Quad Centennial Celebrates 100 Years of Science

The frontiers of sensory perception and cognition, the molecular conversations between microorganisms and host cells, and genomic strategies to understand cancer and develop new drugs were the subjects of the recent HMS centennial, celebrating the 1906 dedication of the newly built Quadrangle.

Three scientific symposia took account of 100 years of biomedical progress and looked ahead toward the next century of scientific discovery. The symposia featured HMS faculty and alumni discussing their latest work.

In the opening symposium on neuroscience, HMS dean Joseph Martin noted that four big questions drive the field: How do cells work together so the brain can function as it does? How can a brain be repaired or cured following injury or disease? What makes us different from one another? How do brains adapt to the changing world?

One telling feature of the amazing pace and growth of neuroscience in the last century is an audience filled with women and scholarly presentations evenly divided between genders, said Carla Shatz (right), chair of the HMS Department of Neurobiology, at the Quad centennial symposia. More than 300 people gathered to hear Michael Farzan (left) and other speakers during the three scientific programs.

Sensory neuroscience offers some clues. “Our problem is to understand how objects in the world are contacted and interpreted by specialized cells in organs and how [information] is processed by the brain,” said Rachel Wilson, HMS assistant professor of neurobiology. Wilson studies the olfactory circuit of fruit flies in hopes of understanding principles that also will apply to humans. Her observations suggest a model of cross-talk and amplified signals that enable the olfactory system to better differentiate among odors as information travels up to the brain, where it might activate behaviors to eat or flee or fight or mate.

Alum David Anderson, the Roger W. Sperry professor of biology at the California Institute of Technology, has literally bottled the smell of “fly fear” in experiments to understand the circuitry of how genes act to help the animal react and survive aversive stimuli. When given a choice, for example, fruit flies will avoid the test tube where other shaken flies have discharged a stress odorant. By combining the tools of systems neuroscience and molecular genetics, Anderson and collaborators Seymour Benzer of Caltech and Richard Axel of Columbia University have identified one component—carbon dioxide—and part of the sensory neuronal circuit necessary for the avoidance behavior. But another elusive component is also needed to activate the neurons.

Likewise, in hearing, key details of the transition between sensing and perceiving are evading persistent inquiry. Using laser tweezers, Howard Hughes investigator David Corey, HMS professor of neurobiology, and his colleagues can measure the tiny mechanical forces at the tips of finely tuned mouse hair cells, named for the bundle of stiff cilia that bend back and forth in unison at specific frequencies. The researchers have found that links between the tips of neighboring cilia can open and close calcium channels with sufficient force to turn the mechanical stimulus of a sound wave into an electrical signal recognizable by the brain. The protein that makes up the channel itself remains a mystery.

In zebra finches, alum Allison Doupe, a professor of psychiatry and physiology at the University of California, San Francisco, is making progress further up the auditory pathway, close to where it connects to motor-control areas. A region of the brain crucial in chicks for learning their scratchy songs seems in adults to switch between producing precise performance for an audience and generating trial-and-error variability important for learning when the bird sings alone. The same region may govern the babbling of children trying to mimic their parents.

“The last century was the century of the gene and cracking the genetic code,” said HMS neurobiology chair Carla Shatz. “This new millennium is the millennium of the mind: if we know our brains, we really will know ourselves.”

Welcome Bacteria
When it comes to self-knowledge, bacteria may hold the key, said Dennis Kasper, director of the Channing Lab at HMS and Brigham and Women’s Hospital. “The striking fact [about the normal microbial colonization of mammalian bodies] is that the number of bacterial cells outnumber host cells by 100 to one,” he said. “Cellwise, we’re mostly other organisms. We’re more prokaryote than eukaryote.”

Kasper’s group has been studying the biological effects of polysaccharides made by a ubiquitous bacterial species in the gut. In harmful bacterial infections, these long-chain sugar molecules are infamously known as virulence factors. But in colonization by beneficial bacteria, they may be important in maintaining the health of the host by being presented by MHC II molecules and activating CD4 T cells. Previously, the MHC II pathway was thought to interact only with proteins. Mice born and maintained in a germ-free environment have defects in their intestinal immune systems and have systemic immune deficiencies. Some of the deficits can be corrected by adding a strain of the beneficial bacteria sporting these polysaccharides on their surface. “The bacteria we live with may actually do us a lot of good,” Kasper said.

Many friendly and unfriendly microorganisms have yet to be discovered, but the rapid accumulation of basic research advances is having a major impact on the scientific response to potentially dangerous new pathogens, said Michael Farzan, assistant professor of microbiology and molecular genetics at HMS. Only eight months after the World Health Organization issued a global health alert for the SARS virus, Farzan’s group, with the Hyeryun Choe Laboratory at Children’s Hospital Boston, published the identity of the receptor for the virus.

Farzan credits Don Wiley’s influential model of the prototypical type 1 fusion behavior of the flu protein and subsequent work from Stephen Harrison’s laboratory, which recently showed that another class of proteins behaves by essentially the same principles. Technological advances from work on HIV, the human genome project, mass spectroscopy, and protein identification algorithms also support the modern detection work essential to understanding the mechanisms of viral entry and the development of new ways to fight infections. For example, antibodies against the ACE2 binding site of the SARS virus may effectively treat or prevent SARS, Farzan said.

Alum Don Ganem, professor of microbiology/immunology and medicine at the University of California, San Francisco, made a strong case for plenty of old-fashioned epidemiological evidence, tight clinical case definitions, and critical thinking in a program of new pathogenic discovery. “If you look hard enough for microorganisms, you will find them,” he said. “Not all are the cause [of disease].”

Genomics and Medicine
New genomic strategies and tools took center stage in the final symposium on cancer and drug design. Researchers at Jackson Laboratory in Bar Harbor, Maine, have developed a new systems genetics approach to create mouse models of common diseases in humans and to study the essential nature of mammalian chromosomes, said alum Richard Woychik, director of the Jackson Laboratory.

Joan Brugge, chair of the HMS Department of Cell Biology, is using an innovative three-dimensional culture system to model alterations in the architecture of glandlike structures in the breast caused by hundreds of genes that have been implicated in breast cancer.

“The 3-D structure allows us to distinguish the biological activities of genes not distinguishable in cells cultured as monolayers in a Petri dish,” she said. “We can not only reconstruct the phenotype, we can deconstruct it.” In general, the models resemble the various histologies of breast cancers found in women. The same models can test the specific effects of chemotherapy agents on aberrant and normal cells in the structure.

Howard Hughes investigator Stephen Elledge, the Gregor Mendel professor of genetics and medicine at HMS, has generated a large database of proteins phosphorylated in vivo during DNA damage. He has used it to identify proteins in dozens of interconnecting pathways that may play a role in cancer. Some of the usual suspects have appeared, as well as new players in DNA replication and recombination, the cell cycle, cellular assembly and organization, cell death, and RNA post-translational modification.

One company has adapted the high-throughput approach to structural biology. Alum Stephen K. Burley, chief scientific officer and senior vice president of research at SGX Pharmaceuticals, described a drug-discovery process that uses a dedicated beam line at the Advanced Photon Source in Chicago for X-ray crystallographic screening of drug fragments to find new protein kinase inhibitors and other oncology targets.

“Our approach is to use crystallography to detect scaffolds (small fragments) bound to the target protein and optimize their fit to the active site under structural guidance,” he said. Ultimately, this approach yields potent inhibitors of the targeted proteins. Clinical testing for one compound in people with chronic myelogenous leukemia who have failed Gleevec is expected to begin in 2007.

—Carol Cruzan Morton

top