TRAINING

What Great Creation

Alisa M. Clyne1* and Garret A. FitzGerald2

CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE

In this case study, an early-career mechanical engineer interviews an established translational bioscientist about mechanisms for merging engineering and biomedicine to
pursue clinically informed research questions.

Case. I am Alisa Morss Clyne, an associate

professor of mechanical engineering and
principal investigator (PI) of the Vascular
Kinetics Laboratory at Drexel University.
I grew up in Illinois, where my parents
worked as scientists at the Argonne National Laboratory. But I frst fell in love with
designing and constructing creations while
working with my dad in his woodshop.
One summer, I attended an engineering
program at the University of Illinois. Tis
experience convinced me to become a mechanical engineer so I could design and create new entities.
I graduated from Stanford University
with a degree in mechanical engineering.
Stanfords program had innovative and
inspiring professors and an emphasis on
creativity and design. Afer graduation, I
channeled my interest in aeronautics and
astronautics toward work as an engineer
in the Aircraf Engines Division of General
Electrics Technical Leadership Program
while earning a masters degree in mechanical engineering.
As part of the masters program, I was
inspired by a lecture on the biomechanics
of the cardiovascular system and decided to
return to graduate school to engage in biomedical engineering research. I chose the
HarvardMassachussetts Institute of Technology Division of Health Sciences and
Technology (HST) because it provided a
mix of clinical and engineering education. I
completed my doctoral research in the laboratory of Elazer Edelman, studying how
diabetes afects endothelial cell storage and
transport of fbroblast growth factor2. Te
HST curriculum included clinical training;
through that program, I completed the frst
year of the medical school curriculum at
1

Mechanical Engineering and Mechanics, College of

Engineering, Drexel University, Philadelphia, PA 19104,
USA. 2Institute for Translational Medicine and Therapeutics, Translational Research Center, Perelman School
of Medicine, University of Pennsylvania, Philadelphia,
PA 19104, USA.
*Corresponding author. E-mail: asm67@drexel.edu

Harvard University and a 3-month subinternship on the hospital clinical wards.

In late 2006, I began my independent
career as an assistant professor at Drexel
University. My lab works on deciphering
how physical forces and
biochemical changes
interact in diseases of
the cardiovascular system; nanoparticle drug
delivery; and devices
to measure cell mechanics. In the spring
of 2012, Drexel granted
me tenure.

rations that will enhance my research, productivity, and contributions to the improvement of human health.
In this Commentary, I interview Garret
FitzGerald, M.D., chair of the Department
of Pharmacology and director of the Institute for Translational Medicine & Terapeutics (ITMAT) at the University of Pennsylvania. My goals for the interview were to gain
advice about (i) how to establish complementary collaborations with investigators in
the biomedical sciences; (ii) how to choose
a research focus for my impending sabbatical; and (iii) the role a bioengineer can play
in leading a large biomedical research and
development team.

INSIGHT
TRANSLATION
At this point in my
academic career, I am
thinking carefully about
whether and how to
move my research toward translation to
the clinic. Te medical
education and clinical
introduction I received
during my graduate
work allowed me, without pursuing a medical
degree, to learn about
disease biology, interact
with patients and physicians, and observe frst
hand how therapeutic
decisions are made in Fig. 1. An engineer looks at physiology.
the clinic. Tis experience taught me that biomedical engineers must understand patho- EXPANDING EXPERTISE
physiology if they hope to contribute to the Q. Alisa: As a PI who has trained in engidevelopment of clinically useful therapies. neering sciences, what are some mechanisms
Perhaps more importantly, interacting with for enhancing my knowledge about human
actual patients crystallized for me the clini- pathophysiology, broadening my repertoire
cal relevance and human impact of my re- of technical expertise, and staying up to date
search. In the next few years, I will have the with the latest challenges in cardiovascular
opportunity to take a sabbatical, and I want disease when I dont spend time in the clinic?
to use the time to learn new skills, explore
A. Garret: Id look at that through the
in vivo disease models, and develop collabo- prism of my own experience. Ive gone on
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sabbatical twice. In 1987, I went to Genentech to learn about molecular biology. I

wasnt going to become a molecular biologist, but rather, to gain some understanding
of the language, scope, opportunity, power
of the tools, and the difculty and limitations of trying to deploy that information.
Ten in 2002, I did the same thing with
informatics. I went to Oxford for 6 months,
then to both Scripps and Genomics Institute of the Novartis Research Foundation,
which are side by side, for 6 months. And
again, not in my wildest dreams did I want
to become a bioinformatics expert. But I
did want to understand the language they
spoke, the reasons why I should care about
informatics, and how it might be relevant to
my own laboratory. Id say both of those experienceson a per-month basis of investmentprobably had a greater yield in terms
of their infuence on my research program
and the way that I run my lab than any other
similar period of time during my career.
So I think thats what youve been through.
Youve gone through something that hasnt
made you a Doctor of Medicine (M.D.), but
has shown you why you should care about
biomedicine and has given you an understanding of disease complexity and how to
judge whether potential collaborators are as
efective as clinical or translational researchers. One of the things I wanted to accomplish
was not just how to build bioinformatics
into my own environment, but also how to
know whos good and whos not. Obviously,
I couldnt assess these scientists on my own,
but another spin-of of the sabbatical investment was that I met friends and collaborators
who are devoutly invested in the business and
who I could then turn to and say, What do
you think of this person? Tey look pretty
good to me.
I think youre in the same situation. So, do
I need to go back every 5 years and spend a
year doing something similar in bioinformatics? Id say no, but do I need to go on sabbatical
again to amplify my experiences and thus infuence my own research? Yes. Im planning,
in the next year or so, to move my research in
the direction of systems biologya shif that
is happening in the entire pharmacology department at [the University of Pennsylvania].
So, do you need to be a clinical clerk again?
No. But what you might do is take time to
refresh, now in a more specifc fashion, your
understanding of biomedical research in the
clinical environment.
Q. Alisa: Having just received tenure, I
have a sabbatical coming up in the next few

years. I can gain more depth in clinical and

translational research, but theres also basic
biomedical researchIve never done RNA
interference or knockout mouse models.
For someone who wants to do translational
research from the more basic science standpoint, which experience do you think has
more value?
A. Garret: Ive read somewhere that, of
the people entitled to take a sabbatical, only
10% do. Te reason for this is fear of fying.
Scientists think their world will fall apart if
they leave it for a while.
Im a huge advocate of scientists taking
advantage of this wonderful opportunity.
I think its one of the reasons to be in academia, actually. Its an opportunity for refreshment and refocus in the personal and
professional domains of your life. So when
youre thinking about your sabbatical, there
are two important questions to ask. Te frst
is a high-level one: In what general research
area does my interest lie? Am I interested in
working in a cardiovascular environment?
Am I interested in targeted drug delivery
thats applied in a cardiovascular environment?
Once youve identifed your broad interests, the next question is: Where and
with whom can I fulfll my specifc career
goals? Tere are laboratories like mine, in
which we work in zebrafsh, in cells, and
(very expensively) in rodents. But, we also
do mechanistic research in human subjects.
Although our group has scientists doing
very diferent kinds of research with very
diferent technologies, our lab meetings are
collective so that everybody, hopefully, sees
the big picture into which what theyre trying to do fts. And in our environment, that
big picture actually spans the translational
divide. What youre looking for is that type
of environment applied to an engineering
application in the clinical domain.
I think the real challenge in this business
is for basic scientists to appreciate the clinical relevance, even if they wish not to pursue
it, of what theyre doing and the complexity of addressing questions in humans. On
the other hand, its crucial to educate people
from a clinical background as to the beauty,
rigor, and precision of basic sciencea precision that you can never hope to obtain in
the clinical domainso that they can harvest the advantage of that precision to enhance the sophistication of the questions
that one can ask in the clinic.
Q. Alisa: In the melding of biology and
engineering, how does one best identify im-

portant unmet medical needs that can be addressed by engineering approaches? Is it by attempting to translate the fundamental research
questions youve been pursuing, or by working
on unmet needs identifed by industry scientists or clinicians?
A. Garret: Im a great believer in the
line from Shakespeare, To thine own self
be true. People are their own best motivators, and ones most satisfying path begins
with a drive that arises from deep within to
address a challenge that has attracted your
attention. Tat challenge may be one that
prompts you immediately to stretch for
clinical information or experience, or it may
be a fundamental one that you hope may be
ultimately projected by you or by other scientists into clinical realization. But the last
thing I think one should succumb to is to
let the perceived priorities of others dictate
ones science.
In one way, a metaphor for motivationdriven science is the fantastic success of
U.S. National Institutes of Health (NIH)
R01-funded (investigator-initiated) research in the United States. Ofen within
our own community, researchers articulate
the tension between R01-funded science
and translational science. But I have both
R01 and translational grants, and I dont
see any tension. If we are to translate efectively clinically signifcant discoveries, we
need individual investigatorinitiated blue
skies research that ofen yields translational
opportunities in completely unpredictable
ways. Without that independent investigatorinitiated fundamental science, there is
no knowledge to translate.
BADGE OF COURAGE
Q. Alisa: One of the next steps, for me, is to
move into NIH-funded work. With my engineering background, how do I convince NIH
grant reviewers that I am capable of conducting translational biomedical research?
A. Garret: Te ideal approach for you in
terms of entry into the NIH environment is
through a program grant, which depends
on interdisciplinary integration. Given your
expertise, Id be surprised if you cant fnd
common ground. Te bar to entry is a bit
lower than an unsolicited RO1 if youre part
of a program grant application, particularly
if its in response to a request for applications
(RFA). But even if youre writing a grant on
your own, you can address the perception of
your inexperience in the biomedical realm
by having collaborators who support and
defend you on that fank.

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Q. Alisa: How do I best showcase my

knowledge and skills to meet and engage collaborators at this transitional stage?
A. Garret: If you have independent
funding, a strong training record, and publications, potential collaborators will take you
seriously. Its all about conveying what you
bring to the table in terms of scientifc expertise. In a sense, its your badge of courage.
Teres a twin track one can pursue to
engage collaborators. Te frst track weve already discussed: apply for funding as part of
an RFA with a focus that fts in with your research. Te secondand probably the more
important trackis to look around your local environment and ask, Who are the scientists I take seriously? Ten once youve made
sure they are aware of your work, you can ask
them whether they are interested in collaboration or whether they know of people you
should meet with a view to potentially harvesting that collaborative opportunity. Youve
joined ITMAT, which has 1700 or 1800
members. One way to investigate researchers
interests is to search the ITMAT database.
Q. Alisa: How do you think engineers
can have the greatest impact in translational
medicine?
A. Garret: I dont pretend to have expertise in the breadth of opportunity afforded by interactions with engineers, but
in a general sense, I think what engineers
bring to the party is that theyre actually
used to making something. Te test of their
accomplishment is whether it works. In
fact, people like me are not used to making
things. In that sense, engineers have more
advanced experience of the translational
process than those of us who are biologists
or physicians. What these other groups
bring to the engineers is a biological sophistication that helps refne both the question and ultimately the tools that are developed to address the question. You can see it
across a whole range of possibilities: stem
cell biology, localized delivery or activation
of therapeutics, and mechanical approaches
to tissue and organ repair. Te breadth of
the opportunity is enormous.
Te challenge is that we have linguistic
and cultural hurdles to overcome, but many
of the great discoveries in medicine have
come from people willing to undertake precisely those types of challenges. We see it
now with computational biology, which is
beginning to change the face of biomedical
research in a fundamental way. I dont for a
moment think that this cant be overcome,
and investments in translational medicine

are rearranging the incentives to foster the

overcoming of this hurdle.
Q. Alisa: What are some characteristics
of an academic research project that is ready
to move from the basic to the translational
realm?
A. Garret: Te most obvious areas are
tissue engineering, nanomedicine, and drug
delivery. To harvest the potential of these
felds requires an understanding, on the
part of all scientists, of precisely what they
are trying to achieve together and why that
could be important as well as coincident
developments on both the biomedical and
engineering sides that then progressively
intrude. You can make all sorts of nanowidgets that wont be translated unless you
take into account the special requirements
of the molecule youre trying to deliver. So,
for example, you may need to model the local concentrations of the molecule, while
at the same time performing engineering
magic to refne the delivery system.
PARTNERING FOR THE CURES
Q. Alisa: Do you think the process of translating academic science requires partnership with
industry?
A. Garret: I think translation can occur
in a thousand diferent ways. Obviously, industry does some things much better than
we do in academia. Perhaps we do some
things better than they do. I think were at an
interesting stage in the drug discovery and
development arena. Traditionally weve had
large vertically integrated companies that
do everything in housefrom fundamental discovery to phase 3 trials to marketing
of drugs. What were witnessing at the moment is the disintegration of these vertically
integrated companies and a move to a more
modular approach to drug discovery and
development; modules will be drawn from
biotechnology companies, academia, and
the pharmaceutical industry and assembled
in diferent ways depending on the nature of
the challenge. In academia, investments in
human capital and infrastructurerefected
in initiatives such as the NIHs Clinical and
Translational Science Awards, for exampleare really designed to enable academia
to play in that space.
So for instance, back in 2004 when we
established ITMAT, we articulated only two
objectives: (i) to increase the number of researchers who can do their science in what
we call the translational space, which was
between proof-of-concept in model systems
and elucidation of drug-response mecha-

nisms and variability in phase 2 trials, and

(ii) to identify and reduce the barriers that
confront these researchers. What we werent
saying is that were supporting researchers
in the translational space in order to increase the likelihood that some either will
transit the space or form partnerships that
enable translation. I think its very important not to dictate to scientists what kinds
of research they should pursue, particularly
in the academic environment, because such
an approach will be unsuccessful. Rather,
institutions should enable their scientists to
doextremely wellwhat they choose to
do and, if appropriate, lower the barriers for
forming partnerships that facilitate translation of their discoveries.
Q. Alisa: Do you think that a situation will
arise in which industry engages academia to
carry out specifc kinds of research projects?
A. Garret: With the advent of National
Center for Advancing Translational Sciences
and recognition of their value, academiaindustry partnerships are poised to be a focus
of NIH as they have become for other funding agencies, such as the Wellcome Trust.
Generally speaking, the interests and behavior of funders have a big impact on the behavior of those who are funded. But I have
two concerns. One is that I think the reason
to be in academia is the freedom of choice
that it confers on its scientists. Tere has been
a drif in the direction of more and more
RFA-type of researchwhere the funder says
Tis is what you should do or Heres a targeted research opportunityat the expense
of unrestricted R01-type research. I can understand the reasons for this, but I think its a
fundamentally dangerous shif in emphasis.
Te other disturbing worldwide trend
since the economic crisis is an increasing
symbiosis between industry and government
funders that includes scientifcally unqualifed politicians who legitimately say Were
investing in biomedical science. Wheres the
yield? Such politicians and some people in
industry then demand a much faster yield
than the scientifc process delivers and shif
the investment in science away from basic
research toward what they see as likely to deliver near-term impact.
An exemplar of this tendency is the country that I come from; Ireland efected such a
shif in resources for science afer a prioritization exercise that was conducted mainly
by people from industry and government,
with only minor representation from Irish
scientists and virtually none from outside.
Tis movement was coupled with a change

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RESEARCH REWARDS
Q. Alisa: As an engineering professor, I spend
a lot of time teaching. Most of the people I

teach dont go into research or academia.

Tey go out and become engineers.
A. Garret: You can say the same thing in
a medical school.
Q. Alisa: Right. So you published an article in Science Translational Medicine (1)
about creating a new discipline of translational medicine. How can we teach students
who are not planning to do research how to
operate in and appreciate the translational
environment?
A. Garret: I think its a challenge. I know
as a physician that the chance to speak to
people, discern what their problems are,
treat them, and make them feel better is
an unbelievably rewarding and intellectually seductive experience. Te di%cult challenge for most of our brethren who will go
down that route is to tell them why they
should care about another sort of intellectual endeavor.
In medicine, if you are well trained, usually by the time youre 35 youll have seen
one of at least most of the types of cases
youll see in your life. Te odds are that as

you get older clinical practice will become

increasingly routine. A great thing about science is that you dont know what youre going to be doing next week. At the beginning
of their careers, young physicians, perhaps
more than other budding scientists, fnd this
knowledge threatening. But as you get older,
the most rewarding thing about research is
the clash of the new, the unexpected, which
keeps you intellectually stimulated. So even
for people who are primarily practitioners,
research can add a dimension to their professional lives that they will appreciate more
and more as they get older. Its the reason
you went back to school to get your Ph. D.
REFERENCES AND NOTES
1. C. Skarke, G. A. FitzGerald, Training translators for smart
drug discovery. Sci. Transl. Med. 2, 26cm12 (2010).

Acknowledgments: The title is from Alls Well That Ends Well

by William Shakespeare.
10.1126/scitranslmed.3004480
Citation: A. M. Clyne, G. A. FitzGerald, What great creation.
Sci. Transl. Med. 4, 154cm10 (2012).

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in leadership of Science Foundation Ireland

(the Irish analog to NIH), which resulted in
an assessment of funding priority that is constrained by the prioritization-exercise guidelines. (It has been said, for example that Higgs
would never now be funded by SFI.) Funding
decisions will then be made on the basis of
the track record of and research proposed by
the investigator but also the perceived impact. So who decides what is impactful? Te
initial plan is for it to be people from industry. But an idea that has been foated is that
crowdsourcing of public opinion should also
infuence research prioritization. I think this
is completely harebrained and dangerous to
the scientifc enterprise. So while I applaud
increasing interactions with industry, I think
we have to be a little cautious about this erosion of a commitment to basic science and
preservation of the autonomy of the independent investigator.