Salk Institute for Biological Studies: InsideSalk

Celebrating 50 Years of Scientific Discovery – The Salk Way

In the Beginning
Salk History

From left to right: Jacques Monod, Gerald Edelman, Melvin Cohn, Leslie Orgel, Robert Holley, Jacob Bronowski, Frederic de Hoffmann, Salvador Luria, Paul Berg, Edwin Lennox, Roger Guillemin

Jonas Salk may not have been fully prepared for the level of instant fame and adulation he received after a much-anticipated press conference in Ann Arbor, Michigan, on April 12, 1955.

The announcement that the polio vaccine he and a team of researchers developed in a Pittsburgh laboratory was deemed safe and effective for humans led to a tsunami of international recognition, including an invitation to the White House and an offer for a ticker-tape parade.

Though Salk and his family proudly attended the White House ceremony where President Dwight Eisenhower thanked him on behalf of the American people, to the amazement of many, he graciously turned down a flashy parade (suggesting the money be used for student scholarships instead). Even more memorably, Salk chose not to patent and profit from the polio vaccine that would protect millions of people.

It would not be the first time Salk's way of thinking appeared unusual – or even provocative. Much like his strategy for developing the polio vaccine, Salk's penchant for addressing and solving problems through unconventional approaches would influence what he was envisioning next: a revered research enclave where some of the world's brightest minds in biological science could freely explore their curiosity in a collaborative and unfettered environment for the benefit of human health.

His vision became a reality in 1960 when Salk – together with a small group of elite scientists ("founding fellows"), seed funding from the March of Dimes, and a gift of 27 acres from the city of San Diego – established the Salk Institute for Biological Studies. He commissioned American architect Louis Kahn, challenging him to design "a facility worthy of a visit by Pablo Picasso."

Completed in 1965 and designated a National Historic Landmark in 1991, the mirror-image laboratory buildings flanked by a sweeping courtyard overlooking the Pacific Ocean is considered among the world's boldest structures by architectural critics. Incorporated in its innovative design was a visionary flexibility that has allowed the interior research space to adapt to five decades of scientific advances.

It is apparent today, as we celebrate the Salk's 50th anniversary, that the brilliant result of the Salk-Kahn partnership is an extraordinary structure that can withstand and can be molded to the evolving conditions required for discovery.

Populating the Temple of Science
Mel Cohn

Melvin Cohn

While basic research has always been at the core of the Institute, Salk envisioned unorthodox collaborations as an approach to solve both biological and social problems. In addition to recruiting several leading scientists in the early years, such as virologist and Nobel laureate Renato Dulbecco, physicist Edwin Lennox and immunologist Melvin Cohn, Salk also brought on mathematician and humanist Jacob Bronowski.

Other high-profile collaborators included founding non-resident fellows such as Nobel laureates Francis Crick and Jacques Monod, and Leo Szilard, the physicist who planted the seed for the creation of the Manhattan Project.

"He really wanted to engage people with multidisciplinary backgrounds," says Salk's son, Peter, who conducted research in his father's lab from 1972-1984. "He was looking for people who were broad in their thinking, comfortable with interdisciplinary work, and taken with the idea of creating an environment where you could relate to individuals on your own level."

Jonas Salk was always inclined to consider the broader implications of his experiments, Peter recalls.

"He applied this way of thinking to his strong interest in human interactions and to the development of the idea for the Institute. I know he saw the Institute from the beginning as an experiment," he says. "And he spent the next several decades as a participant in, and an observer of, that experiment."

Freedom to Think

There was no question that the Salk Institute offered researchers a unique opportunity, says Cohn, a founding fellow who still conducts research in the Conceptual Immunology Group. "Jonas had a vision for the Institute, and it really inspired the way people thought of it," he says.

What the Institute provided Cohn and the others was the freedom to think and explore some of the most profound questions about life's basic principles – a model that still defines the Salk 50 years later.

In those days, science in the United States was, and still is, largely accomplished at research-intensive universities. Although he had the security of tenure at the Pasteur Institute in Paris and obtaining grants wasn't an issue, Cohn, like Lennox, had grown tired of splitting his efforts between teaching and conducting research. Prior to arriving to the Institute in 1963, both had turned down appointments at Harvard, Cohn says.

"In order for us to leave that secure situation, we had to have something else we wanted to do. In that sense the Institute was special," he says. "Salk afforded us the freedom to think about the world. The theory was more important than the experimental, although Renato preferred working in the lab, but it was certainly true of Ed Lennox and myself – and especially a year later when [Chemical Evolution Lab Director] Leslie Orgel came to Salk."

After his arrival, Cohn worked on developing new methodologies of science. Bronowski brought with him eminent philosophers like Karl Popper, with whom Cohn engaged in conversations to address such problems. Szilard was interested in both the mechanisms of memory, and the regulation and limitations on use of the atomic bomb.

Lennox's interests were in the practical applications of science, while Dulbecco and Salk worked in the laboratory conducting research with more immediate missions, seeking treatments for cancer and multiple sclerosis. Bronowski, it turned out, was a master at communicating science, which he did extensively in the community and through his internationally acclaimed BBC television series, The Ascent of Man. He developed much of the material for the series through the many conversations he had with scientists at the Salk Institute, Cohn says.

"We were an interactive group. It wasn't enough that we had some of the world's most creative minds here," he says. "Those creative minds had to interact with one another. So we would meet often to talk about our respective scientific problems and interact experimentally, too."

Collaboration extended into the decision-making process developed by Salk to include three governing bodies: the fellows, the non-resident fellows and the administration.

This organizational and functional model proved essential in the late 1960s when the fellows were discussing ways to expand the Institute's scientific research program. After meetings with the non-resident fellows, it was clear that adding studies in neurobiology was key to the Institute's future – mostly because it offered the strongest opportunities for collaboration with existing scientists at the Institute.

"We really wanted to develop the Institute step-by-step, so in speaking with the non-resident fellows, we specifically agreed that we needed someone who studied the hypothalamus," Cohn says. "This is how we brought [Nobel laureate] Roger Guillemin to the Salk."

Early Discoveries in Neuroscience
Jonas Salk and Roger Guillemin

Jonas Salk and Roger Guillemin

Guillemin was making a name for himself at Baylor College of Medicine after he and his group had successfully isolated brain molecules that scientists were previously unaware even existed. Although he was not particularly eager to uproot his young family from Houston, Guillemin says the opportunity to continue his work at the Salk was impossible to pass up after his first visit in 1969.

"I'll never forget walking through the eucalyptus grove for the first time and seeing this extraordinary place," Guillemin says. "I'm still moved today by what I saw. I thought, 'My God, whatever the offer is, I'll say yes.' My initial meeting took place when the non-resident fellows were here. I was impressed. Jacques Monod, Francis Crick, Salvadore Luria, Bob Holley – I've never seen so many Nobel laureates in my vicinity. It was extraordinary."

Starting in 1970, Guillemin spent the next 20 years as the head of the Laboratories for Neuroendocrinology, where he and his group went on to discover an entire class of neurohormones found to be important for the regulation of growth, development, reproduction and responses to stress. Analogs of somatostatin, one of the brain hormones first identified by Guillemin's lab in 1973, today are used to treat tumors of the pituitary gland and gastrointestinal tract. He received the Nobel Prize for this work in 1977.

Over the decades, new labs have been added to the Institute in appropriately organic fashion as research interests expanded. Today, studies in neuroscience at the Salk Institute, for example, are conducted in nine broad areas of research by at least 24 laboratories – all of which have contributed major discoveries to better understand, and in many cases treat, human disease. Former Guillemin lab members Wylie Vale, who in 1978 formed the Laboratories for Peptide Biology with Jean Rivier and his wife, Salk investigator Catherine Rivier, characterized the corticotropin-releasing hormone (CRF) and ultimately three related hormones, which mediate and regulate the responses to stressors impacting the cardiovascular, gastrointestinal and central nervous systems.

Proof of principle studies using receptor blockers of CRF developed by Jean Rivier and Vale, together with the cloning of the CRF receptor by Vale's group, have led to the development of novel drugs currently being tested to treat major depressive disorder and heart disease.

The Guillemin and Vale/Rivier groups discovered several novel hormones, growth factors and their receptors involved in reproduction and development. Variants of these molecules have lead to the development and clinical testing of treatments for reproductive disorders, including precocious puberty, infertility and endometriosis.

Molecular Neurobiology firmly took root at the Salk in the early '70s, but the '80s and '90s marked the blossoming of Systems Neuroscience. Neurobiologists William Maxwell "Max" Cowan, Floyd Bloom and Francis Crick were among the scientists who helped pave the way for this area of research at the Institute.

Tom Albright Terry Sejnowski

Tom Albright Terry Sejnowski

Cowan had a long association with the Salk – first as a non-resident fellow starting in 1974, along with renowned neurophysiologist Stephen Kuffler, and later as a professor beginning in 1980 when he brought with him a few young promising scientists, including Dennis O'Leary and Paul Sawchenko. Both still conduct research as professors at the Institute.

Cowan later hired Simon LeVay, a British neuroscientist who was an early researcher of the visual system as a means to understand brain function. As Cowan left the Institute in 1986 (eventually to lead the Howard Hughes Medical Institute as Vice President and Chief Scientific Officer), Thomas Albright joined the Salk in 1987 as a young neuroscientist/physiologist whose lab focused on the visual system and cognition.

At the same time, Crick – a strong supporter of Systems Neurobiology and its role to someday help answer some of the bigger questions regarding behavior and cognition – successfully recruited computational neurobiologist Terry Sejnowski in 1989.

Between 1994 and 2000, Albright and Sejnowski brought on board several new assistant professors, each working in a particular area that complements the rest. They include Ed Callaway, E. J. Chichilnisky, Sascha du Lac, Richard Krauzlis, John Reynolds and Geoff Boynton.

Last year, the group launched the Salk Institute Center for Neurobiology of Vision with a $3.8 million grant from the National Eye Institute of the National Institutes of Health. The designation placed the Salk as one of seven NEI centers focused exclusively on the basic research of vision, and understanding that mysterious eye-brain connection.

"I think one of the great features that makes this program so successful is that we've got people coming at the same problem from different directions," Albright explains. "It's worked very well because we chose the right people and there isn't any redundancy.

"Researchers in the Vision Center use anatomy, physiology and behavioral analysis to understand the many stages of visual processing, the plasticity of those stages, and the ways they interact with systems for memory and motor control. And then you have Terry, who is a great computational modeler," he says. "All of these areas ultimately confront questions of mechanism. And one of the most powerful ways of addressing mechanism is through computational modeling."

Credited with pioneering the field of Computational Neuroscience, Sejnowski's lab today is staffed by an eclectic team– with backgrounds in mathematics, electrical engineering, physics, and even philosophy – that aims to learn how the brain works.

His Computational Neurobiology Laboratory uses computer models based on physiological experiments to make predictions that call for additional experiments to test the model. To date, his group has contributed major breakthroughs in understanding how the brain works and developed powerful algorithms that are used in industry.

Today, the Salk Institute's Neuroscience research program consistently ranks among the top in the world. Last summer, it garnered the top discovery spot in the latest international ranking in the "Neuroscience and Behavior" category by Science Watch, a scientific organization that measures the citation impact of research published worldwide.

"Not only was the Institute properly started, but it has evolved in the right ways," Guillemin observes.

A New Operating Model
Salk History

Walter Eckhart, Inder Verma and Tony Hunter

The Institute fine-tuned its research focus soon after Frederic de Hoffmann came on board, first as chancellor in 1970 before his appointment as president in 1972. Less emphasis was placed on the humanities with the passing of Bronowski while greater efforts were focused on hard-core basic research. This opened the door to additional funding, which the Institute was in great need of at the time, while providing the opportunity to hire bright young researchers.

Under de Hoffman's leadership (1970-1988), the Salk Institute flourished in a new way. An extremely well-connected mathematician/ physicist and businessman, de Hoffmann proved to be a strong administrator. The Institute's annual budget grew from $4.5 million to $33 million during his 18-year tenure.

Many longtime relationships with individuals and private foundations were forged during this time, the latter reinforced in part by the Salk hosted tax seminar he created for foundations – now in its 38th year. He also formed the Salk's International Council consisting of worldwide leaders in business and industry who serve as Salk ambassadors.

In 1970 the Institute adopted an academic system to make several junior faculty appointments, beginning with Walter Eckhart (Molecular and Cell Biology), Stephen Heinemann (Molecular Neurobiology), Suzanne Bourgeois (Regulatory Biology), David Schubert (Cellular Neurobiology) and Ursula Bellugi (Cognitive Neuroscience). Most are still conducting research at the Institute, while all maintain a presence here.

Marguerite Vogt, a longtime Dulbecco collaborator who was also among the faculty appointees, was widely admired for being an influential mentor to younger scientists for more than 40 years at the Salk. Today, faculty promotions are independently approved by the resident faculty and the non-resident fellows to ensure the highest quality among its professors.

After the first appointments, Bourgeois and Eckhart, in particular, were tasked to recruit new members to the faculty. Bourgeois, who contributed early work on regulatory protein-DNA interaction and founded the Regulatory Biology Laboratory at the Salk, was also instrumental in bringing several female scientists to the Institute, including Professors Kathy Jones and Beverly Emerson in 1986.

Marc Montminy (Laboratories for Peptide Biology), who uncovered a family of genes that act as metabolic switches, joined the Institute that same year, while Greg Lemke (Molecular Neurobiology), who studies a group of cellular receptors associated with the immune system, joined one year earlier.

Eckhart's role expanded soon after Dulbecco, in whose lab he worked as a post-doc between 1965-1970, briefly left the Institute in 1972 (after making his landmark discovery that demonstrated how tumor viruses could induce cancer).

"After Renato left, [Nobel Laureate and Resident Fellow] Robert Holley submitted our first grant application to the National Cancer Institute (NCI), which provide core funding for us," Eckhart says. "That was essentially the start of the Cancer Research Center at the Salk."

Eckhart directed the Center for 32 years before handing over the reins to Tony Hunter, whom Eckhart recruited to the Institute in 1975. Today, 29 principal investigators, supported by more than 160 post-docs and 70 graduate students, are part of the Salk's NCI-designated Cancer Center.

Key recruitments by Eckhart followed throughout the 1970s, most notably Ron Evans (Gene Expression Lab), Geoff Wahl (Gene Expression Lab), and Inder Verma (Laboratory of Genetics). Each of them made seminal discoveries in cancer research and have since gone on to contribute major findings related to diabetes and metabolism, stem cell research and gene therapy.

This core group of scientists primarily conducted their work in what was then called the Tumor Virology Laboratory. As the Cancer Center grew, the programs broadened to include various areas of molecular, cell and developmental biology.

Hunter and Eckhart discovered tyrosine phosphorylation, a biological process that can trigger the uncontrolled cell growth that leads to cancer. Hunter and Bart Sefton, another early member of the Center, carried the observation further. The discovery later served as the foundation for the development of drugs that today are used to treat leukemia and lung cancer.

Evans began his research on nuclear hormone receptors, which led to his discovery of a large family of receptors that respond to steroids, making them primary targets for treating diseases ranging from cancer to asthma. Wahl demonstrated the role of the p53 gene as a key mechanism in the genetic instability that is a precursor to cancer.

Ron Evans and Fred H. Gage

Ron Evans and Fred H. Gage

In later years, Heinemann isolated and cloned the gene for a glutamate receptor that plays a key role in memory and learning, brain damage, and a range of neurodegenerative diseases. Bellugi discovered that the left hemisphere of the brain is specialized for processing language, including the visual modality of sign language. And Fred H. Gage (Laboratory of Genetics), who joined the Salk in 1995, showed that, contrary to scientific dogma, human beings are capable of growing new nerve cells in the brain throughout life.

Verma, who identified several cancer-causing genes, remembers there were about 20 faculty members in total when he arrived to the Salk in 1974. The South Building was still practically empty except for a couple of labs on the bottom floor, some administrative offices in the middle floor, and a ping-pong and billiards table on the top floor, where they also had a pottery-making area with a kiln. But the environment on campus was the same as Jonas Salk had first envisioned.

"The atmosphere was complete freedom to do whatever you wanted," explains Verma, whose revolutionary gene therapy technology was recently used to successfully arrest a fatal genetic brain disorder in two Spanish boys. "We had no teaching responsibilities or committees to run. My sole job was to park the car and come in. All we did was explore and just do science."

Studying DNA Shared by Plants, Humans

Joanne Chory and John Young

Joanne Chory and John Young

The 1990s also saw the growth of an infectious disease program, which evolved into the Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, headed by Professor John A. T. Young. The Center also includes Salk's newest recruits Ye Zheng and Björn Lillemeier, both assistant professors.

Structural Biology also grew in prominence with the addition of Professors Senyon Choe and Joseph Noel, as did Developmental Biology with the arrivals of Professors Juan Carlos Izpisúa Belmonte, Kuo-Fen Lee and Samuel Pfaff.

De Hoffmann was mainly responsible for establishing the Plant Molecular and Cellular Biology Laboratory at the Institute when he hired the program's first scientist in 1983, Chris Lamb.

"Chris had the vision for the program, and he was willing to take the risk on [plant lab model] Arabidopsis really taking off," says Joanne Chory, professor and director of the Plant Biology Lab, who joined the Institute in 1988. "But what changed in the mid-'80s was that molecular biology and plant transformation revolutionized plant biology. By then, the first Arabidopsis transgenic plants were made, which allowed scientists to think about a whole different kind of experiment because we could now manipulate genes."

Since its founding, that lab has made several seminal discoveries related to genetic adaptation, flowering time and the mechanisms that control how plants perceive and respond to changes in their environment. Today, the Salk Institute is widely recognized as having one of the world's leading plant biology laboratories.

And collaborations aren't confined to the green house. In what is perhaps the best example of Jonas Salk's vision for unconventional interaction, plant biologists are actively working with scientists conducting research with mammalian cells.

"The biology that's carried out by plants can have a direct impact on understanding human biology because many genes and proteins in plants and people are very similar," says Joe Ecker, a professor in Salk's Plant Biology Lab whose lab developed methods that use powerful highthroughput DNA sequencing technology for studying how the genomes of plants and people are regulated. "If I can understand the function of a particular molecular protein in plants, for example, it probably does the same thing in people."

Ecker's sequencing technology is now being applied to understand the dynamics of the human genome, and is providing greater insight into human stem cells' capacity to self-renew and how the epigenome, the mechanisms that control our DNA, contribute to the development of tumors and disease.

The technology has led to additional collaborations with Evans' lab, which is studying protein-DNA interactions and the epigenome in fat stem cells, and Satchin Panda's lab, which is researching how the circadian clock affects the epigenome and gene expression.

Over the last 10 years, Institute leaders made the strategic decision to strengthen the cell biology program and recruited a strong group of young scientists with varied, but complementary, research backgrounds.

Vicki Lundblad and Jan Karlseder each study telomeres and cellular replication. Martin Hetzer focuses on nuclear assembly, while Reuben Shaw studies tumor suppression and gene function. Andy Dillin, director of Salk's Glenn Center for Aging Research, and his team are providing new clues about the aging process and neurodegenerative diseases such as Alzheimer's and Parkinson's.

Other young recruits in the last decade include Leanne Jones (stem cell research); Clodagh O'Shea (adenovirus transformation mechanisms); Satchidananda "Satchin" Panda (circadian rhythms); and Lei Wang (chemical biology).

'Genome-Enabled Science'

After returning to the Institute, Renato Dulbecco made a wise proposal when he suggested in a 1986 Science article that in order to fully understand human disease, it would be necessary to sequence the human genome so that it could be compared to its diseased counterpart.

This set off the Human Genome Project four years later by an international group of scientists who completed the mammoth work in 2003. Ecker likens that discovery to Francis Crick and James Watson's elucidation of DNA's structure in 1953.

"The Genome Project was a sea change discovery. Salk's been around for 50 years, so for 43 years we've been doing non-genome-enabled science – meaning molecular biologists have studied just one gene at a time," Ecker says. "And that's been very profound and lots of great science has come out of the Salk.

"But now we've got all the genes in front of us and you have to ask, 'How are we going to use all that information?' We're at a point that if you don't consider all of the genes, you're probably not going to come up with the right answer," he says.

Finding those answers in today's era of scientific research will rely heavily on emerging technology, in which the Salk Institute is investing through several new initiatives – most notably the Waitt Advanced Biophotonics Center, launched in 2008 with a $20 million grant from the Waitt Family Foundation.

Setting aside the sophisticated microscopes and sequencing machines, scientists at Salk will continue to depend on their imagination and curiosity as the basis for a new era of scientific breakthroughs. It's what investigators at the Institute collectively regard as "The Salk Way."

"The Salk Way is not definable by a known criterion. It is not a recipe or potion that can be bottled and sold," Verma explains. "It is an atmosphere that is felt. It's a community of scholars who interact, thrive on each other's knowledge and good will, and are inspired to do cutting-edge research because of their curiosity to do something which others haven't done."

InsideSalk 04|10 Issue | © Salk Institute for Biological Studies