As a child growing up in a New Jersey suburb of Philadelphia, David Agard was constantly fascinated with learning how the world worked. "I was always either building things or taking them apart." In school, he first was attracted to physics. Then his interests switched to biology, which of course meant a good bit of chemistry. By the time he enrolled as an undergraduate in one of the country's first biophysics departments, Agard had sealed his fate as an innovator. "I've been at this intersection of physics, chemistry and biology ever since."

It is at that intersection that Agard, a UCSF professor of biochemistry and biophysics and Howard Hughes Medical Institute Investigator, has thrived. He is the driving force behind QB3, the Institute for Quantitative Biomedical Research, and serves as its scientific director. A first-of-its-kind endeavor, the institute is funded by both state and private funds and will be headquartered at UCSF's new Mission Bay campus. It was established to accelerate the integration of biology with physical, mathematical and engineering sciences so as to tackle highly complex biological problems.

The institute is a partnership between UCSF, UC Berkeley and UC Santa Cruz. Research done by members of QB3 will likely pave the way for the discovery of treatments and cures for some of the most intractable diseases, such as brain disorders, cancer, and diabetes. Agard says QB3 also promises to allow for the expansion of graduate programs, yield advances in instrumentation and the hiring of a significant number of new faculty members.

The integrative spirit of QB3 is one that mirrors Agard's own research style, which — like many UCSF investigators — revolves around collaboration. "We see that ramping up another order of magnitude." Agard says UCSF will benefit from both an expansion of faculty and graduate programs with respect to its participation in QB3. "It's just extraordinary."

In addition to the exciting future of QB3, Agard says the move will allow some of his own research initiatives to move forward. For example, he and his long-time collaborator, John Sedat, received a large grant from the Keck Foundation to develop a new generation of microscopes, but have yet to begin the work. "We simply don't have the space to do it. Period." Made up of about 20 people, Agard's lab is expected to be moving into the Genentech building in February.

Making QB3 a reality has consumed much of Agard's time for the last two and a half years. So, when he is asked about his hobbies and answers simply "QB3," no one laughs. The enormity and ambition of the project speak for themselves. With the hiring of Marv Cassman as administrative director for QB3, Agard hopes to have more time for hobbies, including woodworking, snow skiing and hiking. In the past, he and his wife, Lisa McConlogue, have enjoyed taking Lindy hop and West Coast Swing lessons -- along with healthy doses of practice at local venues. "I'm really looking forward to doing more dancing with my wife," he says.

Partners in science
Agard grew up in Cherry Hill, New Jersey. He earned his undergraduate degree in biophysics from Yale University. He then did his doctoral studies at CalTech before moving to England for postdoctoral work. In 1983, he joined the faculty at UCSF.

Since then, Agard has been collaborating with John Sedat, professor of biochemistry. It is a collaboration that is better described as a partnership, one that began with the ambitious intention of bringing different disciplines to bear on biological problems. "This is an extremely hard field that no one in the world has tried," Sedat says. " We're just starting to reap the benefits that we sewed so many years ago."

Sedat says that recent advances in computer and other technologies have made all the difference. "We can finally do what we set out to do." Of course, when the technology doesn't exist, Sedat, Agard and their colleagues set out to create it. For example, to advance their studies of chromosome structure, the two labs worked together to create a new kind of electron microscope that used computers, software and mathematical algorithms to create three-dimensional images. "Before us, people were using film."

After 20 years, Sedat says working with Agard remains a pleasant and productive experience. "These days science is very broad based: some ideas are good and some are not. Dave is good at listening and giving feedback in terms of saying 'That's a nice idea and this part is not so good.' That ability is what makes a particular concept work."

How things work
In general, Agard's work has focused on the structure and function of proteins or large cellular complexes. He not only looks at what makes up a protein, but at how the protein comes to take its final shape. Recently, his findings shattered a long-held myth that all proteins fold spontaneously into their most "relaxed" position, or their lowest energy states. Looking at an enzyme that breaks down nutrients for bacteria in the soil, called alpha-lytic protease, Agard and his team discovered a novel folding method that makes the protease 100 times more resistant to attack than other digestive enzymes or other conventional proteins.

"A lot of our work is aimed at trying to understand the molecular basis of biological function," Agard explains. At the cellular level, he has been particularly interested in the mechanism by which the centrosome -- the large organelle responsible for making microtubules -- governs the assembly of the cytoskeleton, the cell's internal frame made up of a network of these microtubules. These studies combine three-dimensional computer reconstruction using electron microscopy with X-ray crystallography, as well as biochemical and functional analyses. The long-term goal, Agard says, is to get an atom-level picture of what goes on during construction of a cell's cytoskeleton.

Though much of his work focuses on basic science, Agard's findings have already begun to guide the study of molecules and cellular structures implicated in human disease. For example, he and his collaborators are taking a close look at the estrogen receptor. Their findings have the potential to inform drug development and discovery for breast cancer and for other cancers, as well. That's because an understanding of the function of receptors will reveal, at the molecular level, how drugs are interacting with their target molecules. Agard considers it a challenge that scientists do not understand the basic mechanisms behind many of the drugs in use today. "By understanding exactly how these drugs work, then one can start to think about how to design even better compounds."

Source: Camille Mojica Rey

Last updated January 28, 2005

David Agard

David Agard, professor of biochemistry and biophysics and scientific director of QB3, specializes in the structure and function of proteins and has co-developed an advanced electron microscope for that purpose. Photos by Christine Jegan.

David Agard