brain’s capacity
to change because of experience,
and curious how factors like child
abuse and neglect could hijack
developmental processes or have such
long-lived consequences for behaviour
and mental health.
What are the greatest challenges
of studying epigenetic effects on
health and development?
Development is a lifelong process,
so to truly understand epigenetic
effects on health and development
studies you need a longitudinal
design. But gathering data, especially
epigenetics data, from the same
subjects repeatedly over a period of
an epigenetic change is coincidental
or causal in relation to an outcome is
another challenge but necessary for us
to really understand epigenetic effects
on health and development.
What do you feel are the most
important findings you have collected
so far through your research and why?
We have shown that poor parenting
early in development can have
multigenerational consequences on
DNA methylation states in the brain.
These data provide an empirical basis
for the far-reaching effects of early
adversity, helping us understand some
of the biology of how factors like child
abuse and neglect can affect health and
development. But we have also shown
that epigenetic manipulations can reverse
these states, and projects underway in
the laboratory suggest these strategies
also rescue aberrant behaviour. Such
data demonstrate that the epigenome
retains malleability throughout life and
suggest it could be a target for changing
brain and mental health.
Do you believe your findings on
rodents could be applied to humans
as well and what evidence is there
supporting this?
Yes. Several reports indicate similar
methylation changes in humans with
a history of maltreatment. Specifically,
they see the same change in DNA
methylation in peripheral measures
that we see in the brains of our
rodents. There is also some evidence
that certain forms of behavioural
therapy and intervention can change
epigenetic states in humans.
What are your plans for further
research and investigation?
We are working to translate our
findings to humans. In current
collaborative research with Dr Mary
Dozier (a clinical psychologist at
the University of Delaware), we are
studying DNA methylation patterns in
parent–child dyads who were involved
with Child Protective Services as the
result of allegations of neglect. We are
also investigating the reversibility of
these epigenetic alterations following
a behavioural intervention programme
(designed by Dr Dozier) that is based
on attachment theory and stress
neurobiology.

58 www.researchoutreach.org www.researchoutreach.org 59
Thought Leader

IAPB: Envisioning the

future of universal eye care
Everyone across the globe needs access to the best possible standard of eye health as advocated by the International
Agency for the Prevention of Blindness (IAPB). IAPB was established as a coordinating umbrella organisation to lead
international efforts in blindness prevention activities and eye health. Research Outreach spoke to CEO Peter Ackland who
discusses IAPB’s mission, the importance of World Sight Day, IAPB’s relationship with the World Health Organization (WHO)
and more in greater detail.

V
ision really matters as it is vital to
our everyday lives. Naturally, sight
is the main sense that people
fear losing the most. According to the
latest data in 2015, 253 million people
are estimated to be visually impaired
worldwide: 36 million of whom are blind
and 217 million with severe or moderate
vision impairment. Another 1.1 billion
people are estimated to have near-vision
impairment. Yet globally, a majority of
all visual impairment can be prevented
or cured. No one understands this more
than the International Agency for the
Prevention of Blindness (IAPB).
IAPB is an alliance of civil society
organisations, corporates and
professional bodies promoting eye
health through advocacy, knowledge
and partnerships.
IAPB’s mission is to eliminate the main
causes of avoidable blindness and
visual impairment by bringing together
governments and non-governmental
agencies to facilitate the planning,
development and implementation
of sustainable national eye care
programmes. We managed to speak
Hi Peter! Can you tell us a bit more
about your role as CEO of IAPB and the
role of IAPB as an organisation?
I have been the CEO of the IAPB for the
past nine years. The most important
part of my job is external representation
of the organisation and creating
partnerships that can help IAPB achieve
its mission – to eliminate avoidable
blindness and visual impairment. IAPB
is a global membership organisation.
All major international not-for-profit
organisations working to improve
eye health are our members and an
increasing number of national level
eye hospitals, research institutions,
foundations and NGOs.
Following on from the previous
question, can you tell us briefly about
the IAPB’s core principles, heritage and
mission as well as its impact?
IAPB encourages membership from as
broad a mix of stakeholders as possible
because we think everyone makes a vital
contribution to achieving our vision of a
world free of avoidable blindness.
IAPB’s key areas of work are advocacy
as well as promoting good practice
passing of four World Health Assembly
Resolutions on avoidable blindness
this century – great recognition of the
importance of better eye health by the
apex health organisation (WHO).
Another area of advocacy success has
been working with major donors such
as Standard Chartered Bank and the
Queen Elizabeth Diamond Jubilee Trust,
who have both chosen the elimination
of avoidable blindness as their main
philanthropic programmes and together
have committed around $200m to eye
health projects.
Can you tell us about the IAPB’s
collaboration with the World Health
Organization (WHO) and their impact
on the IAPB’s goals? (GAP) for 2014–2019. IAPB’s current work ‘World Sight Day’ and its importance for diabetes and the very concerning
IAPB is in official relations with the WHO. with WHO is mainly focused upon the IAPB? How does WSD differ from the increase in people with myopia.
That means we collaborate to promote implementation of the GAP, particularly other global health initiatives at IAPB? Collectively, it is estimated that, by 2050,
better eye health. WHO is accountable at country level. At the most recent World Sight Day (WSD) always falls on the number of people who are blind or
to countries, whilst leading on the WHA in May 2017, IAPB and member the second Thursday of October each have visual impairment could increase
development of policy and guidelines to countries called for WHO to produce a year. It is our major health day of the year from today’s 253m to more than 700m –
promote better health. “World Report on Vision”. Later, this was to raise awareness of avoidable blindness almost a threefold increase.
adopted as an action by all countries and visual impairment and the need for
IAPB and WHO launched VISION 2020: in the full Assembly. WHO intend to better eye health. Improving eye health services and
The Right to Sight, a global initiative in produce the World Report on Vision making them accessible to all needs
1999 and this has had significant success in time for World Sight Day 2018. The This year’s WSD focuses on the launch of emphasis, particularly for those who are
report will lay down the agenda over our latest edition of the IAPB Vision Atlas. most vulnerable for whom services must
the next decade for promoting better We are anticipating that our colleagues be free at the time of access.

Globally there are an estimated 253 million people with serious

eye health for all. IAPB is supporting the and Members in every part of the world
preparation of the report with funding will be using WSD to promote several Can you explain the role of the IAPB

levels of vision loss that substantially impact on their lives
with CEO Peter Ackland who discussed
with us the role of the organisation
and their strategy for the future to help
improve eye health worldwide.
in the development of eye health
services. IAPB is an alliance, so IAPB
staff work closely with our members to
deliver our advocacy objectives. Some
notable advocacy successes include the
in bringing many actors working in the
field of eye health together. The four
World Health Assembly resolutions
have consolidated that understanding,
culminating in the Global Action Plan
and providing our inputs.
IAPB works with a variety of WHO
departments – disability, health systems,
the health workforce, health management
information and ageing – apart from its
Prevention of Blindness unit.
Can you tell us a bit about this year’s
key advocacy messages – using the
Vision Atlas data about their country to
evidence their advocacy ask.
We will also be talking about three major
threats for the future – the increasing
global population and the rapidly
increasing ageing of that population,
the increasing number of people with
Vision Atlas, its importance and how it is
used at IAPB?
The Vision Atlas is one of IAPB’s flagship
projects. It is available in two forms –
online and as a paper publication. We
see it as the first point of reference for
anyone who wants to know the latest
numbers, evidence and issues relating to
eye health.

60 www.researchoutreach.org www.researchoutreach.org 61

The Vison Atlas is built around two
main data sets. The first is the Vision
Loss Expert Group (VLEG) estimates
for global, regional and country
level prevalence and causes of visual
impairment and blindness. A series of
country level maps help visualise this
data. By hovering over a country you
can ascertain prevalence disaggregated
by level of impairment, sex, age and
over time from 1990 through to 2020.
21 Regional maps based on the Global
Burden of Disease studies show the
causes and the change over time.
Several articles bring the data to life
and highlight key issues. The major
risks for the future are looked at as well
as the opportunities – we could for
example eliminate blindness from two
very ancient diseases, trachoma and
river blindness.
The second data set is IAPB’s
country indicator dataset. The WHO
recommends countries collect Global
Action Plan identified indicators to
measure the state of their eye health
services and to monitor change. IAPB
has collected the latest data available
for these indicators for 191 countries.
Again, this is all easily accessible and
supplemented by articles. There is a
focus on the numbers of trained eye
health workforce at country level and
their chronic shortage in many poor
countries, especially in Africa.
Finally, the Vison Atlas contains many
resources and other information such as
the common eye conditions and their
impact on sight loss.
From your website, the IAPB clearly has
some major sponsors supporting them,
from Sightsavers to the Queen Elizabeth
Diamond Jubilee Trust – how do you
attract new supporters and which
organisations do you hope to work
with in the future to work towards the
elimination of avoidable blindness?
Sightsavers and the Queen Elizabeth
Diamond Jubilee Trust are just two of
our 150+ Members – all are equally
important to us. IAPB is mainly funded
from membership fees and additional
grants that some of our members pay to
support particular projects.
A big focus of IAPB‘s work is to promote
collaboration so that our members can
62 www.researchoutreach.org
learn from each other and build upon
each other’s work. This not only mitigates
against re-inventing the wheel but the
collective effort is greater than the
individual parts. We are always looking
for new members to join. We are seeing a
welcome trend; an increasing number of
new members work at the national level.
We also aim at making links with
organisations beyond the eye health
world. I see us becoming very close with
©IAPB
those working in the health workforce,
ageing, diabetes and disability as
particularly important going forward.
What are the highlights from your
recently published 2016 annual report?
Did IAPB achieve it’s set goals?
A major highlight in 2016 was IAPB’s
10th General Assembly, held in Durban.
10GA brought together 1,150 eye care
professionals from 100 countries.
Thought Leader
©IAPB
The President of Liberia (and Nobel
Peace Prize winner), Ellen Johnson Sirleaf,
graced the opening ceremony along
with the South African Minister of Health,
Dr Aaron Motsoaledi. Symposium
speakers included Dr Matshidiso Moeti,
Regional Director, WHO Africa, Mr David
Donoghue, Irish Ambassador to the UN
(and Chair of the final stages of the UN
meetings that developed the Sustainable
Development Goals), Dr Tim Evans from
the World Bank and Dr Francis Omaswa,
of the African Centre for Global Health
and Social Transformation. A talk from
Professor Astrid Stuckelberger on
healthy ageing was a highlight. There
were 42 courses covering a range of eye
health and related topics. We had over
60 sessions with 200 speakers and 250
poster presentations over the three days.
On IAPB’s website, goals are outlined
from 2013–17. What are the future
goals for IAPB in the efforts to achieve
universal eye health?
The most important objective for IAPB
and our members going forward is
the need to achieve greater priority at
country level for eye health. International
resolutions are important but ultimately
it is what individual governments do
that is key. We know most avoidable
blindness and visual impairment is
found within the poorest people in the
poorest countries. Giving these people
access to eye health services is the
key to making sure that the horrifying
estimates for the future made by the
VLEG (700m by 2050) are not realised.
Much greater emphasis must be placed Contact
on improving eye health services and The International Agency for
the Prevention of Blindness
making sure they are accessible to all
(IAPB)
London School of Hygiene and
Tropical Medicine
Keppel Street, London
Improving access requires more trained the treatments they need, through the
WC1E 7HT
eye health staff at primary, secondary provision of targeted social insurance
United Kingdom
and tertiary level and more and better schemes or government funded services
equipped hospitals and eye clinics. It through taxation.
E: communications@iapb.org
requires more work at community level
W: http://www.iapb.org/
and public eye health messaging and it • For more information about the IAPB,
needs increased domestic funding in eye membership and World Sight Day,
health provision. Above all the poorest please visit the website at
need to be protected against out of https://www.iapb.org/
pocket payments, arguably the single
biggest obstacle to poor people gaining
www.researchoutreach.org 63
Health & Medicine ︱Dr Warren Grundfest and Dr Zachary Taylor Right: The cornea forms the outer most layer

A new terahertz medical

of your eye. It is approximately 79% water
by volume. Many diseases can perturb the
endothelium which leads to changes in stromal
water content. These changes are hard to detect
in the early stages.

imaging tool could

IMAGING CORNEAL DISORDERS
Corneal disorders, such as Fuchs’

provide early detection

endothelial dystrophy, affect a
considerable number of people
worldwide – particularly within the
elderly population. They often result

of corneal disease
in chronic vision impairment and
commonly those affected require
surgical intervention. One of the key
physiological problems behind these
disorders is believed to be an increase
in hydration of the corneal tissue, Corneal Morphology

Recent research in medical imaging found that tools
based on terahertz (THz) frequency illumination
could help map the distribution and movement of
water near the surface of body tissues. Dr Warren
Grundfest and Dr Zachary Taylor, at The UCLA
Henry Samueli School of Engineering and Applied
Sciences, are developing a new imaging tool for
non-contact high-resolution measurements of corneal
hydration. This could be a promising method to
accurately detect and study cornea-related diseases
and pathologies, such as Fuchs’ endothelial dystrophy,
intraocular lens implantation complications and
corneal graft rejection.
T
erahertz (THz) imaging is an emerging non-destructive
scanning and imaging technique used within several
settings, ranging from pharmaceutical and biomedical
applications, to integrations in tools for security and aerospace
industries. Ongoing research in THz for medical imaging has
revealed that THz frequency illumination may be ideal for
mapping the distribution and movement of water in physiological
tissues. This might be particularly useful for quantifying the water
content within the corneal tissue which is generally much less
heterogenous than other tissue systems in the human body.
A group of scientists, engineers and clinicians in California are
investigating this possibility, trying to develop an imaging tool
that can provide accurate measurements of corneal hydration, to
help detect and study corneal disorders.
referred to as Corneal Tissue Water
Content (CTWC). In fact, many corneal
disorders are characterised by an
abnormally high CTWC, which causes a
swelling of the cornea and subsequent
blurring of vision. This makes CTWC an
important diagnostic target for doctors
and physicians looking to diagnose
corneal disorders: not only does it allow
the disease to be observed, but it also
indicates potential tissue damage. Until
now there have been no efficient non-
invasive ways of accurately and directly
measuring CTWC in situ. New research
conducted by the Californian researchers
aims to change this.
Dr Taylor and Dr Grundfest are two of
these researchers working to develop
a non-invasive imaging tool based
on THz frequency illumination, which
could help measure the hydration
levels of the cornea’s tissue. Current
methods of measuring CTWC are
based on ultrasonic or optical thickness
measurements, which can be measured
very accurately. However, mapping the
cornea’s hydration using these thickness
measurements can be extremely
inaccurate. Dr Taylor and Dr Grundfest’s
newly-developed imaging system
would allow scientists and clinicians to
acquire spatio-temporal variation maps
of CTWC from patients. The method is
a direct measurement of water content
and therefore avoids the inaccurate and
non-specific thickness to water content
mappings used by current techniques.
THz medical imaging might be
particularly suitable to measure water
content in the cornea because its tissue
• 400 μm – 700 μm thick
• ~ 79% water by volume/weight
• Provides the majority of the focusing power of the eye
• Refractive power and optical scattering strongly linked to water content
structure and geometry is generally
much less varied than any other tissue
in the body (e.g., in the lungs, liver, etc).
Furthermore, this variation is typically
less than the wavelength of the target
THz illumination enabling researchers to
treat the cornea as a perfectly spherical,
hydrated film sitting on top of a body of
water (aqueous humour).
INITIAL TESTING
Before they began developing
their imaging tool, Dr Taylor and Dr
Grundfest studied the cornea and its
electromagnetic properties extensively.
From this, they proposed the first ever
Corneal disorders affect a considerable
number of people worldwide, and can
often result in chronic vision impairment –
commonly requiring surgical intervention
CTWC gradient models, as well as
devised ways to identify CTWC from
variations in THz reflectivity. The team
initially tested their new imaging tool
on the corneas of live rabbits. They
attempted to measure their CTWC using
a custom-built THz imaging system
and millimetre-wave reflectometer
and explored correlations between
the imaging data and central corneal
thickness (CCT) measurements.
Initial results were very promising but
revealed unanticipated electromagnetic
properties. Data from the millimetre
wave measurements correlated well
with CCT, while the THz and CCT
measurements demonstrated no
correlation. From their findings, the
procedure appeared to alter the
thickness of the cornea but not the
CTWC. This perturbation in thickness,
combined with the constant corneal
water content, created a standing wave
resolvable with the millimetre wave
system and unresolvable with the THz
system. This is the first experimental
validation of a long-held belief that
trends in CCT are not necessarily
associated with changes in CTWC.
Two key concepts were extracted from
this initial work. Firstly, the cornea is
an optical thin film at THz frequencies.
Secondly, successful clinical translation
of the technology will require non-
contact measurements; a mode of
operation generally not possible at THz
frequencies.

64 www.researchoutreach.org www.researchoutreach.org 65

Above: Postdoctoral researcher Shijun Sung
scanning his cornea with a prototype THz
imaging system. The system scans the imaging
beam while the patient’s head stays fixed using
standard ophthalmic chin and forehead rests.
TRIAL AND ERROR: FURTHER
TESTING
To address the challenges identified in
the first stage of work, Dr Taylor teamed
up with researchers from TU Delft in
the Netherlands, Chalmers University
in Gothenburg, Sweden and VTT in
Helsinki, Finland. A new optical system
was designed, constructed and tested in
partnership with colleagues specialising
in physical optics. Pilot testing of the
system was completed on a group of
volunteers, which informed modification
in preparation for upcoming pilot clinical
trials. This work has produced what is
believed to be the first non-contact THz
image of a live human’s cornea ever to
be published.
A PROMISING TECHNOLOGY
Through their initial studies, Dr Taylor
and Dr Grundfest collected a number
of observations that will be useful
for the research community and
their development of THz frequency,
ophthalmologic imaging tools. Their
research has been met with a huge
degree of excitement by the scientific
community, with two of their research
studies receiving the 2015 Terahertz Best
Paper Award, in May last year.
66 www.researchoutreach.org
Subject 1: Left eye, en-face
Reflectivity at 650GHz
• Image acquisition time: ~20 seconds
• Imaging subject stays completely stationary
• Optics modification was crucial to imaging feasibility success
Above: En face, non-contact, THz reflectivity maps of cornea from a volunteer
subject. More reflectivity equates to higher water content.
Dr Taylor and Dr Grundfest’s imaging
tool could make a real difference to the
way corneal disorders are diagnosed
and studied
If perfected in a way that allows for
accurate imaging and measurements
of CTWC, Dr Taylor and Dr Grundfest’s
imaging tool could make a real
difference to the way corneal disorders
are diagnosed and studied. The aim is
to provide a non-invasive and accurate
way of measuring hydration of the
corneal tissue – something that is not
yet possible. Not only does this research
Behind the Bench
Dr Grundfest
E: zdeis@seas.ucla.edu T: + 1 858 663 1823 W: http://www.ee.ucla.edu/zachary-taylor/
W: http://www.bioeng.ucla.edu/zachary-taylor-ph-d/
Research Objectives
Dr Taylor and Dr Grundfest’s research
focuses on developing a new imaging
tool for non-contact, high resolution
measurements of corneal hydration. Their
collaboration since 2011 at The UCLA Henry
Samueli School of Engineering and Applied
Sciences has led to many publications and
the Terahertz Best Paper Award in 2015.
Funding
• National Institutes of Health (NIH)
• National Science Foundation (NSF)
• Telemedicine and Advanced Technology
Subject 1: Right eye, en-face Research Center (TATRC)
Q&A
When and how did you first start
developing the THz-based imaging
tool to measure corneal hydration?
This imaging programme grew out of
initial work on burn wound severity
assessments using THz imaging.
Burn wounds are characterised by
rapid accumulation and resorption
of oedema (excess tissue water).
One of the key challenges with burn
wound imaging is accounting for/
overcoming physiological variation,
and we are always on the lookout for
more predictable tissue systems. By
chance, an ophthalmology colleague
mentioned difficulties in obtaining
accurate measurements of corneal
hydration. A cursory review of corneal
properties revealed extremely limited
physiological variation and limited
tissue heterogeneity on the relevant
length scales. Our excitement was
further increased by the inadequacy of
optics based systems. We started with
offer a more efficient way of diagnosing imaging excised bovine cornea which
corneal disorders, but also of exploring led eventually to NIH funding.
the relation between specific disorders
and the tissue’s CTWC. What do you feel have been your
most promising findings so far?
Our most promising finding is that
the cornea is a lossy thin film at THz
frequencies. This means that corneal
tissue may exhibit specific, narrow band
properties as a function of morphology
Dr Taylor
Collaborators
Sophie Deng, MD, PhD, Professor of
Ophthalmology, Jules Stein Eye Institute,
University of California at Los Angeles.
Bio
Dr Grundfest received his BA from
Swarthmore College in 1974, before
completing his MD at Columbia University
in 1980. He completed his Surgery
Residency at the Cedars-Sinai Medical
Center, and is currently a Professor at UCLA
in the Departments of Bioengineering,
Electrical Engineering and Surgery.
and reflectivity measurements; combined
with thickness maps this will enable
accurate maps of absolute water content.
Optical thin film metrology is a mature
field and we are currently adapting these
techniques to the measurement of tissue
water content.
Who do you believe could benefit the
most from future applications of the
tool developed through your research,
and why?
We believe that ophthalmologists will
benefit the most, initially. Numerous
corneal diseases associated with
abnormally raised CTWC are detected
through visual assessment where the
water content is sufficiently high to
make the cornea appear cloudy. THz
imaging may enable detection of these
pathologies long before they become
visually detectable thus enabling earlier
intervention and improved patient
outcomes.
How long do you think it might take for
your tool to enter healthcare settings
and what remains to be done until
then?
We are confident that our THz imaging
technology can assess corneal water
content in vivo. The major challenge for us
will be uncontrollable patient movement.
Most of the planned use cases will be in
the clinic with patients sitting in a chair,
in a fashion similar to what you may have
seen at the optometrist. People can’t
Dr Taylor received his BS in electrical
engineering from UCLA in 2004. He later
went on to study the same discipline
at the MS and PhD level at UCSB. He
currently works as an Adjunct Assistant
Professor at UCLA in the Departments of
Bioengineering, Electrical Engineering, and
Surgery.
Contact
Dr Zachary Taylor
420 Westwood Plaza
5121 Engineering V
University of California
Los Angeles, CA 90095-1600
sit perfectly still and the eye exhibits
rapid movements, called saccades,
that contribute to uncertainty in eye
positioning. The timeline for clinical
translation rests largely on our ability
to overcome uncontrollable corneal
movement.
What are your plans for future
research and investigation?
We are focused on three major thrusts.
The first is extensive optical redesigns
to enable rapid scanning. The second
is incorporating phase sensitive source
detector technology to enable rapid,
coherent detection of magnitude
and phase. The third is a large pilot
human trial to understand the unique
constraints associated with operating
THz components in the ophthalmology
clinic setting. Following successful
completion of these engineering and
evaluation tasks we plan to conduct
a large scale clinical trial on patients
undergoing corneal graft surgery.
In the long term, we would like to
investigate applications in traumatic
brain injury and are currently evaluating
the physiological mechanisms that link
elevated intracranial pressure to raised
CTWC.
www.researchoutreach.org 67
Health & Medicine ︱ Prof Christian Beste
Unveiling the
neurobiological processes
behind cognitive control
T
The biological underpinnings of human mental processes involved he biological underpinnings
in acquiring knowledge, processing information and understanding of cognitive control, the mental
experiences, have been substantially investigated throughout the years. function that allows individuals
Prof Christian Beste, working at University Hospital Carl Gustav Carus, to multitask, perform goal-directed
in Dresden, Germany, has carried out extensive research to try and activities such as driving or preparing
understand the neural underpinnings of human goal-directed behaviour. a meal, and develop strategies to
His studies are based both on clinical and empirical observations, as he cope when working on a number of
believes an integration of both might lead to more exhaustive results. things simultaneously, are not yet fully
understood. Research in cognitive
psychology and neuroscience has
been thoroughly investigating the
mental processes involved in cognitive
control, trying to identify the parts of
the brain and neurobiological processes
associated with them.
COGNITIVE PSYCHOLOGY AND
ITS LINKS TO BIOLOGY
For many years, scientists have
studied and tried to identify the
mental mechanisms underlying
human beings’ behaviour and actions.
In psychology, these are referred to
as cognitive processes and include
all mental processes involved in
language use, attention, memory,
perception, thinking, and problem
solving. Cognitive psychology research
is of particular importance as it aims
to develop theories explaining the
underpinnings of mental processes
that occur in healthy individuals, as
well as particular disturbances of these
observed in those affected by particular
medical or psychiatric disorders.
Once these theories are developed,
neuroscientific studies can then try to
link them to actual biological processes
occurring in the brain, which can help
to develop effective treatments for
particular cognitive impairments or
shed light on the biological dynamics
behind them.
68 www.researchoutreach.org
Conceptual approach to study action
control processes. Basic science
approaches are combined with
clinical/applied science approaches
to examine the relevance of fronto-
striatal networks in action control.
Therapy evaluation
biomarker
Basic science
INTEGRATING RESEARCH
AND CLINICAL WORK
Throughout his career, Prof Beste
has worked on investigating the
neurobiological foundations of
cognitive processes. As a student,
he worked as an undergraduate
research assistant in a Neurological
department of the University Hospital
(Ruhr-Universität Bochum) and at the
Institute for Cognitive Neuroscience,
Department of Biopsychology (Ruhr-
Universität Bochum). Prof Beste
explains: “I did both (basic research and
practical clinical work), because I felt
that both ‘sides’
are important to
integrate and that
We identified a number of
each of these sides ‘neurobiological bricks’ that are central
for cognitive control mechanisms
can ‘learn’ so much
from each other
by simply trying to
incorporate the ‘other perspective’.”
At the time, his work focused on the
neuropsychological diagnostics of
neurodegenerative diseases, such
as Parkinson’s disease (PD) and
Huntington Disease (HD), progressive
diseases of the nervous system
characterised by a variety of symptoms,
including jerky body movements and
cognitive impairments. “I became
frustrated by the very apparent
oversight that diagnostic procedures
were not orientated and constrained by
the underlying pathoneurophysiology
Fronto-striatal circuits
Action control
Clinical/applied science
and changes in structural neuroanatomy
of the different disease,” says Beste.
Motivated to read more about the
anatomy and neurophysiology of the
‘basal ganglia’, part of the brain that
has been found to be associated with
HD and PD, Prof Beste came across
theories by Prof Peter Redgrave and
colleagues, identifying the basal
ganglia as playing a central role for
those processes required to decide
between different options or different
ways to act. “I was really fascinated
by this work, which stands very much
in contrast to ‘research traditions’,
that focus on the importance of the
neocortex in these basic cognitive
functions,” says Prof Beste. Inspired
by this research, Prof Beste became
increasingly interested in the brain
mechanisms that enable ‘action
selection’ – the essential ability that
allows individuals to select actions
to perform in the moment.
THE BIOLOGICAL PROCESSES
BEHIND COGNITIVE CONTROL
Most cognitive psychologists define
cognitive control as a set of mental
Experimental psychology
EEG/MRT
Neurobiology/genetics
functions allowing human beings to
work on different tasks simultaneously
and complete goal-directed activities.
More recently, research aims to
identify the parts of the brain and
processes involved in cognitive control,
particularly those necessary to cope
in multi-tasking situations.
Prof Beste carried out a series of
experiments that identified many
biological mechanisms and anatomical
structures involved in these mental
processes, which were previously
almost unknown: “We identified
a number of
‘neurobiological
bricks’ that are
central for cognitive
control mechanisms
also playing a role
in multi-tasking,”
he says. “Moreover, we were able to
show which functional neuroanatomical
structures are causally involved in multi-
tasking and determine the efficacy and
strategy applied to cope with multi-
tasking situations.”
The professor and his colleagues found
that levels of GABA and glutamate
in a part of the basal ganglia called
the striatum could predict particular
neurophysiological processes measured
using electroencephalography (EEG),
a method of recording electrical
activity in the brain. They also found
www.researchoutreach.org 69

Illustration of functional
neuroanatomical networks and
neurobiological systems involved
in multi-component behaviour
and multi-tasking.
Multitasking and functions necessary for
this are very central for our ability to
cope with requirements in daily life
70 www.researchoutreach.org
that diseases specifically affecting
microstructural elements of the basal
ganglia had profound effects on
cortical neurophysiological mechanisms
underlying cognitive control.
LINKS TO NEUROLOGICAL
DISEASES AND PSYCHIATRIC
DISORDERS
In a further series of experiments, Prof
Beste and his colleagues evaluated the
role of EEG measures and experimental
paradigms related to cognitive control
as biomarkers for the progression of
neurodegenerative diseases as well as
neuropsychiatric disorders. They found
that combining neurophysiological
measures with experimental paradigms
tapping into the functions of some of
the striatum’s circuits helped to point
out early disease progression in PD
and HD and are useful to discover novel
facets of deficits in neuropsychiatric
disorders, e.g., attention deficit
hyperactivity disorder (ADHD) or
Tourette Syndrome. The changes
tracked could predict clinically relevant
parameters for progression of these
diseases better than parameters
that are currently in place. The same
measures also appeared able to
effectively assess subtle changes
in medication treatments in these
diseases and disorders.
A COMPREHENSIVE APPROACH
Prof Beste’s research provided great
insight into the neurobiological
dynamics of mental processes
associated with goal-directed activities.
Through an integrative approach that
combines basic and clinical research,
he and his colleagues were then
able to identify particular areas and
processes in the basal ganglia which
are associated with multi-tasking
and appear to be adversely affected
in neurodegenerative diseases and
psychiatric disorders.
These brain areas and processes could
also be impaired in other conditions
that are characterised by impairments
in cognitive control, including
psychiatric disorders. Excitingly, his
findings may well provide a basis for
further research, ultimately leading to
an increasingly accurate understanding
of the biological underpinnings behind
goal-directed behaviour in humans.
Behind the Bench
Professor Christian Beste
E: christian.beste@uniklinikum-dresden.de T: +49 351 458 7072 W: http://www.actionlab.de
W: http://www.researchgate.net/profile/Christian_Beste
Research Objectives
Prof Beste is a neurophysiologist and
cognitive neuroscientist who aims to
combine clinical and basic research to
understand the neural underpinnings
of human goal-directed behaviour and
neurology cognitive control.
Funding
• Deutsche Forschungsgemeinschaft
(DFG)
• Bundesministerium für Bildung und
Forschung (BMBF)
• Else-Kröner Fresenius Stiftung (EKFS)
Q&A
You have taken a novel
approach to your research into
neurodegenerative disorders
by combining clinical and basic
research. How did you come to
study this field?
When I was a student I was working in
many labs on different topics related
to cognitive neuroscience, but I also
worked in a neuropsychological
department at a hospital. There, I
was involved in neuropsychological
testing and diagnostic procedures
in patients with various neurological
diseases. Doing so, I wondered
increasingly whether the tests we
apply in clinical routines do really
have a solid neurobiological basis. I
thought that if this is not the case, then
we are very likely to miss diagnostic
sensitivity and specificity. At this time,
I mainly worked with patients with
neurobiological basal ganglia diseases
(e.g., Parkinson’s Disease, Huntington
disease). This led me to read about
the neurobiology and physiology of
• Friede Springer Stiftung
• BIOGEN
• GENZYME
Bio
After graduating in Psychology in 2006
at the Ruhr-Universität Bochum, Prof
Beste received his PhD in 2007. Before
establishing an independent Emmy-
Noether Group at the Ruhr-Universität
Bochum in 2012, he was Post-Doc
at the University of Münster, TU
Dortmund and the MRC Cognition and
Brain Science Unit (Cambridge).
basal ganglia-prefrontal cortical networks
in relation to cognitive functions and
I became fascinated by this topic. My
previous, current and future research
is a constant development of aspects
that had fascinated me when I was an
undergraduate student.
Why is multi-tasking so vital for
cognitive function?
I think that multitasking – or what we
think of as multitasking – is very central
for our ability to cope with requirements
in daily life. I cannot think of a situation
in which such abilities may not be
relevant – except deep meditation for
example. Because ‘multitasking’ is a
complex cognitive function and requires
large-scale network organisation, these
processes especially are very central
when thinking of diagnostic procedures
suitable to detect even subtle changes in
brain functions.
What most fascinates you about
neurobiological research?
It is the complexity of interacting neural
processes and how this complexity may
Contact
Professor Christian Beste
University Hospital Carl Gustav Carus
Dresden and Institute of Psychology
TU Dresden
Fetscherstraße 74 
01307 Dresden
Germany
result in seemingly simple observable
behaviour that fascinates me.
How can neurodegenerative
diseases help us investigate brain
function?
It is not so much the
neurodegenerative disease per
se, but various diseases that affect
brain function – including psychiatric
disorders. I strongly believe that
when you are interested in the
question “How does the brain manage
to deal with situations requiring
cognitive control e.g. ‘multitasking
situations’?” a good strategy is to
approach this question from different
angles. Disorders of the CNS provide
these different angles necessary to
gain a more comprehensive picture
about the underlying neurobiological
mechanisms. In particular, when there
are clear and specific neurobiological
changes (e.g., in the case of XDP
patients) this approach allows us to
gain insights into the mechanisms
important for human goal-directed
behaviour.
www.researchoutreach.org 71
Health & Medicine ︱ Dr Marion Kavanaugh-Lynch
Community
collaborations
targeting breast cancer
Dr Marion Kavanaugh-Lynch
directs the California Breast
Cancer Research Program of
the University of California. Her
latest work with the QuickStart
programme in California offers
coaching for partnership teams
formed between communities
and academics to conduct
participatory research. With
a focus on the environmental
factors in breast cancer and
social disparities in breast
cancer, she has forged
an important partnership
between the California Breast
Cancer Research Program,
Commonweal and the Orange
County Asian and Pacific Islander
Community Alliance.
72 www.researchoutreach.org
B
reast cancer affects millions of
people around the world and
innovative research is essential to
end this disease. The state of California
alone invests $15 million into various
research projects each year, raising the
important question – what is the best
way to invest these precious resources?
At the California Breast Cancer Research
Program, this responsibility falls to its
director – Dr Marion Kavanaugh-Lynch.
Dr Kavanaugh-Lynch and partners from
Commonweal and the Orange County
Asian and Pacific Islander Community
Alliance are developing a programme
to encourage members of the local
community to engage in their own
research projects. Approximately 70%
of breast cancer cases could have an
environmental cause and, with wide
ranging social disparities in outcomes,
the more insight that communities can
contribute, the better.
QUICKSTART
This innovative programme, known
as QuickStart, delivers face-to-face,
telephone-based, and online sessions
for either established or newly
formed partnerships. Throughout the
programme, teams develop a research
plan. This includes firstly, identifying
the problem and formulating a research
question; secondly, designing a research
plan; and thirdly, developing a budget
and writing a grant proposal.
All partnerships include a Community
Co-Principal Investigator and an
Academic Co-Principal Investigator.
The Co-Principal Investigators share
QuickStart Faculty provide support to Fellows
leadership on the research project and
ensure an adequate representation
of both community and academic
perspectives. The Community Co-
Principal Investigator represents a
group within the community and should
have the trust of their organisation, as
well as the skills to communicate with
all members of the research team and
the broader community, who may be
impacted by the research. The Academic
Co-Principal Investigator must have
allocated time for research. Their skill
set and knowledge base should align
as closely as possible to the research
interests of the Community Co-Principal
Investigator. The QuickStart programme
allows for thorough development of
the research
Approximately 70% of breast cancer
question and
helps partnerships
discern where
specific expertise
cases could have an environmental cause
is required.
Eligibility is largely unrestricted,
provided participants are willing to
commit to all aspects of the programme.
The practicalities of taking part in the
QuickStart programme are made evident
to applicants in the brochures and
application forms they receive. For those
willing to undertake the commitment,
including four days of face-to-face
sessions, online weekly assignments,
and telephone coaching, the benefits
are huge. The three-month programme
provides opportunities for both the
academics and the community
members involved.
Academics can gain critical insights
into the realities of breast cancer in
specific communities, as well as improve
their likelihood of receiving funding
for a project, due to the demonstrably
high level of stakeholder interest.
They will also maximise the potential
dissemination of their research, having
actively engaged with the groups most
likely to benefit during the primary
stages.
Likewise, community members can gain
valuable research skills – improving
the reputation of the organisation they
represent and gathering data for their
own campaigns. Both academics and
communities increase their chance of
creating actual long-term change to
policy and practices.
COLLABORATIONS AND
PARTNERSHIPS
The type of research created by
partnerships in the QuickStart
programme is community-based
participatory research. The
programme specifically focuses on the
environmental causes of breast cancer
and social disparities experienced
by breast cancer
sufferers.
It is hoped that
successful completion
and evaluation of
this project will lead to an established
method of delivering a curriculum of
this nature to the public. Ultimately,
it is expected that the partnerships
that participated in the QuickStart
www.researchoutreach.org 73
 Behind the Bench
Capacity building for Community
and Academic Fellows

Dr Marion Kavanaugh-Lynch
E: marion.kavanaugh-lynch@ucop.edu T: +1 510 987 9878 W: http://cbcrp.org/index.html

Research Objectives Collaborators research and developing rigorous

QuickStart supports community-
academic teams in conducting
community based participatory
research (CBPR) related to breast
cancer. This is a rare opportunity to
get technical assistance directly from a
potential funder on a research proposal
that the teams develop over the course
of the programme. Participants build
their partnerships and workshop a
research idea through in-person and
online sessions. QuickStart participants
develop the expertise to collaboratively
develop research questions, plans and
grant proposals.
Funding
• Senaida Poole, PhD, Program Officer,
Community Initiatives and Public
Health Sciences, California Breast
Cancer Research Program (CBCRP)
• Heather Sarantis, MS, Women’s
Health Program Director,
Commonweal
• Mary Anne Foo, MPH, Executive
Director, Orange County Asian and
Pacific Islander Community Alliance
(OCAPICA)
Bio
Dr Kavanaugh-Lynch’s
accomplishments include championing
the role of advocates and survivors in
the peer review process, developing
evaluations of the programme. In
recent years, she led a national panel
that developed research strategies
to explore the role of environmental
contaminants in breast cancer, breast
cancer disparities, and prevention of
breast cancer.
Contact
Marion H E Kavanaugh-Lynch, MD,
MPH
California Breast Cancer Research
Program 
University of California, Office of the
President, 300 Lakeside Drive,
6th Floor, Oakland, CA 94612-3550
USA

QuickStart has been described as

programme will be able to submit grant National Institutes of Health (NIH) a successful model for funding
applications to the California Breast
community-based participatory
Cancer Research Program Community “invaluable and career changing” and
“an excellent combination of scientific
Research Collaborations awards, as well
as to other funding sources.

content and team building exercises”

In order to maximise the reach of the
project, Dr Kavanaugh-Lynch has
formed important partnerships with
organisations to enable expansion
of the opportunity to diverse cross
sections of Californian communities.
These partner organisations include
Commonweal and the Orange County
Asian and Pacific Islander Community
Alliance (OCAPICA). Commonweal is
a California-based non-profit health
and environmental research institute
which seeks to engage in activities
to improve public health. Their
activities span education, research and
charitable work, with the impact of their
programmes not only improving the
health of individuals, but also enhancing
the health of the global environment.
OCAPICA works to benefit the
health and wellbeing of Asian and
Pacific Islanders living in Orange
County, California. Their involvement
in this project is testament to the
importance of encouraging maximum
diversity of groups benefitting from
and contributing to the QuickStart
programme. The project is supported
by the National Cancer Institute of the
National Institutes of Health.
Previous programmes have resulted in
successful research funding for more
than half of their participants, and
the range of topics studied has been
diverse. Projects can be broad in their
intended impact or can target a small
and specific group of people. Examples
of previous projects include an
investigation into the effect of benzene
exposure on air pollution, as well as a
study encouraging teenage mothers to
persist with breastfeeding to protect
against future incidences of breast
cancer. QuickStart has been described
as “invaluable and career changing” and
“an excellent combination of scientific
content and team building exercises”.
The academic accomplishments of Dr
Kavanaugh-Lynch within the field of
breast cancer research, alongside her
continued advocacy for the voices of
all members within a community to
be heard, will ensure the QuickStart
programme helps all participants to
achieve their full potential.
More info on QuickStart:
http://cbcrp.org/funding-opportunities/
crc/quick-start-training.html
www.commonweal.org/program/
quickstart
Q&A
When developing the programme
did you need to build in flexibility to
accommodate the different cultures
throughout California?
Yes. We continually evaluate our
progress and refine aspects of the
programme so that community
and academic organisations across
California can participate. For example,
we have shortened the schedule so
that partnerships attend four days of
in-person sessions (down from six).
Also, we have revised our application
process to provide technical support
to organisations that are interested
in participating but would like our
support in finding a partner for the
programme.
Can this method of programme
be applied nationwide or even
worldwide?
Absolutely. We are exploring different
methods of delivering the curriculum to
eventually deliver a programme that can
be delivered to anyone, anywhere.
What do you hope the impact of
involving more people from the
community in research projects
will be?
In order to promote global well-being
and health, scientific discoveries must be
applied to address the lived realities of
people in their communities. Academic
scientists cannot do this alone, and
neither can community organisations.
But working together, they can transform
their worlds.
What has the feedback from the
academic Co-Principal Investigators
been like? Have they had any
surprises along the way?
They have learned that forging
productive partnerships and working
collaboratively can be very time-
consuming. But they have found
that the rewards are profound. Their
research theories come alive and
transform lives.
Is there scope to tackle research
questions about other diseases
using a programme like QuickStart?
This sort of research partnership can
be used to tackle any disease that the
community is concerned about.

74 www.researchoutreach.org www.researchoutreach.org 75
Health & Medicine ︱ Professor Christian Schulz
Dual origins of M
ost people with an interest in
biology will be able to tell you
tissue macrophages
that macrophage cells are an
important component of our immune
system. By engulfing and digesting
microbes, cellular debris, foreign
substances and anything else that isn’t
a healthy body cell, they help to protect
us against injury and infection. It is now
clear that macrophages are present in
Macrophages – large white blood cells that play a role in tissue homeostasis and immunity – have long been thought all tissues under steady state conditions,
to derive solely from monocyte cells in the circulating blood. Accumulating evidence now shows that a large and that these tissue-resident cells play
proportion of the macrophage populations ‘resident’ within tissues is in fact derived during embryonic development, tissue-specific roles: tissue remodelling,
independent of monocytes. Professor Christian Schulz from Ludwig-Maximilians-Universitat, Munich, is at the angiogenesis (blood vessel formation)
forefront of this research. He hopes that understanding the molecular regulation of these cells during development and regulation of cell metabolism, to
and within their tissue of residence will help design interventions to treat a wide spectrum of diseases in which they name a few. Tissue-resident macrophages
have been implicated. are exquisitely adapted to their local
environment, acting as regulatory cells of
tissue function, and this makes them an
attractive target for modern medicine.
Understanding the origin and regulation
of these cells will be an important first
step in the development of intervention
strategies to control and instruct
macrophage populations.
TWO BEGINNINGS
During development, haematopoiesis
(including macrophage production)
first takes place in the yolk sac (yolk sac
haematopoiesis). Soon thereafter the
foetal liver becomes a hematopoietic
site expanding hematopoietic stem
cells that migrated from the aorto-
gonado-mesonephros region (foetal
haematopoiesis) but also of macrophage
progenitors that derived from the yolk
sac. Towards the end of gestation, foetal
haematopoiesis switches from the liver to
the bone marrow.
Until recently, it was believed that tissue-
resident macrophages were constantly
replenished from pools of circulating
monocytes (macrophage precursors)
produced by foetal haematopoiesis.
However, this concept has been
questioned following reports that
macrophages in the brain, liver, skin,
and many other organs proliferate and
self-renew. For example, donor-derived
The team used a technique known as pulse-
labelling to map the fate of developing
macrophage cells in mouse embryos
76 www.researchoutreach.org
tissue macrophages have been reported
to persist for many years in transplanted
liver and skin in human patients. The
hypothesis was therefore raised of two
distinct origins of macrophages: the first
being yolk sac haematopoiesis which
produces mature macrophages, the
second being foetal haematopoiesis
which produces blood monocytes.
Professor Christian Schulz and colleagues
therefore decided to reinvestigate
the origin and development of tissue-
resident macrophages.
TWO POPULATIONS
Among various biological tools, the
team used a technique known as pulse-
labelling to map the fate of developing
macrophage cells in mouse embryos.
They showed that macrophages derived
from the yolk sac (YS) circulate in the
blood and colonise the embryo, starting
with the head region, nine to ten days
after fertilisation. By ten days after
fertilisation, the cells could be detected
in most tissues, where they continued
to divide. They remained detectable
in tissues throughout development.
From twelve days onwards (around the
time that foetal haematopoiesis begins
Fate mapping
(green) of yolk-sac-
derived alveolar
macrophages
in the liver) a second population of
macrophages appeared.
Prof Schulz and colleagues set out
to determine the origin of these
newcomers. They re-examined
macrophage development, this time
using mice with a deleted Myb gene.
The team had previously used this
mouse model to show that the protein
Myb is required for foetal but not yolk
sac haematopoiesis. The results were as
hypothesised: YS-derived macrophages
developed as normal but the second
population of macrophages did not
appear, indicating that they are indeed
of the foetal haematopoiesis. YS-derived
macrophages accounted for most
macrophages in tissues of embryos at 16
days after fertilisation.
Importantly, fate mapping models
provided evidence that YS-derived
macrophages persist in many tissues of
adult mice, in some of them (i.e., brain,
liver) throughout life. These findings
support the view that there are two
origins of macrophages in adult tissues;
the first are derived from the yolk sac
during early embryonic development
and the second are derived from foetal
haematopoiesis in the liver and later the
bone marrow.
A CLEARER VISION
Thanks to this work and further work
by Prof Schulz and others, we now
www.researchoutreach.org 77

First appearance of macrophages in the mouse embryo at embryonic day
E9.75
(before the initiation of definitive hematopoiesis)
Above: Yolk sac-derived macrophages develop
in tissues in the absence of foetal definitive
hematopoiesis
Right: Appearance of macrophages in the mouse
embryo 9.75 days after fertilisation (before the
initiation of foetal definitive hematopoiesis)
have a clearer vision of the origin
and development of macrophages.
Macrophage progenitor cells appear
in the yolk sac and then invade the
developing embryo. They colonise all
foetal tissues, particularly in the head
where they give rise to all of the brain
microglia, which will continue to self-
renew throughout adulthood.
Later, foetal haematopoiesis produces
monocytes. They circulate in blood
and need to be continuously renewed
by definitive haematopoiesis. In some
organs, they differentiate and replace
tissue macrophages over time (e.g.,
lung). However, this population seems
more important in the setting of tissue
injury or inflammation. Here, monocytes
are recruited from blood into tissues,
where they differentiate into phagocytes
to fulfil specific jobs/duties. They may
also renew resident macrophages if
needed.
78 www.researchoutreach.org
E9.75
Yolk sac
Thanks to this work... we now have
a clearer vision of the origin and
development of macrophages
MOVING ON
Professor Schulz has now turned his
attention to the biology of macrophages
in relation to their developmental paths
in cardiovascular disease. Similar to the
work described in this article, current
projects utilise in vivo lineage tracing
and fate mapping, as well as models for
time- and site-specific gene deletion.
Behind the Bench
Prof Christian Schulz
E: christian.schulz@med.uni-muenchen.de T: +49 89 4400 73092 W: http://www.sfb914.med.uni-
muenchen.de/principal_investigators/principal_investigators/schulz_christian/index.html
W: http://www.klinikum.uni-muenchen.de/Medizinische-Klinik-und-Poliklinik-I/de/Research/Basic-
Research/People/index.html
Research Objectives
Prof Schulz’s work focuses on the
role of macrophages in tissue
homoeostasis and inflammation,
specifically processes associated with
cardiovascular disease.
Funding
• The German Research Foundation
(DFG), specifically the Collaborative
Research Centre (SFB) 914 (project
A10)
• The German Center for
Cardiovascular Research (DZHK)
• Leopoldina National Academy of
Sciences
Macrophages Q&A
What first piqued your interest in
tissue-resident macrophages?
I was intrigued by previous reports
that in organ transplant patients
Embryo tissue macrophages of donor origin
persisted for years. This indicated
their self-renewal capacity and their
independence of bone marrow
500 µm
haematopoiesis.
Can you give some examples of the
tissue-specific functions of tissue-
resident macrophages?
• Initiation and resolution of
inflammationx
• Clearance/waste disposal (liver,
spleen)
• Regulation of metabolism
The team also carries out genomic • Angiogenesis and vascular
analysis and proteomics to determine remodelling
macrophage programming by the • Development: bone
local environment and disease-specific
signals. This work could eventually aid
morphogenesis, ductal branching,
neuronal connectivity
the development of strategies to control
the remodelling of cardiovascular tissues, A fate mapping model was used to
for example, after myocardial infarction. report the persistence of yolk-sac-
Collaborators
• Jon Frampton (University of
Birmingham)
• Frederic Geissmann (Memorial Sloan
Kettering Cancer Center New York)
• Elisa Gomez Perdiguero (Institute
Pasteur Paris)
• Jeff Molkentin (Cincinnati Children’s
Hospital Medical Center)
BIO
Dr Christian Schulz is Professor of
Cardiovascular Immunology at the
LMU Munich. He trained in Internal
Medicine and worked as a Postdoctoral
Fellow at the Technical University
derived macrophages in adult tissue-
resident macrophage populations. Can
you explain briefly how this worked?
We used a so-called inducible Cre/lox
system, which enabled us to generate
cell type- and time-specific expression
of a fluorescent protein. By inducing
expression specifically during early yolk
sac haematopoiesis, we were able to
identify these fluorescent YS-derived
cells later in embryonic development as
well as in adult animals.
The development of tissue-resident
macrophages has been characterised
using mouse models. Are there
likely to be differences between
macrophage development in mice and
humans?
A yolk sac also exists in humans.
I was intrigued by previous reports
that in organ transplant patients tissue
macrophages of donor origin persisted
for years
Munich. He then moved to the United
Kingdom for postdoctoral work at the
Centre for Molecular & Cellular Biology
of Inflammation and later became a
Senior Lecturer at King’s College in
London.
Contact
Prof Christian Schulz
Medizinische Klinik und Poliklinik I
Klinikum der Universität München
Ludwig-Maximilians-Universität
München
Campus Großhadern
Marchioninistraße 15
81377 München, Germany
It produces haematopoietic cells, which
are thought to enter the foetus in early
life. However, whether this concept
identified in mice (and zebrafish) holds
true in humans is unknown. Notably,
tissue macrophages in humans
can persist autonomously for years
[see comment above on transplant
patients].
What are the potential therapeutic
targets of your research?
We need to understand the regulation
and programming of macrophages
that fulfil tissue-specific functions in
humans. This could potentially be used
as therapeutic targets in chronic tissue
inflammation to induce inflammation
resolution and improve metabolism
and remodelling.
www.researchoutreach.org 79
Health & Medicine ︱ Professor Ghada Bourjeily
The dangers of sleep
disordered breathing
in pregnancy
Professor Ghada Bourjeily and
her team from Brown University
are focusing their research
efforts on understanding
the manifestation of sleep
disordered breathing (SDB) in
pregnancy and the consequent
impact on maternal and foetal
health.
80 www.researchoutreach.org
W
e spend one third of our
life sleeping. As we rest,
damaged tissues are repaired
and cognitive function and energy
levels are restored in preparation for an
active day ahead. Sleep deficiency can
greatly impact our health, highlighting
the importance of good quality sleep.
Abnormal breathing patterns during
sleep, otherwise known as Sleep
Disordered Breathing (SDB), are a
common cause of sleep inadequacy. SDB
includes a wide spectrum of conditions,
from snoring to obstructive sleep apnoea
(OSA). OSA occurs when throat muscles
relax during sleep, causing the upper
airway to collapse. Obstruction reduces
airflow for around ten seconds or more,
resulting in low levels of blood oxygen
saturation (hypoxia). In the long-term,
OSA-associated hypoxia can lead to
potentially fatal conditions such as
Sleep disordered breathing research team. Back row, left to right: Greg Salgueiro, MS, RD, LDN, CIC;
Rebecca Lynn; Susan Martin, LDN, IBCLC; Cindy Brosnan, RRT; Patrizia Curran, MD; Christine Allenson,
MA, OT, CHES
Front row, left to right: Beth Hott, BA; Tamara Sequeira, RN; Maggie Bublitz, PhD, Ghada Bourjeily, MD,
Annaly Aldana, BA, Eva Adodoadji, MD, MPH
hypertension, cardiovascular disease and
diabetes mellitus.
PREGNANCY-ASSOCIATED SDB
Interestingly, pregnant women are
at a higher risk of developing SDB,
due to the physiological changes that
occur during pregnancy. For example,
plasma volume increases and capillary
engorgement causes airway mucosa to
thicken, resulting in nasal congestion as
the lining of the nose, larynx and trachea
swells. This can lead to gestational
rhinitis development, which usually
improves immediately after delivery.
Nasal congestion is a major risk factor
for SDB, therefore pregnant women are
particularly at risk. Furthermore, during
the later stages of pregnancy, the gravid
uterus causes the diaphragm to elevate,
reducing the functional residual capacity
of the lungs by 20%. This may impact
oxygen reserve and further contribute
to upper airway collapsibility. Snoring
is also much more frequent in pregnant
(14–45%) compared to non-pregnant
women of reproductive age (4%).
The strong association between
SDB and pregnancy raises a number
of questions: i) does SDB cause
detrimental effects in the mother
and foetus / newborn? ii) what
physiological or biological factors
predict the development of SDB in
this young population? and iii) what
are the mechanisms that result in these
adverse effects? Professor Bourjeily and
her colleagues have dedicated their
research efforts to investigating these
interesting questions.
GESTATIONAL HYPERTENSIVE
DISORDERS
Professor Bourjeily and others have
shown that pregnancy-associated SDB
(including snoring and OSA) increases
the risk of developing gestational
hypertensive disorders such as
hypertension and pre-eclampsia, even
after considering other risk factors such
as obesity. Gestational hypertension
complicates approximately 6% of all
pregnancies and pre-eclampsia is a
severe pregnancy disorder, characterised
by high blood pressure and either a
high level of protein in the urine or other
systemic manifestations. The condition to the controls (57.5%). In addition, the and hypertensive disorders. Sleep
may deteriorate further to ‘eclampsia’ team has demonstrated that placenta disturbance is associated with high
and seizures may occur which may secreted blood markers are altered in levels of interleukin-6 in the later
threaten the lives of the mother and child. women with OSA compared to controls. stages of pregnancy. This inflammation
Pre-eclampsia is also associated with Professor Bourjeily hypothesises that marker is strongly associated with pre-
pulmonary oedema, liver abnormalities placental hypoxia that may occur as a eclampsia. Nevertheless, much more
and renal failure. Though pre-eclampsia consequence of SDB could trigger a research is needed to fully understand
is a short-lived condition, it has been cascade of events that lead to pre- this relationship.
suggested to be a precursor of future eclampsia. The hypoxic placenta
development of cardiovascular disease. secretes a variety of different soluble GESTATIONAL DIABETES
molecules into the bloodstream that In a study conducted on 1000 patients,
So, how does SDB cause pre-eclampsia? impacts maternal endothelial function. Professor Bourjeily also demonstrated
One of the possible mechanisms In fact, endothelial abnormalities have that there is a significant association
could be placental hypoxia. In a study, been demonstrated in patients with between gestational diabetes and third
performed by Professor Bourjeily OSA, regardless of the severity level. trimester SDB (which includes snoring,
and her team, a quantitative analysis Endothelial dysfunction is characterised gasping and apnoeas) regardless of
of immunohistochemical markers of by an imbalance of hormones that other factors such as BMI and smoking.
hypoxia were compared between the control blood pressure. Consequently, In addition, in a large population-
placentas of pregnant women with hypertension can develop which, if not based sample that included over 1.5
OSA/snoring and non-snoring controls. monitored, can lead to heart disease. million women, a diagnosis of OSA
Expression of the hypoxia marker was associated with an increased
carbonic anhydrase was more prevalent Furthermore, inflammation could risk for gestational diabetes, after
in OSA placentas (91.3%) compared be the missing link between SDB adjusting for multiple risk factors.
www.researchoutreach.org 81

AIRFLOW
LIMITATION
SYMPATHETIC
ACTIVATION
AIRWAY
COLLAPSIBILITY
WEIGHT GAIN
AIRWAY EDEMA
FLUID SHIFTS
HORMONES
INFLAMMATION
Gestational diabetes affects 2–10% of
pregnancies and is characterised by
glucose intolerance. Serious pregnancy
complications can result from gestational
diabetes, including pre-eclampsia,
increased risk of caesarean delivery and
preterm labour. In addition, gestational
diabetes is strongly associated with
future development of type II diabetes,
a highly morbid condition.
Excessively high blood glucose levels,
as a result of SDB, may be related to
a range of interlinking factors. For
example, airflow limitation and hypoxia
can result in increased sympathetic
activation (part of the nervous system
Professor Bourjeily and others have shown that pregnancy-
associated SDB (including snoring and OSA) increases the
risk of developing gestational hypertensive disorders such as
hypertension and pre-eclampsia
involved in the ‘fight or flight response‘),
which can i) inhibit insulin secretion
from the pancreas, ii) exacerbate insulin
resistance (cells cannot respond to
insulin signals which trigger glucose
uptake from the blood) or iii) stimulate
glucose release from liver cells into the
bloodstream. Additionally, oxidative
stress can damage pancreatic beta cells,
where insulin is produced, resulting
in a reduction in insulin secretion.
82 www.researchoutreach.org
SDB in
PREGNANCY
AROUSALS INTERMITTANT
HYPOXEMIA
OXIDATIVE
INFLAMMATION THROMBOSIS
STRESS
PLACENTAL
INJURY AND
DYSFUNCTION
PRE ECLAMPSIA
Proposed mechanism for the link between sleep
disordered breathing and preeclampsia
Dr Bourjeily is currently investigating
additional pathways that may link SDB
and gestational diabetes.
FOETAL RISK AND DELIVERY
Results from studies focusing on
the consequences of SDB on foetal
outcomes are conflicting. SDB (both
snoring and OSA) appears to be
associated with preterm birth (birth
occurring before 37 weeks gestation) in
multiple studies, including Dr Bourjeily’s.
The risk of growth restriction and small
for gestational age remains controversial.
Dr Bourjeily is currently investigating
the risk of growth restriction and other
neonatal outcomes in a large population-
based dataset that linked maternal
and neonatal records. Other potential
adverse foetal impacts include reduced
heart and growth rate. Despite these
inconsistent findings, the majority of
studies provide supportive evidence
that suggests that women who snore,
have short sleep duration and OSA are
at a higher risk of caesarean delivery,
compared to controls.
OBESITY
Behind the Bench
Professor Ghada Bourjeily
E: hada_bourjeily@brown.edu T: +1 401 444 8664 W: http://vivo.brown.edu/display/gbourjei W: http://bit.ly/2y61vTO
ENDOTHELIAL
DYSFUNCTION
Research Objectives
Prof Bourjeily’s work studies the links
between sleep disordered breathing,
pregnancy and perinatal outcomes. She
looks at both the effect on pregnancy
outcomes and the potential for long-term
implications for these women.
Funding
NIH, Chest Foundation
Collaborators
• Geralyn Messerlian, PhD Professor of
Pathology, Brown University
• Maggie Bublitz, PhD, Assistant Professor
of Psychiatry and Human Behavior and
FUTURE STUDIES Medicine, Brown University
The work of Professor Bourjeily and her
colleagues has greatly advanced our
Q&A
knowledge regarding the effects of
pregnancy-induced SDB. However, more
research is needed to fully understand
mechanisms behind the association. The
Why is sleep disordered breathing so
team are now focussing their research
prevalent in pregnant women?
efforts on exploring why SDB prevalence SDB is more prevalent in pregnant
more than doubles in later stages of women compared to non-pregnant
pregnancy compared to earlier stages. young women likely because so
By determining the physiological factors many physiological changes occur in
that predict the onset of SDB in late pregnancy that may impact the upper
pregnancy, the team are aiming to create airway, the lungs and the heart. The
upper airway, including the nose and
a model, alongside simple testing, that
the laryngeal area, appears to be more
can be used as a preventative tool, to oedematous (swollen) in pregnancy and
identify SDB development. The patient this may significantly contribute. Resting
lung volumes also change in pregnancy,
potentially impacting the upper
airway. Pregnancy hormones may also
play a role in the development or the
worsening of this condition in pregnancy.
We do not understand yet which of these
changes has the biggest impact on its
development but are hoping to get more
answers in the near future.
can then be treated before the SDB
becomes more severe. As SDB is a SDB is related to gestational diabetes
and hypertensive disorders. Are
relatively easy condition to treat with
there any other conditions that could
ways that are not thought to negatively actually be caused by SDB?
impact the foetus, investigating this Though it makes biological sense
condition that may impact up to a third of that gestational hypertension and
all pregnant women should be a priority. gestational diabetes could be caused
by sleep disordered breathing, research
to date does not confirm causality.
Hence, we talk about associations.
• Fusun Gundogan, MD, Associate
Professor of Pathology, Brown University
• The obstetric medicine team at Lifespan
under the directorship of Dr Lucia Larson,
Associate Professor of Medicine, Brown
University, division director of Obstetric
Medicine, and Peg Miller, Associate
Professor of Medicine, Brown University
and Chief of Women’s Services at Lifespan
• Marshall Carpenter, MD, Maternal Fetal
Medicine, and the obstetric team of
providers who help facilitate patient
recruitment
Bio
Ghada Bourjeily is associate professor of
medicine at the Warren Alpert Medical
Future studies that look at the impact of
therapy on these outcomes or establishing
a temporal relationship between these
conditions can help us establish causality
further. In a recent study we have shown
that SDB has been associated with other
severe maternal illness such as pulmonary
oedema, congestive heart failure, risk of
admission to the intensive care unit, as
well as an increased risk of a hysterectomy.
There also appears to be an elevated risk
of requiring a Caesarean delivery once
diagnosed with SDB.
How does pregnancy-induced SDB
affect foetal health?
The foetus and the placenta may be target
organs in the case of SDB, just like the heart
and the kidney may be impacted by SDB.
To date, there has been quite a few data
linking SDB to preterm birth with a recent
study showing an increased risk of both
induced and spontaneous preterm birth.
Data are inconsistent in showing evidence
of growth restriction. What is lacking in the
literature is an understanding of the timing
of development of SDB and how SDB
pre-dating pregnancy would differently
impact foetal growth. For instance, is it
possible that long standing SDB may cause
some protective mechanisms to take effect
further protecting the foetus compared to
SDB that develops in pregnancy? These
are questions we do not have answers to at
this time.
School of Brown University in the divisions
of pulmonary, critical care and sleep
medicine, and obstetric medicine. She
is the director of women’s research at
the women’s medicine collaborative at
the Miriam Hospital and director of the
pulmonary disease in pregnancy program.
Contact
Ghada Bourjeily
Associate Professor of Medicine
146 West River Street,
Providence
RI 02904
USA
Are women affected by the
impacts of pregnancy-induced SDB,
following birth?
This is an area where the research
is still lacking. In an indirect way, we
could say that if SDB is increasing the
risk of pre-eclampsia for instance,
and pre-eclampsia is associated with
short term risk factors and long term
adverse cardiovascular risk factors, SDB
may be increasing the risk of future
cardiovascular disease. However, we (the
collective we) have not yet studied how
or whether SDB could impact (mediate
or catalyse) the link between pre-
eclampsia and cardiovascular disease,
or the link between gestational diabetes
and type II diabetes for instance.
What further research will
you be conducting?
We would like to focus our future
research on better understanding
mechanisms of these associations as
those may be quite different in the
pregnant population due to the duration
of the exposure, the accelerated
outcomes, the hormonal milieu and
other factors associated with pregnancy.
We also would like to identify
therapeutic targets and understand
barriers to therapy in women who may
be minimally symptomatic.
www.researchoutreach.org 83
Thought Leader

HRA: making science open,

managed and well-funded
Back in 2015, the Health Research Alliance (HRA), a multi-national consortium of non-profit organisations in the field of
biomedical research, announced the selection of Dr Maryrose Franko as its new Executive Director. Bringing over 70 non-
profit and non-governmental funders of biomedical research together, the HRA is the number one place to go for non-profit
organisations seeking to enhance return on their investment in biomedical research. But HRA is about much more than
just the “nuts and bolts” of grantmaking. Dr Franko leads the organisation in its commitment to popularising research and
taking care of science’s most valuable asset – its people.

H
ealth Research Alliance’s story
began in 1998, when a group of
private funders met to discuss the
role of philanthropy in financing medical
research in America. Some of them
later began to meet regularly, which led
to the foundation of Clinical Research
Alliance. CRA efforts were aimed mainly
at gathering data on medical research
and sharing knowledge, best practices
and experience among its members.
But, when the CRA convened over 70
representatives of biomedical research
foundations and voluntary health agencies
in 2004, they broadened the scope of
their activities to include issues that did
learning in areas like grantmaking and
communicating impact. I also do that
by making sure HRA gives its members
a voice in conversations important to HRA
members, thus increasing the openness
and reusability of the science we fund
– not only publications, but also data
and other research outputs.
I work closely with the co-chairs of each
HRA’s Interest Groups to set agendas,
convene meetings/webinars, facilitate
communication with members of the
Groups and conduct research as needed
to guide actions. This means I spend
quite a bit of time building relationships
model for scholarly communication which
is why I was honoured to be invited
to serve on the COS board.
Can you tell us about the HRA and
briefly outline HRA’s core mission?
In 2005, the HRA was formally
incorporated. 21 funders formally joined
the Alliance in 2006. Today, we now have
almost 80 members, and are still growing!
Our mission and core values are all about
maximising the impact of biomedical
research to improve human health.
To achieve that we collect and share data
and analysis about non-profit funding

Our mission and core values are all about maximising the
impact of biomedical research to improve human health

not fall neatly into the clinical research
category. Thus, in 2005, CRA became the
HRA which since then, has built one of the
largest searchable databases (called the
HRA Reporter) of grant awards covering
over ten billion dollars’ worth of available
grant-money from 2006 till today,
supported young scientists at the early
stage of their careers, and advocated
for open access to scientific data and
publications. Now, with Dr Maryrose
Franko, at the helm, HRA is on its way
to accomplish even more than that.
Hello Dr Franko! Can you tell us what
your role involves as Executive Director
of Health Research Alliance (HRA)?
HRA’s mission is to increase the
impact of HRA Members’ funding for
biomedical research. I facilitate members’
with members and other organisations
with shared goals. I also lead HRA’s
communications and its financial
management.
Can you also tell us about your
additional role as a board member
for the Center for Open Science?
As a member of the Center for Open
Science Board of Directors, I promote
the COS mission, help COS meet all
legal obligations based on state law and
the by-laws of the board, and maintain
financial transparency and accountability
for the organisation. We also review
annual financial statements making
sure that the financial management
is sound and we approve the budget.
HRA is a strong believer in the value and
robustness of COS’s open, public goods
for research and training in the field,
address issues key to accelerating its
development, and help the research
community communicate with funders.
How influential has the HRA been on
investment in biomedical research?
HRA does not formally advocate but
our members do. The Alzheimer’s
Association, for instance, has had a major and other federal organisations helps interact, learn, network, and collaborate, experiencing at the onset of their careers.
impact on investment in Alzheimer’s to demonstrate the value of investment and are especially valuable in enabling
research. They have very generously in biomedical research. deep exploration of important issues in Another HRA’s initiative is The HRA
shared their successful strategies with basic discovery and translational research. Reporter, a real-time, searchable database
the rest of the HRA community and some Can you tell us more about the HRA’s of awards made by our members.
members can already point to increases current plan of action to achieve HRA also has six working groups dealing Currently, the database represents
in funding in their own research space. its mission? with common problems in biomedical over $10 billion in funding and over
A rising tide lifts all boats so the fact The HRA has a very comprehensive research like making science more ‘open 35,000 separate grants from 2006 to
that we speak with one voice about the strategic plan. We host semi-annual and reproducible’, introducing new drugs the present. Additionally, we use this
importance of biomedical research and Members’ Meetings which are the and therapies, awarding grants, and all database to publish reports, like the 2014
work with universities, the NIH, the FDA, principal venue by which HRA members kinds of issues young researchers are report “Bringing Non-Profit Funding

84 www.researchoutreach.org www.researchoutreach.org 85
 Thought Leader
© Michelle Mishina

of Biomedical Research Into the Light”
which provided an enlightening analysis
of grants for biomedical research from
foundations and grant-making charities.
Finally, we publish e-newsletters and
other updates to members and the
external community about our initiatives,
The early involvement and leadership
of BWF not only was pivotal in creating
HRA, but the affiliation with the Fund
provided HRA with legitimacy in its early
days. The Burroughs Wellcome Fund
Board and staff were also instrumental
in encouraging private funders of
to enable members open and public HRA doesn’t fund research itself, so
access policies, and grantees’ access to we don’t have a funding strategy. But I
an HRA-branded data repository. We would like to see PhD scientists trained
have also developed the only database of and opportunities created so that they
non-profit funding of biomedical research, can use their training to contribute to
so the inclusion of organisation’s awards the advancement of human health in ways
in the HRA Reporter database is valuable. other than as academic professors.

I also would like to see widespread open

We need to make the public understand that investment in

access to publications and other research
outputs, as the ability to access and

biomedical research is an investment in the future of our kids reuse research data, materials, and other
research products have become even

and grandkids more vital to advancing science.

One last area where I think HRA might

highlights from the Member’s meetings,
items of interest available on the website,
information on upcoming meetings,
webinars, and other activities and other
information of interest to the membership
and the broader biomedical community.
Which organisations have contributed
to the and establishment of the HRA
and support of its mission?
The engagement of the Burroughs
Wellcome Fund, for example, was
extremely important in the early days
of the HRA, and BWF continues to be
one of our very engaged members.
biomedical research and training to
collaborate and to share information
which resulted in the formation of HRA
in 2005.
In addition to increased financial support
in the form of ad hoc grants and other
support mechanisms, staff members
from organisations such as: the Doris
Duke Foundation, the Damon Runyon
Cancer Research Foundation, the
American Cancer Society, the Donaghue
Foundation, the Alzheimer’s Association,
Foundation Fighting Blindness and many
more, contribute countless hours of their
time toward advancing the HRA mission.
This is on top of their very demanding
day jobs!
How does the HRA compare
to other organisations of non-
profit research funders? What
makes the HRA different?
HRA is very action-oriented,
so at HRA Member’s
Meetings, and via
the Interest Groups
members work together
to create valuable
resources. We are
wonderfully helpful
peers – and there is
easy access to other
HRA members to
compare policies
and procedures
and learn from each
others’ experiences.
We also provide
infrastructures such
as an ORCiD
consortium,
a portal
Organisation’s award data becomes part
of an aggregate analysis of philanthropic
biomedical research funding which is
an important resource for HRA members
for landscape analysis and benchmarking,
but also for the broader scientific
community. Membership also comes
with free participation in two Members’
Meetings a year that cover both cutting-
edge science and policy topics, and nuts
& bolts advice.
Do you think biomedical research
receives as much funding as it should
and what are ways of improving this?
Of course, biomedical research could
never receive as much funding as it
should. Funded generously or even
adequately, it could not only significantly
improve human health and longevity
around the globe but can also increase
our quality of life. It also has the potential
to be an economic driver for not only
communities but for individuals as well.
We need to recognise the value of robust
and rigorous science and put in place
infrastructure to encourage and reward
thorough science. We need to celebrate
science and scientific researchers.
Philanthropy, researchers, academic
institutions but also the government
should play an important role in this
celebration. Celebrations of scientific
accomplishments and accomplished
scientists should be as widely publicised
as celebrations of teams winning the
Super Bowl or the World Series. We also
need to help scientists become better
at communicating the value of science.
Everyone should be able to name an
influential scientist (still living!) just like
everyone can name an athlete or an
actor. If the general public recognises
the value of biomedical research then
we won’t have to fight as hard every year
to increase budgets for NIH, NSF and
other funding for biomedical research.
This is not something that the US should
skimp on. For starters, we need to help
the American public understand that
investment in biomedical research is both
an investment in the US economy and
an investment in the future of our kids
and grandkids.
From a personal perspective, are there
any achievements you are particularly
proud of?
When I was a member of HRA (long
before I was the Executive Director),
I co-founded HRA’s Early Career Scientist
working group, which has evolved
into the Research Workforce and Early
Career Development Working Group.
There are so many thorny issues that
affect the research workforce and HRA
members are  tackling many of these by
implementing strategies and measuring
outcomes. These are very hard issues (lack
of diversity especially in senior positions,
lack of opportunities in the academic
setting, physician-scientist shortage,
inappropriate reward structure especially
HRA's annual
member's meeting
in academia, flat NIH funding and low
success rates especially for early career
investigators, training that doesn’t train
for 21st century job landscape, etc.,)
but HRA along with HRA members are
working to have an impact where we can.
I am also very proud to be part of HRA’s
very important Open Science efforts. I
personally believe that funded research
needs to be open so patients and
families can make informed decisions,
and boards/donors are able to evaluate
the impact of funding. Even more critical
is the requirement that resulting data
be published in an easily accessible and
machine-readable format to enable reuse
and analysis by other researchers. Only
then can the impact of the funding be
multiplied – increasing the potential for
significant and far-reaching advances
and scientific innovation. HRA’s Open
Science Task Force is making great strides
in providing advocacy and resources to
organisations that wish to and can move
toward funding science that is more open.
What are your hopes for biomedical
research improving human health in
the future and how will HRA’s research
funding strategy play into this?
have an impact is on Health Services
Research. In an Annals of Internal
Medicine article, the authors determined
that “On the basis of contemporary data
from 2009 to 2013, the median age of
survival of patients with Cystic Fibrosis
in Canada was ten years greater than
in the United States (50.9 vs. 40.6 years,
respectively). The adjusted risk for death
was 34% lower in Canada than the
US”. This is disturbing and something
that is not addressed by traditional
biomedical research, but is an area where
we might be able to leverage contacts
and resources. This is a new initiative
so how much we can impact this area
remains to be seen. HRA hopes to
address the disparities in outcomes linked
to address and not genetic code.
• To find out more information about
HRA and their tremendous support for
biomedical research, please visit their
website at www.healthra.org.
Maryrose Franko, PhD
Health Research Alliance
P.O. Box 13605
65 T. W. Alexander Drive
Research Triangle Park,
North Carolina 27709
USA
E: maryrose@healthra.org
T: +1 240 393 2968
W: www.healthra.org

86 www.researchoutreach.org www.researchoutreach.org 87
COMMUNICATION
Social media and
the rise of video
Since the innovation of Tim Berners-Lee’s World Wide Web and the introduction of Google in 1998, the successive trend
of online development has been in social media. Patrick Bawn takes a look at how important using video has now become
across these platforms, especially within science.
W
ith the world living in a time
of online interactivity, and
people becoming more and
more immersed in using social media
platforms, the landscape of human
interaction has been forever changed.
The millennial age and the rapid
emergence of technology has seen social
media platforms becoming increasingly
recognised as the go-to place for news
and keeping up to date. On Facebook
alone, there are 20,000 people online
every second, with the average American
spending around 40 minutes a day on
the site. Recent statistics also show that
Twitter has almost 320 million active users
per month – representing a huge scope
for potential interactions.
Not only that, but since YouTube’s
inception in 2005, video has really taken
off as a mainstream marketing channel,
engaging audiences during the time that
they spend online. You only need to check
It is time for the scientific
community to embrace videos,
making true, accurate research
accessible to everyone
88 www.researchoutreach.org
your Facebook newsfeed to witness first-
hand the number of videos posted online
each day. In fact, on YouTube alone,
there are over 300 hours’ worth of video
uploaded by users every minute.
SENSATIONAL SCIENCE
This extensive emergence represents
an opportunity to bridge the ever-growing
gap between researchers and the general
public. Due to the accessibility and
plethora of information now available
online, science must engage fully with
this medium in order to be represented
in a way that is accurate – telling the story
as it is meant to be told.
Sensationalised articles based on limited
research are easy to come by with the
growth of the internet, so it is important
for science to move alongside this
technological expansion. Becoming
familiar with the methods in which videos
can be used on social media could help to
attract a new demographic of widespread,
Social Media
for Scientists
tech-savvy consumers – ultimately aiding
scientific research in the long run.
BRIDGING THE GAP
Nowadays, watching videos through
RSM was born out of multiple
social media channels is the main method
used by people to view content and
conversations with researchers who
access stories. It is time for the scientific
community to embrace this method
see a real benefit in connecting
as well, making true, accurate research
accessible to everyone – in a simple
with a broad audience over an
and engaging format.
ongoing basis. Social Media can
For more information on turning your
research into a simple yet effective
now be considered one of the
animation, please visit our sister company
SciAni at www.sciani.com.
most prominent and important
engagement tools of the modern
era. We help you get the ball rolling
and can even provide long term
Social Media Management support.
Start your Social Media journey now:
www.researchsocialmedia.com
 Partnership enquiries: simon@researchoutreach.org
Careers and guest contributions: emma@researchoutreach.org

www.researchoutreach.org