Systems Biology at Harvard's Bauer Center for Genomics…

         Systems Biology at Harvard's
      Bauer Center for Genomics Research
                                   Laura Garwin
                                                 to their essentials. The eleven Bauer Center
The Bauer Center for Genomics Research, at       Fellows include two mathematicians, a
Harvard      University,     is    a      new    biophysicist, and a computational biologist
interdepartmental initiative whose goal is to    who are already at the center, and two
identify general principles underlying the       physicists who will be arriving over the next
structure, behavior and evolution of cells and   eight months. Their work exemplifies these
organisms. Although we carry the                 types of contribution.
"genomics" label, what we do could just as
well be described as "systems biology". The      Lani Wu and Steven Altschuler, pure
unifying themes of our research are a system-    mathematicians by training who spent six
level approach to biology, and close             years at Microsoft working on problems
interactions among experiment, theory and        ranging from video compression to speech
computation. Our scientists come to biology      recognition before being drawn into biology,
from many disciplines, including physics,        have a number of collaborations with
mathematics and computer science.                experimental biologists both inside and
                                                 outside the center. In one, with Professor
Research at the Bauer Center is done by          Rong Li of Harvard Medical School, they are
Fellows -- young scientists appointed for up     investigating the self-organizing processes
to five years, who lead their own small          that underlie the establishment and
research groups. The Fellows form a truly        maintenance of cell polarity in budding
collaborative group of scientists; at last       yeast. Experiments had suggested the
count, there were ten pairwise collaborations    existence of a positive feedback loop
among the eight groups currently in the          involving an activated form of the protein
center. Interactions among the Fellows are       Cdc42, required for cell polarization, and the
promoted both by what they share (an             Cdc42-dependent assembly of actin cables,
interest in uncovering general principles in
biology,      and    a    commitment       to
interdisciplinary research) and by their
differing backgrounds and expertise,
allowing them to tackle problems together in
ways that none of them would have devised
separately.

Physicists and other quantitatively inclined
scientists can contribute to molecular and
cell biology in various ways -- for example,
by formulating mathematical and computer
models and analytical tools, developing
sensitive and accurate techniques for data
collection, and bringing to the subject a
                                                 The Bauer Center for Genomics Research.
predilection for reducing complex problems
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which deliver Cdc-42 to the cell membrane.        stresses and deleterious mutations in the
In this picture, a stochastic increase in the     bacterium E. coli (ref. 2). At the Bauer
local concentration of activated Cdc42 on the     Center, Kishony will extend this work to
membrane increases the probability of actin       budding yeast, using his growth rate assay to
polymerization, and hence further promotes        perform a comprehensive and quantitative
the accumulation of Cdc42 at the site. Wu         perturbation analysis of fitness with respect
and Altschuler simulated this process             to both internal (genetic) and external
mathematically, and were able to predict          (environmental) perturbations. He will use
                                                  these data to reconstruct genetic circuits in
                                                  yeast, and to generate testable hypotheses
                                                  regarding the nature of interactions between
                                                  pairs of genes.

                                                  Another physicist making the transition into
                                                  biology is Sharad Ramanathan, a theoretical
                                                  physicist on the technical staff at Bell Labs,
                                                  who will be starting as a Bauer Center
                                                  Fellow early next year. Ramanathan hopes to
                                                  transfer insights from work he has done on
                                                  electronic communication networks to the
                                                  problem of signal transduction in biology. In
                                                  particular, he is interested in questions
 Mathematicians Steven Altschuler and Lani Wu.

conditions       (subsequently         verified
experimentally) in which yeast cells would
develop one, two or more polar caps of
Cdc42 (ref. 1). In nature, cell polarization is
usually controlled by spatial signals, but the
intrinsic polarization mechanism modelled
by Wu and Altschuler may be used to
amplify a small initial asymmetry.

Roy Kishony, a postdoctoral fellow with
Stanislas Leibler at Rockefeller University,
                                                   Meeting of minds: the Bauer Center café.
will be joining the center as a Fellow in
August. Kishony has a Ph.D. in theoretical        related to fidelity and cross-talk in the
physics (his thesis was about the ignition        mitogen-activated protein (MAP) kinase
criterion in inertial confinement fusion), but    cascades in yeast. Another Fellow,
for the past four years he has been working       biophysicist Kurt Thorn, is approaching
as an experimental biologist. Kishony is          signaling in yeast from a different angle,
addressing fundamental questions in               developing fluorescence-based techniques
evolutionary genetics, using new techniques       such as fluorescence resonance energy
for obtaining quantitative physiological data.    transfer (FRET) to monitor the association of
In particular, he has developed a                 signaling proteins in living yeast cells. His
bioluminescence technique that allows             new techniques should allow many proteins
accurate, automated measurements of               to be monitored simultaneously in real time,
bacterial growth rates at very low cell           providing data to which computational tools
densities, and has used the technique to study    can be applied to decipher the structure of
the interaction between environmental             signaling pathways.

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                                                         encourage visits, ranging from one month to
Many of the Fellows share an interest in                 two years, from theorists who are interested
reconstructing biological networks, and will             in interacting strongly with the experimental
benefit from collaborating with the center's             biologists in the center.
latest arrival, computational biologist Aviv
Regev. Regev is using computational                      There are of course many types of barrier --
approaches to look for modular organization              caused by differences of language, culture,
(ref. 3) in biological networks, and to                  assumptions and philosophy -- that need to
characterize the behavior of modules (ref. 4).           be surmounted when scientists from different
                                                         disciplines start to work together. By
It will not have escaped the notice of DBP               bringing Fellows from many fields into the
members that there is a new influx of                    same building to work closely together, we
physicists     and      other    physical     and        are learning how to lower these barriers. But
computational scientists into biology (see               we will not be content merely to do
http://www.aps.org/apsnews/1102/110204.html). The        successful interdisciplinary research within
Bauer Center's Systems Biology program                   the center's walls. Instead, our aim is to
(http://cgr.harvard.edu/research/systems_biology.html)   catalyze fruitful interactions between the
aims to facilitate such career transitions, with         center's Fellows and faculty in the
jointly mentored postdoctoral fellowships                surrounding departments, and among faculty
designed to integrate quantitative scientists            in different departments. To this end, we
into biology, and a two-week summer school               hold a weekly series of "Genomics Talks", at
featuring lectures and laboratory experiments            which the speakers are asked to make
that will introduce postdocs and advanced                themselves intelligible to a mixed audience,
graduate students from physics, mathematics,             and where there is no such thing as a stupid
computer science and engineering to                      question. Although we have a long way to
experimental biology. One of the center's                go, we consider it a sign of success that two
main aims is to promote an intimate                      of the most dependable audience members at
                                                         these talks are condensed-matter theorists
                                                         from Harvard's physics department. An
                                                         equally important venue for interdisciplinary
                                                         interactions is the Bauer Center's café --
                                                         after all, scientists from all disciplines have
                                                         to eat!

                                                         References

                                                         1. Wedlich-Soldner, R., Altschuler, S., Wu, L. & Li,
                                                         R. Science 299, 1231-1235 (2003).
                                                         2. Kishony, R. & Leibler, S. J. Biol. 2: 14 (2003).
                                                         3. Hartwell, L. H., Hopfield, J. J., Leibler, S. &
                                                         Murray, A. W. Nature 402, C47-52 (1999).
                                                         4. Segal, E., Shapira, M., Regev, A., Pe'er, D.,
                                                         Botstein, D., Koller, D. & Friedman, N. Nature
                                                         Genetics 10.1038/ng1165 (2003).

 Biophysicist Kurt Thorn.                                Author contact information:
                                                         Dr. Laura Garwin, Bauer Center for
symbiosis between theory and experiment, of
                                                         Genomics Research, Harvard University, 7
the kind that is normal in physics, but has
                                                         Divinity Avenue, Cambridge, MA 02138,
been all too rare in molecular and cell
                                                         lgarwin@cgr.harvard.edu
biology. In addition to welcoming theorists
into the Systems Biology program, we also
                                                         Bauer Center website: http://cgr.harvard.edu
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