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SCIENCE

Seven wonders ofscience

Here's how the winners of 2017's Gairdner Awards have changed your
world with their achievements in medicine andbeyond

ILLUSTRATIONS BY MURAT YUKSELIR/THE GLOBE ANDMAIL

IVAN SEMENIUK , ANDR PICARD , CARLY WEEKS AND STEPHANIE NOLEN
MARCH 28, 2017

This year's Gairdner Awards, PROFILES OF THE WINNERS

announced Tuesday, honour Lewis Kay David Julius Huda Zoghbi Rino
pioneering work on vaccines, Rappuoli Akira Endo Antoine M. Hakim
Cesar Victora
stroke, pediatric care and a range
of fundamental discoveries that
have advanced medicalresearch.

The winners come from around the globe but they share a common passion
for discovery.

LEWIS KAY, WINNER OF THE CANADA GAIRDNER INTERNATIONAL AWARD

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One of the world's foremost surveyors of thesmall

by Ivan Semeniuk

Something about Lewis Kay's laboratory at the University of Toronto makes

visitors feel like they were miniaturized while passing through thedoor.

All around the meandering basement facility are enormous metal cylinders,
like giant soda cans, standing apart from benches loaded with
electronicequipment.

The "apart" bit is important. Each cylinder can

generate a magnetic field many hundreds of
thousands of times more powerful than Earth's.
Get too close to a machine while it is running,
and pocket change and metal tools have a
tendency to takeflight.

"I've lost a lot of credit cards here," Dr. Kaysays.

With these devices, Dr. Kay, 55, has become one of the world's foremost
surveyors of the small. His specially is nuclear magnetic resonance NMR.
The field has become indispensable to biomedical researchers trying to
understand the intricate behaviour of proteins inside humancells.

Now those efforts have earned him one of this year's five Gairdner
International awards the most prestigious science prize Canada bestows on
biomedical researchers from anywhere in theworld.

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Given the competition, it is no surprise Canadians seldom win the

international award. Too many big discoveries are happening elsewhere. Born
in Edmonton and based in Toronto, Dr. Kay is the first homegrown winner of
the $100,000 award in nineyears.
Explaining what Dr. Kay does can get a bit technical, which tends to keep his
type of science out of the limelight. (As he observes in passing during my visit,
this is his first media interview in his 25 years of research at U ofT.)

But developments in NMR have drawn a bevy of Nobel Prizes since the 1950s.
And the Gairdner awards are often good predictors of Nobelglory.

Briefly stated, Dr. Kay uses the magnetic fields in his giant cans to line up
atoms the way an ordinary magnet might line up the needle of a compass. In
this case, the atoms happen to be the building blocks of a protein, like
individual pieces of Lego that are part of a larger, more intricate structure.
While the atoms are in his apparatus, Dr. Kay jiggles them with bursts of radio
energy, and then measures how they respond. Collectively, the measurements
enable him to discern the structure of the larger protein, as though tapping a
bunch of Lego blocks might produce a 3D image of what they have been used
tobuild.

"It becomes a game of changing angles, phases, durations and delays so that
you can tease out the information from these multitude of particles," Dr.
Kaysays.

Where Dr. Kay has excelled is by adding a fourth dimension to the equation:
time. Not only can he see what proteins look like, he can watch them change.
This is a key advance, since many biochemical reactions that are crucial for
life involve proteins changing shape. He has also pushed the technology
toward visualizing ever-larger and more complex groups of proteins that
allow a cell's essential machinery to operate and sometimesfail.

In one recent project, he collaborated with Aaron Schimmer of Princess

Margaret Cancer Centre in Toronto to understand the structure of the
proteasome, a barrel-shaped cell component whose working parts are hidden
inside. The structure is a target for certain forms of cancer therapy. While
waxing poetic about what he calls the molecular "dance of life," Dr. Kay says
this patient-oriented research is his truemotivator.

"Certainly I like the physics, but the end result has to be a drop-
deadapplication."

Lewis Kay of the University of Toronto is one of the winners of this years Gairdner Awards in biomedicalscience.

HANDOUT

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DAVID JULIUS, WINNER OF THE CANADA GAIRDNER INTERNATIONAL AWARD

Physiologist's work sheds light on 'how we interpret

theworld'
by Ivan Semeniuk

"I've always been fascinated by the interaction

between plants and animals," says David Julius,
a physiologist at the University of California
San Francisco. By that, Dr. Julius means
interactions that have evolved at the molecular
level and that can reveal much about the
human sensory system and its
neurochemicalunderpinnings.

In the 1990s, Dr. Julius began pondering the way the body responds to
sensations of heat and cold and their links to the perception of pain.
Compared to other sensory systems, such as vision or smell, this important
form of "somatosensation" was poorlyunderstood.

His way into the problem was to study molecules that arise naturally in
plants, including capsaicin, the ingredient that makes hot peppers taste hot.
Dr. Julius worked out the precise way in which capsaicin selectively triggers
nerve fibres involved in the perception of heat and found the gene responsible
for this capability. Similarly, by employing the molecule menthol, which gives
mint its characteristic coolness, his group tracked down the related
mechanism involved in sensingcold.

Dr. Julius' discoveries have unlocked key insights into these sensory channels
and helped reveal how they are affected by tumour growth, infection and
injury. The work has additional relevance as researchers look for ways of
mediating pain that do not rely on addictive substances. Ultimately, it sheds
light on the complex and invisible system that allows us to have a conscious
experience of oursurroundings.

"It's really how we interpret the world," Dr. Julius says. "The world is a
physical environment, but the way we enjoy it or see it is wholly dependent
on all these molecular devices that wehave."

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HUDA ZOGHBI, WINNER OF THE CANADA GAIRDNER INTERNATIONAL AWARD

Child neurologist uncovered key gene and found

hercalling

by Ivan Semeniuk

The rare childhood disease known as Rett

syndrome begins as an unseen presence that
slowly but relentlessly emerges to rob those it
strikes from the chance to grow up as a fully
developed individual. The disorder occurs
almost exclusively in girls, and typically does
not reveal itself until after a child has reached
her first birthday. Then, little by little, cognitive
and neurological setbacks mount. In a sad reversal of normal human
development, many milestones of the first year of life are lost, including
social, language and motorskills.

"When I saw these girls, I was totally intrigued and disheartened by watching
their course," says Huda Zoghbi, a child neurologist who became fascinated
with Rett syndrome as a young researcher in the1980s.

Working with few initial clues, including the case of a mother with two Rett
syndrome daughters by two different husbands, Dr. Zoghbi became convinced
the disorder was caused by a rare mutation on the X-chromosome. In males
the mutation is nearly always lethal in utero, but in females, who have two X-
chromosomes, probability dictates the mutation will be active in about half of
an individual'scells.

An investigator at the Baylor College of Medicine in Houston, Texas, the

Lebanese-born physician and researcher spent years tracking down the
responsible gene. Resisting criticism that the work would lead to nothing, Dr.
Zoghbi and her team eventually found the gene, known as MECP2, in 1999. It
is now known to be a key player in nerve cells and a regulator of other genes,
leading to a cascade of harmful effects when it is impaired. The finding sheds
light on related disorders, includingautism.

Since that discovery, Dr. Zoghbi has been working on ways to counteract the
mutation. As a doctor, she says, "it was hard to see patients and not be able
offer anything meaningful. When I went into research that's when I found
mycalling."

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RINO RAPPUOLI, WINNER OF THE CANADA GAIRDNER INTERNATIONAL AWARD

Medical pioneer helped vaccine makers to hit their mark

moreeasily

by Andr Picard
In 1975, when Rino Rappuoli was studying
biology at Siena University in Italy, he attended
a lecture by Albert Sabin, the legendary
researcher who developed the oral
poliovaccine.

"It was obviously very inspirational," he says

with a laugh. Dr. Rappuoli, who is now chief
scientist and head external R&D at GSK
Vaccines, is being honoured for his groundbreaking work onvaccines.

In particular, he pioneered a concept called reverse vaccinology, which has

revolutionized vaccine development. For more than three centuries, scientists
have tried isolating pathogens, growing them in the lab, then exposing people
to a weakened form to generate antibodies and immunity. But this approach
ishit-and-miss.

What Dr. Rappuoli did instead was decode the genome of a bacterium, then
identify proteins that are good vaccine targets. This approach led to the
creation of the first vaccine for meningococcal B, a bacterial infection that
tends to spread in young people, and which has a mortality rate of about 25
percent.

"For the first time in the history of vaccinology, we didn't grow organisms in a
lab, we just used information in the computer to design a vaccine," Dr.
Rappuoli says. It was then tested and proved effective. (In Canada, the MenB
vaccine is sold under the trade nameBexsero.)

Reverse vaccinology is now standard practice, and has been used, for
example, to develop a vaccine forEbola.
"Today, we don't even start to look at vaccines without looking at the genome
first," Dr. Rappuolisays.

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AKIRA ENDO, WINNER OF THE CANADA GAIRDNER INTERNATIONAL AWARD

Scientist's discovery gave heart-disease patients a new lease

onlife

by Carly Weeks

Today, cholesterol-lowering statins are among

the most widely used pharmaceutical drugs
around the world and are credited with saving
countless people from heart disease andstroke.

Akira Endo, a Japanese scientist, discovered the

first statin in 1973 after examining about 6,000
fungi culture extracts. Dr. Endo was looking for
a specific agent that could inhibit a key enzyme involved in cholesterol
synthesis. He discovered ML-236B, also known as compactin or mevastatin,
which effectively lowers "bad" low-density lipoprotein (LDL) cholesterol. The
discovery would eventually prompt major pharmaceutical companies to
produce cholesterol-lowering statins. Some of the most well-known on the
market today include atorvastatin, sold under the brand name Lipitor, and
rosuvastatin, sold under the Crestor brandname.

"I am deeply moved," Dr. Endo said by telephone about the award. "Millions of
people extended their lives through statin therapy. I'm very happy to
knowthat."

He said he became interested in pursuing cholesterol-lowering agents when

he was working in New York City in the late 1960s and learned that heart
attacks were the No. 1 cause of death in the United States, while stroke was the
top killer inJapan.

Joseph Goldstein, chairman of the department of molecular genetics at the

University of Texas Southwestern Medical Center, who won a Nobel Prize for
his work on cholesterol and statins, said Dr. Endo's work paved the way for
the development of a new class of drugs that saves thousands of lives ayear.

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ANTOINE HAKIM, WINNER OF THE CANADA GAIRDNER WIGHTMAN AWARD

A man on a mission to show that stroke is preventable,

treatable andrepairable

by Andr Picard

In the early 1970s, when development of the oil

sands was just in its infancy, Antoine Hakim
was a chemical engineer working at Syncrude
in Fort McMurray, Alta. It was an exciting,
lucrative time, "but I didn't feel like I was
helping people," hesays.

Dr. Hakim, who is now emeritus professor of

neurology at the University of Ottawa, decided to leave the oil-and-gas
business and try biomedical engineering, and thenmedicine.
After graduating from Albany Medical College, Dr. Hakim did his residency at
the Montreal Neurological Institute and focused his research on strokes. It was
an unpopular area, he says, "because the mind was devastated and the person
was devastated but, at the time, there was nothing we coulddo."

There are two types of stroke: An ischemic stroke occurs when a clot impedes
blood flow (and oxygen) to the brain; a hemorrhagic stroke occurs when a
blood vessel bursts in the brain. In both cases, regions of the brain die and
people lose function, such as memory or the ability to speak or use
theirlimbs.

In the early 1980s, Dr. Hakim found that when a person suffered an ischemic
stroke (about 80 per cent of all strokes), there is a penumbral region around a
stroke's ischemic core in plain language that means part of the brain
affected retained energy and could resume function if blood flow
wasrestored.

"It's as if the region of the brain doesn't die; it just holds its breath waiting for
help," hesays.

It meant the harm caused by stroke was gradual, not immediate and, if treated
quickly, could belimited.

Dr. Hakim, who is receiving the 2017 Gairdner Wightman Award for
outstanding leadership in medicine and medical science, has essentially
dedicated his career to demonstrating that stroke is preventable, treatable
andrepairable.

His most difficult task, he says, was changing attitudes and making the system
more responsive. After all, if "time is brain" as the axiom states in stroke care
 the system has to be responsive. That means ensuring stroke patients get
prompt care, from paramedics through to the ER, andrehabilitation.

Dr. Hakim was instrumental in the creation of the Canadian Stroke Network
in the 1990s, a network of centres of excellence designed to improve stroke
care. He also championed a stroke strategy that has been adopted by most
provinces (and implemented inEurope).

As a result, many hospitals created stroke units, paramedics were trained to

treat stroke differently, and prevention programs were launched. (The most
notable method of getting people to treatment quickly, from the Heart and
Stroke Foundation, stressed key indicators of stroke, such as a crooked face,
slurred speech and an inability to hold one's arms uptogether.)

Dr. Hakim also became an evangelist for tPA (tissue plasminogen activator), a
clot-busting drug that, if given promptly, can prevent a lot of the brain
damage fromstroke.

In 1999, less than 2 per cent of stroke patients were getting tPA; by 2004, it
was 42 per cent, which is close to the theoretical maximum. (Only about half
of stroke patients benefit from thedrug.)

About 50,000 Canadians suffer stroke each year and, as result of improved
care, the number with debilitating damage hasplummeted.

Dr. Hakim says much of his success is due to applying an engineer's problem-
solving approach to medicine. But his greatest achievement, he says, is
knowing that some patients who would have been severely disabled by a
stroke now walk out of hospital with almost nosymptoms.

"If you don't have brain health, you don't havehealth."

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CESAR VICTORA, WINNER OF THE JOHN DIRKS CANADA GAIRDNER GLOBAL HEALTH
AWARD

In a Brazilian town, this researcher upended conventional

wisdom onbreastfeeding

by Stephanie Nolen

There is a joke in the city of Pelotas, in the far

south of Brazil: the average family, they say, is
comprised of a mother, a father, two children
and a public health researcher. Pelotas'
population is often called the world's most
examined, because of a study that began in
1982, when researchers set out to track every
one of the 6,011 babies born there that year.
New cohorts have been enrolled every 11 years for a total of nearly 30,000
participants but the first group, now well into their 30s, is still regularly
being visited by a field worker totingquestionnaires.

The man who dispatches the fieldworkers is Cesar Victora, an epidemiologist

whose body of work in Brazil and more than 50 other countries underpins
much of what Canadian parents take as received wisdom on their children's
health. He defined the growth standards that pediatricians plot on charts, and
he did the work that proved breastfeeding has an enormous range of positive
effects on children, from higher intelligence to higher incomes and less disease
asadults.
It is the breastfeeding work for which Dr. Victora is being recognized with a
Gairdner Award (announced on his 65 th birthday) and it is his most
(inadvertently) controversial finding. Rather than trying to shame women
who do not want to or cannot breastfeed, Dr. Victora says, he wants to
demonstrate that breastfeeding is "the responsibility of a society, not an
individualwoman."

When he began his case-control studies on the impact of breastfeeding, the

average Brazilian woman breastfed for just three months today the median
length of breastfeeding is 14 months and it was Dr. Victora's research that
drove much of the policy shift that made this possible. The shift happened, he
says, because the Brazilian government established paid maternity leave;
banned baby formula advertising; made it mandatory for businesses to have
feeding rooms and breaks for nursing mothers; and carried out a vast public
education campaign that so thoroughly changed minds that breastfeeding is
now nearly universalhere.

"For the cohort study, we take every birth all social classes and conditions,"
he said. "Brazil is a very unequal country in terms of wealth and we are
documenting the social determinants and how they affect people from cradle
to grave. I think that's an important message for global health: it's not just
about poor countries and diseases of poverty, it's about humankind and how
we can improve health early on regardless of whether a person is rich
orpoor."

Zoom/Pan 500 km
 Pelotas

Leaflet | OpenStreetMap

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THE GAIRDNER AWARDS: PASTWINNERS

Natures scissors
The five researchers who won in 2016 were central players
in the discovery and development of a revolutionary gene-
editing technique that carries enormous potential for many
areas of biology.

Secrets of the cell

The 2015 Gairdner Awards winners were known for
scientific discoveries that reach deep into the inner
workings of cells.
FOLLOW IVAN SEMENIUK,ANDR PICARD,CARLY WEEKS ANDSTEPHANIE NOLEN ON TWITTER
@IVANSEMENIUK @PICARDONHEALTH @CARLYWEEKS @SNOLEN

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