On the Faculty

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This article by Barbara Fox was prepared for the April 30, 2003 edition of U.S. 1 Newspaper. All rights reserved.

Meet the Minds of the Icahn Laboratory

When Princeton University first planned to create a

genomics institute in January, 1999, Shirley M. Tilghman was to be

the director. But when she became president of the university in 2001,

genetics pioneer David Botstein was named to the institute post.

Botstein, who remains at Stanford University through June, has established

key genetic techniques that are used today. In 1980 he and three colleagues

proposed a method for mapping genes that laid the groundwork for the

Human Genome Project. He also led the effort to map and sequence the

yeast genome, which in 1996 was the first large genome of its kind

to be sequenced. "He has been a leader in thinking about the databases

that are necessary in a post-genome era to collate and integrate all

of the data that are coming in from so many sources," says Tilghman.

Botstein has also been effective at integrating approaches from disciplines

outside biology, such as physics and engineering, says Tilghman: "He

understands both the enormous promise of that kind of research and

the difficulty of it. He doesn’t underestimate how hard it is."

David Botstein grew up in New York City, where both his mother and

late father were physicians. His brother, Leon Botstein, is the president

of Bard College, and his sister is a physician. With a bachelor’s

degree from Harvard and a doctoral degree from the University of Michigan,

Botstein taught at Massachusetts Institute of Technology from 1967

to 1988 and was vice president for science at the biotechnology company

Genentech for two years, before taking a teaching position at Stanford

School of Medicine.

Botstein says he is looking forward to doing both research and teaching

at Princeton. "The emergence of the data from the Human Genome

Project completely changes the way biology can and will be done,"

he says. "The question of what kind of preparation young people

should have in order to enter into this exciting new world requires

serious thought."

"My experience and the experience of the people around me is that

students ask very good questions, and you know you are in an area

in which not enough is understood when you can’t give a straight answer

to a relatively simple question," he says.

Based on similar projects at MIT, Botstein hopes to develop a series

of undergraduate courses called "project labs," emphasizing

current research questions and cutting-edge techniques and challenging

challenge students to address the same kinds of questions being investigated

by the institute’s faculty.

"They’ll be faced with the interdisciplinary problem right from

the beginning. For those with talent for it, I think that will guide

their subsequent choice of how to educate themselves in a much better

way than following in the path of standard disciplines," says

Botstein. "We are recognizing that biology has become, in the

post-genome-sequence period, an information science and these young

people are world leaders in that intersection of biology and information

science."

— Barbara Fox

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On the Faculty

The intradisciplinary research in the Carl Icahn Laboratory

will focus on biological networks. Five faculty members in the Lewis-Sigler

Institute will have their laboratories and offices in the new Icahn

building, and the sixth member, Harold Shapiro, — the president

emeritus of the university — will participate in seminars on bioethics

but will keep his current office. A seventh faculty member, interim

director James Broach, will retain his laboratory in the molecular

biology department. David Botstein, the director, moves in on July

1.

To be appointed are five Lewis-Sigler fellows, who will teach and

be able to do research without having to raise grant money. In the

coming years additional research groups will be added. Together with

assistants and graduate student fellows, the building will house from

10 or 12 research groups and 125 to 150 people.

Saeed Tavazoie: Molecular Biologist

Saeed Tavazoie, a molecular biologist, is studying the

properties of intracellular networks — called transcriptional

networks — that regulate the expression of genes. These networks

control the intuitive behaviors of cells, such as expression, adaptation

and differentiation.

Scientists have been using genetic and biochemical techniques to discover

how genes are regulated at a single location, but little is known

about the global structure of transcriptional networks — their

overall connectivity and organization. "In addition, we lack the

conceptual framework for integrating such knowledge into a predictive

understanding of their dynamics," writes Tavazoie. "We are

using genomic, computational, and analytic methods to address these

challenges."

Among the research activities in his laboratory are the development

of algorithms for inferring the structure of networks from genomic

data, and the development of new methods to validate computational

predictions of networks. He also tries to elucidate combinatorial

logic — what happens when more than one "connection" of

a transcription factor and a DNA binding site is regulating the activity

of a gene.

"Evolution provides us with a unifying perspective," writes

Tavazoie. "Our long-term goal is to better understand how the

structural and dynamical properties of networks reflect, and depend

on, the physical, chemical, multicellular, and ecological contexts

in which they have evolved."

Stas Shvartsman: Chemical Engineer

Stas Shvartsman, a chemical engineer, takes a multidisciplinary

approach — using reaction engineering, transport theory, applied

mathematics, and computation — to study the computational biology

of cell signaling networks.

Because defects in these networks may lead to a range of diseases,

he wants to develop mechanistic, predictive models of them. These

models could be used to assign the functionality of signaling networks

in different organisms. "Organisms as diverse as fruit flies and

humans rely on homologous molecular components and network architectures

for similar biological functions," writes Shvartsman.

Mona Singh: Computer Scientist

Mona Singh, a computer scientist, develops computational

methods for predicting protein-protein interactions within an organism

solely on the basis of sequence information. "We are particularly

interested in developing algorithms for genome-level analysis of protein

structure, function, and interactions," writes Singh.

"Since a genome contains a complete `parts list’ of an organism,

whole-genome data allows one to begin to address exhaustively the

problem of determining and predicting which proteins can interact

with each other. Traditionally, knowledge of protein-protein interactions

has been accumulated from biochemical and genetic experiments; however,

as whole-genome data accumulates, it becomes increasingly necessary

to develop computational methods for predicting these interactions.

Computational methods have already proven to be a useful first step

for rapid genome-wide identification of putative protein function

and structure, but research in the problem of computationally determining

biologically relevant partners for given protein sequences is just

beginning."

"Much of our work on predicting protein structure and protein-protein

interactions has focused on the coiled coil motif. The coiled coil

is a common and important structural motif that mediates protein-protein

interactions, and is found in proteins involved in transcription,

in cell-cell and viral-cell fusion events, and in maintaining the

structural identity of cells. We have developed highly effective sequence-based

methods for identifying whether a given protein sequence can take

part in a coiled coil structure, and are currently developing novel

computational techniques to predict whether two coiled coil proteins

interact with each other, and if so, what the nature of this interaction

is."

William Bialek: Physics Professor

William Bialek, a physics professor, is interested in

attaching numbers to the intuitive assumption that living systems

"do a good job" at solving many different problems. Even single-celled

organisms, such as bacteria, sense their environment and control their

internal chemistry, he says. "The same problems of sensing and

control occur for every cell in our own bodies, but we also use our

brains to build an internal representation of the world and to learn

the rules that operate in the world."

For each of these different problems Bialek has explored the theoretical

limits to what biological systems can do given the "hardware"

that they have to work with. In many cases he and his colleagues have

been able to show how an organism has selected a set of nearly optimal

mechanisms for its most crucial tasks. This search for optimality

has led, for example, to the discovery of new phenomena in the neural

code, the "language" that the brain uses to process the information

that we take in through our eyes, ears and other senses.

John J. Hopfield: Computational Biologist

John Hopfield, a computational neural biologist, examines

how the neural circuits of the brain produce such powerful and complex

computations. All his work is with computers, using systems of differential

equations to model and represent aspects of neurobiology.

"I do computer simulations of the way that large networks of neuro

cells behave," says Hopfield. "The basis for these models

is a century of research in neuro biology. The models make predictions

and I can then go to friends in a neurobiology laboratory to find

out if those predictions have some kind of correspondence to reality."

"While the brain is totally unlike modern computers, much of what

it does can be described as computation. Associative memory, logic

and inference, recognizing an odor or a chess position, parsing the

world into objects, and generating appropriate sequences of locomotor

muscle commands are all describable as computation," says Hopfield.

"We seek to understand some aspects of neurobiological computation

through studying the behavior of equations modeling the time-evolution

of neural activity."

"Identifying words in natural speech is a difficult computational

task which brains can easily do," writes Hopfield. "We use

this task as a test-bed for thinking about the computational abilities

of neural networks and neuromorphic ideas."

Hopfield also studies how rats or garden slugs employ their sense

of smell to understand what objects are present in the environment.

"We have been studying how such computations might be performed

by the known neural circuitry of the olfactory bulb and prepiriform

cortex of mammals or the analogous circuits of simpler animals,"

says Hopfield.

David Tank: Biophysicist

David Tank, a biophysicist, studies cellular and circuit

mechanisms of persistent neural activity and chemical dynamics in

neurons. Persistent neural activity is a form of neural circuit dynamics

associated with short-term memory.

"Persistent neural activity is a sustained increase or suppression

of action potential firing elicited by a brief sensory stimulus or

motor command," Tank writes. "Across the population of participating

neurons, the pattern of sustained changes in action potential firing

is correlated with the information held in short term memory, while

disruption of persistent activity produces deficits in memory-guided

behavior. These characteristics suggest that the memory is actually

the dynamic state of the circuit."

"Many of our experiments are designed to test the hypothesis that

persistent activity is produced by positive feedback implemented by

recurrent excitation through synaptic connections and to explore the

importance of particular synaptic currents."

Tank is also trying to measure the chemical and electrical dynamics

of neurons by using laser scanning microscopy to study the concentration

of calcium in nerve terminals in the mammalian brain.

James Broach Molecular Biologist

James Broach, a molecular biologist, is the acting director

of the Lewis-Sigler Institute until David Botstein takes over this

summer. Broach will not be moving his laboratories to the Icahn building

but will have a close association. He studies how cells process information

gleaned from their environment to make decisions regarding growth

and development. Using baker’s yeast as a model organism, he employs

new genomic analysis tools to examine the cell’s response to nutrient

availability. He monitors simultaneously the changes in activity of

every one of the 6,000 genes in the organism.

One outcome of this analysis is a deeper understanding of the function

of the yeast version of the human Ras oncogene, the gene most often

mutated in human cancers. The analysis conducted by Broach’s group

identifies therapeutic targets that could be used to reverse the tumorigenic

state of those cancers.


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