Inside Salk; Salk Insitute

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."

From left: Joseph Noel, Joseph Ecker, Reuben Shaw, Ronald Evans, Terrence Sejnowski, Samuel Pfaff and Joanne Chory

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

Joanne Chory

Plant Molecular and Cellular Biology Laboratory, HHMI Investigator 1997–present

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.

Joseph Ecker

Joseph Ecker

Plant Molecular and Cellular Biology Laboratory, HHMI Investigator 2011-present

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.

Ronald Evans

Ronald Evans

Gene Expression Laboratory, HHMI Investigator 1985–present

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.

Joseph Noel

Joseph Noel

Jack H. Skirball Center for Chemical Biology and Proteomics, HHMI Investigator 2005–present

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.

Samuel Pfaff

Samuel Pfaff

Gene Expression Laboratory, HHMI Investigator 2008–present

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.

Terrence Sejnowski

Terrence Sejnowski

Computational Neurobiology Laboratory, HHMI Investigator 1991–present

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."

Reuben Shaw

Reuben Shaw

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."