The Howard Hughes impact

For almost two decades, Joseph Ecker studied the genetics of
Arabidopsis thaliana, a small flowering plant with a rapid life cycle that's become
a staple model organism in plant biology labs. He helped spearhead the international
effort to sequence the Arabidopsis genome and worked out how the plant
turns its genes on and off. Ecker became one of the top Arabidopsis researchers
in the world. But in the process, he realized that the underlying questions he
was asking and methods he was developing to study gene regulation weren't just
relevant to plants. He started wondering what his approach could allow him to
discover about animal cells and human health.

For a plant biology lab to shift its focus to animal cells or human cultures
requires extensive resources, new equipment and new support staff. For Ecker,
though, help came at just the right time in the form of a five-year appointment
from the Howard Hughes Medical Institute (HHMI) and the Gordon and Betty
Moore Foundation (GBMF), awarded to him in 2011.

With the award, Ecker became the seventh scientist at the Salk Institute to
join the current ranks of HHMI-funded scientists. While most federal grants offer
researchers money for a specific project, HHMI works differently. Through sporadic
competitions, scientists are chosen based not on a specific project but on the
merit of their entire research portfolio. As HHMI investigators, researchers then
receive research support and their full salary and benefits from HHMI, although
their labs remain at their home institutions. The appointment lasts for five years
and can then be renewed in five-year increments. In Ecker's case, a collaboration
between GBMF and HHMI provided additional research support.

"Having this kind of funding gives scientists
the freedom to actually do experiments rather than
spend time writing grants," says Ecker. "It's already
had a big impact on my ability to follow my nose."
Recently, he says, a colleague who studies vision in
macaque monkeys approached him about collaborating
on a project to study how genes involved in vision
are regulated. Rather than worry about how to fund
the project, Ecker moved right into brainstorming
what the collaboration could accomplish.

His story is more than just a testament to
the power of being well funded. It highlights all the reasons that the HHMI model of science works so
well, particularly at Salk: both institutions emphasize
collaboration and the idea that the best science
takes place when talented researchers have the
time and resources to pursue whatever ideas come
their way. For the seven Salk scientists currently
working under the auspices of HHMI—six as HHMI
investigators and one as part of HHMI's early career
scientist program—the benefits of Howard Hughes
support are clear and have helped push all to be
more creative, productive, accomplished researchers.

Legacy of an Aviator

Howard Hughes

In the late 1940s, businessman, film
producer and aviator Howard Robard Hughes, Jr.,
then one of the richest people in the world, was
looking for new ways to invest his money. Funding
basic scientific research had been a lifelong
dream of his, and he began making it a reality
with the help of a group of like-minded advisors.
In 1951, he granted money to six scientists, and
two years later he officially chartered the Howard
Hughes Medical Institute.

Since Hughes's death in 1976, the institute
has grown, and its mission has crystallized
on supporting biomedical researchers through
flexible, long-term support.

"We like to say that we focus on 'people,
not projects,' and that is reflected in our unique
funding structure," says Erin O'Shea, HHMI's
vice president and chief scientific officer. "We
look for people with innovative ideas—big
thinkers—and give them freedom to follow
their instincts."

Today, HHMI has more than $16 billion
in assets and is the nation's largest private
supporter of academic biomedical research.
In 2012, it granted $78 million toward science
education and $695 million in support of
basic research. Three hundred scientists at
70 institutions are HHMI investigators, and
among their ranks are 17 Nobel laureates.
HHMI has been one of the largest funders of Salk researchers, providing more than $75
million in support—a fact that is celebrated
on the list of donors posted at the entrance to
the Institute.

For scientists—at Salk and elsewhere—an
appointment as an HHMI investigator not only
means financial support but opportunities for
collaboration with other HHMI researchers,
idea sharing at annual HHMI conferences and a
recognition that they are at the top of their field.

A Second Home

When Ron Evans, director of Salk's Gene
Expression Laboratory, was appointed an HHMI
investigator in 1985, he didn't fully appreciate
the effect the grant would have on his career.
"I knew very little about Hughes—the institution
didn't circulate much information back then
and was much more private than it is now," he
says. "But in retrospect, it was really catalytic
in its impact on my research. It was basically
like adding jet fuel to a race car."

In the same year as his HHMI appointment,
Evans discovered a new class of proteins, nu -
clear proteins known as receptors that mediate
the action of steroid hormones such as corti -
sol, estrogen and testosterone. The discovery
opened up a deluge of questions and follow-up
experiments for Evans. How many of these
nuclear receptors existed? Does the discovery
of new receptors imply the existence of new
hormones? If so, what other physiological
processes might be controlled by these new
hormone-sensing receptors?

"We were a relatively small, young lab all of a sudden facing this huge
biological problem," says Evans. "So it was the perfect timing
to be brought into this Hughes system that was really geared toward
risk-oriented, cutting-edge research."

In the decades since, Evans has defined about 50 receptors known as
the steroid receptor superfamily and realigned his focus on new hormone
signaling pathways that are intertwined with issues of metabolic disease,
insulin resistance, obesity and muscle growth. He's elucidated how two
receptors, dubbed PPAR gamma and PPAR delta, control whether fat is
broken down for energy or stored in the body, providing a potential drug
target to help treat metabolic disease. And his lab showed that by activating
PPAR delta in mice with a newly designed drug, the animals not
only lost weight but gained greatly improved running endurance. His
"exercise in a pill" drugs were rapidly (and illegally) adopted as a new
class of performance enhancers. For his findings, Evans has won some of
the preeminent prizes in biology—the Wolfe Prize in Medicine, the Albert
Lasker Award and the Albany Medical Center Prize, among others.
Throughout it all, Evans has been inspired, pushed and supported both
by his colleagues at Salk and his fellow HHMI investigators.

Joanne Chory, holder of the Howard H. and Maryam R. Newman Chair
in Plant Biology, studies how plants respond to patterns of sunlight,
shade, temperature and moisture to alter their growth and maturation
and strive to survive. Her research has implications within agriculture
for learning how to optimize the production of crops. It also has broader
lessons about how organisms coordinate the growth of different
tissues and respond to factors in their environments.

"A critical part of being in the HHMI organization is that we have the
benefit of having two intellectual communities," says Evans. "For 30 years,
I've had a home at Salk and I've had a second home with HHMI. And
getting the benefit of having two home bases for research has really been
a game changer."

The two institutions, he says, fit particularly well together because of
their similar approaches to science. Both encourage researchers to pursue
questions that they're passionate about, whatever they may be.
"Hughes has a great model for thinking about how to best do science
through collaboration, creativity and risk taking, and Salk is the place
where this all comes together," Evans says.

Allowing Cutting-Edge Science

The freedom to be creative as a scientist and pursue your interests
is certainly key to being successful, but also important in a research lab
is the ability to have the latest technology and the best-trained staff
possible. For Samuel Pfaff, a professor in Salk's Gene Expression Laboratory
and an HHMI investigator since 2008, access to such resources,
possible only through his HHMI funding, has been integral to advancing
his research program.

Joe Ecker, holder of the Salk International Council Chair in Genetics,
is an expert in the model organism Arabidopsis thaliana, having
spent decades studying its genetics and how its gene expression
is regulated. Recently, he's begun applying these lessons to other
organisms and cell types, looking at the epigenetics of stem cells,
brain development and the human liver, among other systems.

Pfaff studies how nerve cells are formed and correctly wired in a
developing brain. His research has implications for developmental brain
diseases and neurological disorders such as amyotrophic lateral sclerosis
(ALS). But understanding brain development requires looking at neurons
from every angle—studying how patterns of gene expression vary between
neurons, testing how genetic mutations in mice change the development of
the animals' brains, and using cutting-edge microscopy to see how neurons
are arranged and what areas are active when.

"Looking at this whole landscape of the brain requires some pretty
costly equipment," says Pfaff, "and also relies on the ability of a lab to
recruit people who know how to use the equipment." Since becoming an
HHMI investigator, he says, both these things have become easier.

Last year, Pfaff took advantage of the latest microscopy technologies in
his lab to reveal which molecules on the end of a growing nerve cell and
in its surroundings are responsible for guiding the direction of the cell's
growth. He's also expanded his lab to have the capabilities to do experiments
on embryonic stem cells, letting his team discover how genes cycle
on and off in stem cells, controlling their ability to differentiate into new
cell types. The work required access to RNA sequencing technologies,
which allowed him to analyze which genes were being expressed when.

In the 1980s, Ron Evans, holder of the March of Dimes Chair in
Molecular and Developmental Biology, discovered a new family of
proteins known as receptors that are sensors for hormones and dietary
nutrients such as fat. Since then, he's discovered a superfamily of
48 members and focused in on the fat-sensing receptors that control
obesity, metabolism, muscle growth and cardiovascular endurance.
His ideas have changed how scientists think about weight gain,
diets and exercise.

Pfaff's lab group has also become one of only
a few in the country with the capability to screen
mice with random genetic mutations for any
defects in neural system development. Such socalled
random mutagenesis screens are usually
reserved for use with model organisms that are
cheaper and have faster generation times, like
flies and worms. The method is now giving Pfaff
the chance to find brand-new genetic pathways
involved in brain and spinal cord development.

"Both here at Salk and within the HHMI
community, scientists are striving for a much
higher standard than elsewhere," Pfaff says. "We
want to be the best at what we do and not just
add noise and modest contributions to the field."

In the current economic climate, funding for
basic research is hard to come by, and Pfaff says
that researchers should consider doing science
to be a privilege. It's through the joint support
of Salk and HHMI, he says, that he enjoys the
privilege of being a scientist.

Joe Noel, holder of the Arthur and Julie Woodrow Chair, is interested
in how the enzymes and metabolic products made by plants have
changed over evolutionary history and what these changes mean
about the coevolution of plants and animals. His research is not only
vital to shedding light on the past but also for understanding how
plants produce defenses and signaling molecules, which could help
optimize agriculture.

Sharing the Wealth

In Salk's Plant Molecular and Cellular Biology
Laboratory, director Joanne Chory says that her
appointment as an HHMI investigator isn't just
a boon to her work; it has had an impact on the
entire plant science community. Chory's appointments
at Salk and HHMI helped to introduce
these two biomedically oriented institutions to
the wonders of plant genetics, variation and
adaptation to new environments.

Together with Gerry Fink, a former non-resident
fellow of Salk and member of the Medical
Advisory Board of HHMI, she introduced a select
group of plant biologists to HHMI's scientific
leadership during a 2009 workshop at HHMI
headquarters in Maryland. This led to the
appointment of 15 new HHMI and Gordon and
Betty Moore investigators in 2011.

HHMI's commitment to this new program
sent an important message about the importance of plants to human health and the long-term
sustainability of our planet. Despite its central
role in feeding and clothing humans, plant
biology is one of the most poorly funded areas
within the life and biomedical sciences.

Sam Pfaff, holder of the Benjamin H. Lewis Chair, studies how
neurons are formed and correctly wired in a developing brain and
how nerve cells connect the spinal cord to muscles in the body.
His research has implications in developmental brain diseases and
neurological disorders such as amyotrophic lateral sclerosis (ALS)
and Alzheimer's disease.

"This is because the discipline of plant
biology does not have a strong advocate in
Washington," says Chory. "Funding for plant
biology labs has traditionally come from agencies
that have other things on their minds. Having
to distribute food stamps and manage farm
subsidies, the USDA has not had the time to
develop strategies for supporting long-term basic
research. Likewise, the National Science Foundation's
mission is to help create a scientifically
literate public."

With the funding she's received from HHMI,
NIH and other federal funding agencies, Chory
has made a number of seminal discoveries
about the mechanisms of plant growth, including
the finding that plants, like animals, use steroid hormones to control growth, development and sexual reproduction.
However, unlike the nuclear receptors studied in the Evans lab, Chory
showed that plants use a unique class of cell surface receptors, called
LRR receptor kinases, to bind plant steroids and thus control plant growth.

Over the past 15 years, she and Joe Noel, a fellow Salk professor and
HHMI investigator, have discovered how the plant hormone auxin is
synthesized and how its levels are regulated to control plant growth and
development. Understanding where and when plants alter the levels or
sensitivity to these two hormones explains how plants outcompete their
neighbors for light. More recently, she has identified how chloroplasts
signal to the nucleus and, together with Noel, how smoke from forest fires
spurs dormant seeds to begin growing.

Using cutting-edge microscopy and electrochemical methods,
Terry Sejnowski, holder of the Francis Crick Chair, studies how the
brain changes at a molecular level after something new is learned.
His experiments, revealing the complexity of how the brain stores
information, help researchers better understand disorders in which
memory and learning are affected, such as Alzheimer's disease.

"Having long-term funding from HHMI has allowed us to integrate our
research," says Chory. "Over the past 25 years, we have amassed a unique
toolkit, which, along with collaboration with colleagues, has enabled my lab
members to go from a genetic screen to gene discovery to cell biology to
crystal structure and back to ecological response."

Straddling Disciplines

Ecker, the newest HHMI investigator at Salk, already notices parallels
between HHMI and Salk and sees why Salk researchers fit so well with the
HHMI system. Both institutions, he says, encourage scientists to collaborate
and learn from colleagues not only working on similar projects, but
those in drastically different fields.

At HHMI's annual meetings, researchers from all areas—from neuroscience
to cancer and structural biology to plant science—present their latest
work for each other. Similarly, at Salk, weekly seminars and regular faculty
meetings bring together all scientists from across the Institution.
"It's great to be forced to go to meetings that really expand your
horizons," says Ecker, "because you really never know where your next idea
is going to come from."

Molecular and Cell Biology Laboratory, HHMI Early Career Scientist
2009–present

Reuben Shaw's group focuses on a molecule called LKB1 in human
cells. LKB1, an enzyme, adds phosphates to other proteins and affects
the metabolism of cells. Shaw has found links between the enzyme
and both cancer and diabetes. He is funded by HHMI through the
early career scientist program, which aims to jump-start the careers
of promising young scientists.

For Ecker, learning about fields outside Arabidopsis has paid off.
With the help of Salk and HHMI, his lab has successfully expanded and
collaborated to study stem cells, soybeans and even mice. Most recently, he collaborated with Terrence Sejnowski of Salk's Computational
Neurobiology Lab, who is also an HHMI investigator. Together, the team
used the methods that Ecker had developed in plants to study the chemical
marks on genes inside neurons in the brains of mice. Their results—which
show that the types of chemical marks change as neurons mature—is
paradigm-changing for the fields of epigenetics and brain development.
Tom Insel, director of the National Institute of Mental Health, named the
discovery one of the ten most important of 2013.

Carl Rhodes, a senior scientific officer at HHMI, says the unlikely
pairing of a computational neurobiologist and a plant scientist-cumepigenomics
guru is precisely the kind of creative science HHMI seeks to
foster. "For us, it's a great story," he says, "because you've got two HHMI
investigators from very different areas of expertise coming together to
tackle a problem from a totally new angle."

The study, Ecker says, wouldn't have progressed as fast or efficiently
if the team hadn't been able to turn to its HHMI funding to support
the project.

"A lot of the science that becomes most informative is science that's on
the edge of disciplines," he says. "But the flexibility to work across disciplines
is very difficult because of the way our federal grant system works."
At both Salk and HHMI, however, such cross-disciplinary studies and
collaborations are encouraged. By putting top-notch researchers in proximity
to each other, letting them share ideas and giving them the space and
resources to follow up on their ideas, both institutions help foster the kind
of science that changes the way people think about the world. Whether
a discovery revolves around how the brain works, how plants grow or how
genes are regulated, the HHMI-supported researchers at Salk are changing
the way we think.

"HHMI and Salk have a shared culture and a shared concept as to what
the goal is, which is great science and great truths in advancing different
tiers of knowledge for the benefit of mankind," says Pfaff. "Salk aggregates
the people within the actual structure itself; Hughes creates a structure
that distributes the people in different environments. So it's actually very
nice to get the benefit of both. It's a very special thing for those of us who
are here and who are embedded in the HHMI system."