Architect of the Future: Refocusing On Basic Research

Mon, 11/20/2006 - 6:58am

Dr. Gerald Rubin is a researcher who works to understand the genomic structure of the Drosophila melanogaster, or common fruit fly. Rubin is also Vice President and Director of the Janelia Farm Research Campus (JFRC), the recently opened research facility of the Howard Hughes Medical Institute (HHMI), Chevy Chase, Md. Following six years of intense design, planning, and construction of a very unique laboratory structure and organization, the JFRC staff are now ready to get on with the real business of research into their two chosen life science disciplines—neuroscience and microscopy/imaging.

But to say that JFRC is unique is like saying that the Empire State Building is just another skyscraper. JFRC is definitely a unique facility, but so too is the HHMI organization and their collection of investigators, and so too is the organizational infrastructure that has been established for the JFRC, and the staff that are beginning to populate this modern facility in Ashburn, Va. It has taken a very unique individual to pull all of this together in a seamless and successful manner—and that person is R&D Magazine’s 41st Scientist of the Year, Dr. Gerald Rubin.

To create, develop, and implement a totally new basic research facility of the size and scope that the JFRC is, takes someone who has a good understanding and experience in the basic research process—what works and what doesn’t. Enter Rubin with his background at one of the leading basic research organizations in Europe—the Medical Research Council (MRC), his experience in leading edge genomic science, and his knowledge of the HHMI overall infrastructure—he’s been a HHMI investigator since 1987.

Professor David Haussler at the Univ. of California, Santa Cruz, himself an HHMI Investigator and R&D Magazine’s 2001 Scientist of the Year describes Rubin a little more succinctly, “Gerry is a hard-nosed visionary. A rare breed. Both eminently practical, realistic, no nonsense, get the job done, but also way ahead in his vision. He is tireless. Janelia Farm was a big gamble, but he’ll pull it off.”

Getting started

Dr. Gerald Rubin, Vice President and Director,
Janelia Farm Research Campus,
Howard Hughes Medical Institute, Ashburn, Va.

• BS, Biology, Massachusetts Institute of Technology, Cambridge
• PhD, Molecular Biology, Univ. of Cambridge, UK
• Postdoctoral Fellow, Dept. of Biochemistry, Stanford Univ. School of Medicine, Calif.

• Assistant Prof. of Biological Chemistry, Sidney Farber Cancer Institute, Harvard Medical School, Boston
• Instructor, Embryology course, Marine Biology Laboratory, Woods Hole, Mass.
• Staff Member, Carnegie Institution of Washington, Dept. of Embryology, Baltimore, Md.
• John D. MacArthur Professor of Genetics, Dept. of Molecular & Cell Biology, Univ. of California, Berkeley
• Head, Div. of Genetics, Dept. of Molecular & Cellular Biology, Univ. of California, Berkeley
• Investigator, Howard Hughes Medical Institute
• Adjunct Prof., Dept. of Biochemistry & Biophysics, Univ. of California School of Medicine, San Francisco
• Associate Faculty Member of the Cell & Molecular Biology Div., Lawrence Berkeley National Laboratory, Calif.
• Director, Drosophila Genome Center, Univ. of California, Berkeley
• Prof. of Genetics, Dept. of Molecular & Cell Biology, Univ. of California, Berkeley
• VP for Biomedical Research, Howard Hughes Medical Institute
• VP and Director of Planning, Janelia Farm Research Campus, Howard Hughes Medical Institute

• Member, Scientific Advisory Board, Athena Neuroscience, Inc.
• Member, Scientific Advisory Board, Tularik, Inc.
• Co-Founder and Chair of the Scientific Advisory Board, Exelixis Pharmaceuticals, Inc.

• Phi Beta Kappa
• Phi Lambda Epsilon
• National Science Foundation, predoctoral Fellow
• United States Churchill Foundation Fellow
• Helen Hay Whitney Foundation Fellow
• Co-winner, Passano Foundation Young Scientist Award
• Co-winner, American Association for the Advancement of Science Newcomb Cleveland prize
• American Chemical Society Eli Lilly Award in
Biological Chemistry
• Co-winner, National Academy of Sciences U.S. Steel Foundation Award in Molecular Biology
• Genetics Society of America Medical
• Member, National Academy of Sciences
• Fellow, American Association for the Advancement of Science
• Fellow, American Academy of Arts and Sciences
• Fellow, American Academy of Microbiology
• Howard Taylor Ricketts Award, Univ. of Chicago
• ScD, Univ. of Cambridge, UK
• Member, Institute of Medicine
• Co-winner, George W. Beadle Award of the Genetics
Society of America

Rubin was born in Boston, Mass., in 1950 to a school teacher mother and an electrician father. Considered an underachiever in elementary school, he blossomed in junior high school and was accepted to the selective Boston Latin School where he excelled, doing extracurricular work in a cancer research laboratory at Massachusetts General Hospital, Boston. Planning to major in chemistry at the Massachusetts Institute of Technology (MIT), Cambridge, Rubin quickly found that biology was more to his liking, especially after taking a biology course with Nobel laureate Salvador Luria. Working summers at the Cold Spring Harbor Laboratory in N.Y., also gave him a taste of experimental science.

After receiving a BS in biology at MIT, Rubin received scholarships to the Laboratory of Molecular Biology at the Medical Research Council (MRC) at the Univ. of Cambridge in the UK where he received his PhD in 1974. Rubin’s doctoral thesis was “Studies on a 5.8 S Ribosomal RNA” in which he sequenced yeast RNA made up of 158 bases. This sequencing work took Rubin about two years to accomplish a little over 30 years ago, something which now can be accomplished by automated instruments in about a second, which still amazes him.Rubin’s tenure at the MRC-LMB was at the same time that a number of bioscience luminaries were there, such as Sydney Brenner, James Watson, Francis Crick (of the double-helix discoverers Watson and Crick), Fred Sanger, and Max Perutz. “My time at the MRC was a tremendous experience,” says Rubin, “here were all the role models that I had heard about.”

Following his tenure at the MRC, Rubin did post-doctoral work as a Helen Hay Whitney Foundation Fellow in Prof. David Hogness’s biochemistry laboratory at Stanford Univ., Calif. “My post-doc work was just at the beginning of the era of genomic analysis and learning what to do with it,” he says. His work in Hogness’s lab got him started on working with fruit fly genomes, where his initial project was to compile the first library large enough to represent the fruit fly’s entire genome.

From Stanford, Rubin did a stint as an assistant professor of biological chemistry in the Sidney Farber Cancer Institute at Harvard Medical School, Boston, followed by an appointment as a staff member in the Dept. of Embryology at the Carnegie Institution of Washington, Baltimore, Md. In 1982, while at the Carnegie Institution, Rubin collaborated with developmental biologist Allan Spradling to insert foreign genes into the embryos of multicellular organisms—creating transgenic Drosophila—and revealed that the genes were expressed in the cells of the adult. This was the first successful germ-line genetic engineering of a multicellular animal and was published in Science with numerous citings. “This was my greatest personal accomplishment as a scientist,” says Rubin.

Following some heavy negotiating, Daniel Koshland, a biochemist at the Univ. of California, Berkeley, convinced Rubin to switch coasts and he accepted a position as the John D. MacArthur Professor of Genetics in the Dept. of Molecular & Cell Biology at UC-Berkeley in 1983. In 1987, Rubin became Head of the Division of Genetics at UC-Berkeley, while also becoming an HHMI Investigator, and accepting a position as an Adjunct Professor in the Dept. of Biochemistry & Biophysics at the Univ. of California School of Medicine, San Francisco—a position he still holds.

J. Craig Venter, R&D Magazine’s 1998 Scientist of the Year, and head of Celera Genomics, Rockville, Md., approached Rubin in 1998 to collaborate with him to sequence the Drosophila genome as practice for the human genome sequencing effort that was going on at that time—with ‘friendly’ competitor Francis Collins at the National Institutes of Health. After some deliberation as to the ethics of this collaboration, Rubin agreed to work with Venter which culminated in the March 2000 announcement of the nearly complete sequencing of the 120 million units of DNA contained in Drosophila’s five chromosomes. As a result of this work, Venter and Rubin, along with colleagues Mark Adams and Susan Celniker received the American Association for the Advancement of Science (AAAS) Newcomb Cleveland Prize.

Also along the way, Rubin accepted a position as Associate Faculty Member of the Cell & Molecular Biology Div., of the Dept. of Energy’s Lawrence Berkeley National Laboratory, Calif., and Director of the Drosophila Genome Center at UC-Berkeley. Rubin stayed at his professor position at UC-Berkeley until 2000, when he accepted a position at the Howard Hughes Medical Institute as the VP of Biomedical Research, paving the way for Rubin’s involvement in the Janelia Farm project.

Idealistic, but Effective
The Janelia Farm Research Campus led by R&D Magazine’s 2006 Scientist of the Year Dr. Gerald Rubin complements the flagship investigator program of the Howard Hughes Medical Institute (HHMI), Chevy Chase, Md. The more than 300 HHMI current investigators are widely recognized for their creativity and productivity. They carry out their research on the campuses of universities and other research organizations throughout the U.S. R&D Magazine’s 2001 Scientist of the Year David Haussler from the Univ. of California, Santa Cruz, considered being accepted as an HHMI Investigator one of his greatest accomplishments.

HHMI is a non-profit medical research organization with an endowment of approximately $14.8 billion (2005). The Institute has awarded more than $1 billion since 1988. Founded in 1953 by aviation pioneer Howard R. Hughes, the Institute was to be committed to basic research, to probe the genesis of life. While his other endeavors have faded, HHMI stands at Hughes’ most enduring accomplishment. A group of trustees assumed responsibility for the Institute in 1984 and reaffirmed its primary purpose of medical research.

HHMI carries out its charter with its own scientific teams, who can also serve as faculty members at their host institutions. Investigators are selected through a solicitation process and those selected are appointed for five- or seven-yr terms, which may be renewed. HHMI appoints scientists, rather than awarding grants, thus providing outstanding researchers with the resources and flexibility to follow their own scientific paths and not be limited by a rigid framework (or paperwork). The institute will consider unsolicited proposals to its programs, but it rarely funds them. It does not make grant awards for investigator-initiated research.

HHMI has a series of programs in addition to its investigator awards. Its HHMI-NIH (National Institutes of Health) Research Scholars Program gives outstanding students at U.S. medical schools the opportunity to receive research training at the NIH in Bethesda, Md. Scholars spend nine months a year on the NIH campus, conducting basic, translational, or applied medical research under the direct mentorship of senior NIH researchers. HHMI provides the administration and funding for the program, including salaries and benefits.

HHMI also has an International Program that supports biomedical scientists outside the U.S. and provides funding for selected courses and workshops. Its Precollege Science Education Program supports a variety of precollege grants to biomedical research organizations to engage in community outreach to pre-kindergarten to 12th grade students and teachers.
The HHMI Undergraduate Biological Sciences Education Program provides grants to selected undergraduate institutions and to individuals through the HHMI investigators/professors.

At the Janelia Farm Research Campus, HHMI also offers a graduate program in partnership with the Univ. of Chicago and the Univ. of Cambridge, UK. Students can earn a PhD in four to five yr, after spending the first year at the Chicago or Cambridge campus and then completing their training at the Janelia Farm lab. This program has just begun with initial applications for 2007 due in mid-Dec. 2006.

Building Janelia
The idea of the Janelia Farm Research Campus began in 1999 in a discussion between HHMI President Thomas Cech, David Clayton, HHMI VP and Chief Scientific Officer, and Rubin about the ways that the HHMI could expand the boundaries of biomedical research. “The number of HHMI Investigators had grown from 127 when I first became an Investigator in 1987 to more than 300 when we talked,” says Rubin. These three scientists saw that to expand the HHMI charter beyond the pure funding aspect of individual investigators that a multidisciplinary, collaborative research environment needed to be developed that was free of the intellectual and financial dependence that traditional academic institutions created.

They sketched their initial vision on the back of a napkin in a Boulder, Colo., restaurant, and it evolved into what would become JFRC. Their final vision became the development of an independent research lab staffed with the equivalent of HHMI Investigators, but investigators who did not have the umbilical cords to their host facilities and, as a result, were freer to work on their research. The Trustees of the HHMI approved their proposal and the purchase of the nearly 700-acre Janelia Farm property along the Potomac River in Loudon County, in Northern Virginia in 2000.

And through an international competition, Cech, Clayton, and Rubin choose architect Rafael Viñoly, whose vision for a campus structure matched their scientific vision. The JFRC would be a unique center where scientists from around the world could work collaboratively to create and exploit the new tools of biomedical science. When fully staffed (in 2008/9), JFRC would be able to house its own investigators and a permanent research staff of 300, as well as visiting researchers.

During the first several years, the group did a great deal of listening, evaluating, and synthesizing as to what physical, organizational, and research structure would work best. To facilitate this process, Rubin became VP and Director of Planning for JFRC in 2002, which was modified again to VP and Director of JFRC in 2003, the title he currently holds.

David Brown (left, corporate-sponsor Thomson Scientific), Scientist of the Year Dr. Gerald Rubin, and Tim Studt (right, R&D Magazine) at R&D’s awards banquet on October 19, 2006.

Implementing a vision
The physical structure of JFRC, while large, involved, and complex (overall cost was in excess of $500 million), was likely one of the easier issues for Rubin to solve, especially with the support of the Rafael Viñoly architectural and construction team and HHMI architect and senior facilities officer Robert McGhee and a host of other support staff. This is not to say that the overall guidance of the design, construction, and modification phases of the JFRC structure over the past six years were not time consuming and taxing, for they were. As with any construction project, each of its components has definitive start and complete aspects that can be addressed according to a written project schedule.

Of more long-term and ideological concern was the selection of the research direction, research structure, and physical staff, all of which fell also into Rubin’s area of responsibility and expertise. For starters, Rubin looked to the past as to what basic research facilities appeared to be the most productive, creative, and innovative. Rubin didn’t have to look very far for these answers, as he chose the structure of AT&T’s Bell Labs and the MRC to emulate for JFRC—their previous high-profile eras, not their current, somewhat attenuated forms.

Looking at these groups, Rubin found several overarching topics that created the research environment that he desired:
1. The creation of small research groups appeared to work best from an innovation standpoint. Bell Labs worked with groups of two to three researchers, while MRC worked with groups of four to six. In contrast the average HHMI Investigator has a group size of about 15.
2. Research was funded internally, eliminating the time required for writing grant proposals and requests. Outside grant applications were not permitted.
3. Select different and difficult problems to solve than what other groups were already working on. Originality, creativity, and collegiality were valued and supported at the Bell Labs and MRC facilities.
4. Provide a generous amount of support resources in terms of physical and infrastructure for the researchers.
5. Create an environment that allows the researchers to self-assemble into collaborative teams.
6. Ensure that the scientists become actively involved. Group leaders within the Bell Labs and MRC facilities were generally active bench scientists.

Unfortunately, no institutions in operation today, fully fit these descriptions. The funding mechanisms that supported Bell Labs in its heyday was destroyed in the breakup of the AT&T monopoly and the MRC collapsed from the imposition of tenure by the British civil service, as well as competition from the Wellcome Trust’s research laboratories. So building a basic research facility and infrastructure is by no means a guaranteed premise just because you and your management group have high ideals and goals.

“We definitely consider Janelia Farm to be an experiment in basic research,” says Rubin. He hopes to see ‘truly unanticipated discoveries’ starting to come out the JFRC labs in five to 10 years—results that might not have come to light in any other environment, other than Janelia Farm. That’s the kind of environment that will be the ultimate determiner of Janelia Farm’s success.

Choosing the scientific areas for JFRC to focus on was similarly difficult. “If it was on the NIH roadmap, we didn’t want it at Janelia Farm,” says Rubin. He didn’t feel that JFRC should compete for resources, people, or funds for the projects its scientists were working on. As a result, two specific technical areas were chosen as focus areas:

Basic neural science—How similar neural mechanisms are handled throughout all the different life forms. Areas like cell signaling, nervous system forms, and the like. “We’re trying to understand the basic biological rules that once invented, it’s used over and over again throughout the biological world,” he says.

Better optical imaging tools – This is a combination of imaging hardware, computational processing, and image processing tools that would benefit those researchers working in other areas, like basic neural science.

Once the technical areas were identified, Rubin’s personality came into play as he worked his charm to convince the world’s leading researchers to come and work in an experiment. This wasn’t as difficult as it might seem, he explained, in that there’s generally a small group, 10% to 20%, of the researchers that work in a certain area that would fit and want to work in an environment like the one being created at Janelia Farm. There are those who like the large support staffs that big academic facilities provide, and then there are those who are tired of the work involved in continuously applying for grants, just to do their job.

As of this writing, seven Janelia Farm Group Leaders have accepted positions at JFRC. They, along with their bios and background information can be found on the Janelia Farm Web site, Eric Betzig stands out as the typical researcher likely to walk the glass hallways of Janelia Farm. Betzig has a PhD in applied and engineering physics from Cornell, worked at Bell Labs, and then spent some time at his father’s machine tool company in Michigan. After a while, though, he became restless and went back to working on the development of microscopy systems for biomedical applications. He has filed a patent for his optical lattice microscopy and, as a new JFRC group leader, has already begun preliminary experiments to demonstrate new applications of his technique.

Betzig likes the mechanisms that Janelia Farm will have in place to take the tools that a physicist like he creates, and take it through the development phase to turn it into something that biologists are going to be able to use. “Ultimately, it comes down to impact,” he says. “You want to create instruments that are going to have an impact.”

Looking ahead
As the construction and validation turmoil concludes for the now officially opened and inaugurated Janelia Farm, Rubin expects to spend a little more time on bringing his Drosophila genetics work to bear on issues of gene expression regulation in the brain—Rubin is also a group leader within the JFRC complex and has his own lab.

He’ll obviously split this time with his main responsibilities in bringing the number of group leaders up to about 30 or so and making sure that things run smoothly. He’ll also continue his mentoring activities—“one of the major accomplishments in my career has been seeing that more than 50 of my former students and post-docs now run their own labs, with three chosen as HHMI investigators and two elected to the National Academies of Science.”

Building a Research Campus of the Future: Janelia Farm
From groundbreaking in November 2002, to the official opening on September 6, 2006, the Janelia Farm Research Campus (JFRC) of the Howard Hughes Medical Institute (HHMI) has been the focus of a great deal of attention from the scientific community. Located in rural Loudon County in Northern Virginia, the laboratory is the first privately-funded major basic research facility to be built from scratch in more than 25 years.

Designed by internationally renowned architect Rafael Viñoly, the first-of-its-kind 68,786 m2 JFRC features five acres of green roof and one of the world’s largest installations of structural glass. The campus includes a laboratory building, conference guest rooms, and apartments for visiting scientists, the structure, siting, and layout of which, match JFRC’s high scientific ideals.
Indeed, the architectural design of the buildings and laboratories are aimed at achieving JFRC’s central objectives—collaboration and flexibility. The facility was built to support a permanent research staff of 250 with another 100 visiting scientists, who, residing in their onsite apartments will be ensured of close integration within the permanent Janelia Farm research staff and community.

Everything about the facility itself reflects back upon the goals and vision of the research that will be performed there. “It is a building about nature. Nature is the centerpiece of research at Janelia Farm, and the building follows that idea,” said Rafael Viñoly at the groundbreaking ceremony. With nearly 700 acres of HHMI-owned wooded and meadow to work with, only 60 acres was actually developed, providing a natural heavily wooded (with extensive animal populations) buffer zone to the outside urban community.

Janelia’s 16,723 m2 rooftop is planted with large swaths of indigenous grasses making it the second largest green roof in the U.S. The green roof also retains 95% of storm water minimizing site drainage into storm sewers. It’s also possible to walk along the top level of the roof, which seems like an extension of the meadow, without realizing that there are state-of-the-art research labs below. All of the trees that were cut on the site were also recycled—stumps and softwoods were ground into mulch and small trees and limbs were chipped for the waste-to-energy plant. Another 35,000 feet of hardwoods were milled into random-width plank flooring for the guest rooms and visitor housing.

With most of the JFRC below ground, that part of the structure that is exposed to the outside environment is done so through nearly 13,935 m2 of structural glass that took about 85,000-man-hr (or 41-man-yr) to install. The glass itself is international in nature, with most of it manufactured in Belgium, fabricated in Austria, and assembled in Albany, N.Y. and New Brunswick, Canada. The design pushed the limit of structural glass-production capabilities, with 60 custom dies manufactured for the aluminum extrusions that hold all of it together. The glass doors between rooms were also unique, being manufactured in Singapore and later assembled in California. Additionally, design validation of the entire structural glass component took a full year of independent testing. And when the glass walls and roof panels weren’t fully adequate, six large square atriums were dropped into the length of the structure to bring more natural light into the interior of the building.

Every structural component within the JFRC stressed its long-term basic research capabilities, including an allotment for future non-programmed space for scientific uses that have yet to be determined.

—Tim Studt


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