At the Intersection of Physics and Biology
By Jason Socrates Bardi
Every
biologist is, at heart, a chemist.
And every chemist is, at heart, a physicist.
And every physicist is, at heart, a mathematician.
And every mathematician is, at heart a philosopher.
And every philosopher is, at heart, a biologist."
—Anonymous
The path that connects physics to biology has long been something of
a one-way street.
Down it generations of scientists trained in classical and modern physics
have passed on their way to successful careers at the forefront of biology—solving
some of the most difficult problems in the field and inventing new techniques,
most notably molecular biology, and new technologies.
In fact, some of the most powerful techniques in structural biology
were discovered by physicists. The physicist Wilhelm Conrad Röntgen
discovered X rays in 1895. X ray diffraction in crystals was discovered
by a physicist (Max von Laue) and applied to determine the structure of
atoms in those crystals by a father–son team of physicists, William
Henry and William Lawrence Bragg. Nuclear magnetic resonance (NMR) was
also independently discovered by two physicists, Edward Mills Purcell
at Harvard and Felix Bloch at Stanford, just after World War II. And electron
microscopy was invented by physicist Ernst Ruska in the 1930s.
The scientific world recognized those individuals and their achievements,
and each in turn won a Nobel prize—in physics—for their accomplishments.
The impact of these technologies on biology is immeasurable.
So where, one might wonder, is the rainbow trail from biology to physics?
What famous biologists became productive physicists? What contributions
have biologists made that physicists find indispensable?
Rest assured, there are some. One is the area of emergent phenomena—out
of a seemingly random pattern of fluctuations or motions comes behavior
that is highly cooperative and ordered.
"The very early seed of those ideas existed in physics, but the conceptualization
and development of the principles [of emergent phenomena] really matured
through applications and studies in biological systems," says Charles
L. Brooks III, professor of molecular biology at The Scripps Research
Institute (TSRI). "Now those ideas are making their way back to cluster
physics and other areas."
And, Brooks adds, researchers in La Jolla are poised to bring more ideas
from biology to physics. A consortium of local research institutions has
just been awarded $10.5 million over the next five years from the National
Science Foundation to establish the world's leading center in the emerging
field of theoretical biological physics.
Biological physics is an umbrella term that includes, in the traditional
sense, areas such as spectroscopy and structural biology, which use the
discoveries and the laws of physics to study problems in biology. But
more importantly, biological physics also forges ahead with research that
uses biology to advance ideas in physics.
"We think that new principles of physics will emerge from studying biology,"
says Brooks. "It's a new venture."
A Center at the Interface
Headed by investigators at the University of California, San Diego (UCSD),
the new Center for Theoretical Biological Physics, or CTBP, will combine
the intellectual resources of TSRI, the University of California, San
Diego's Division of Physical Sciences, the San Diego Supercomputer Center
at UCSD, and The Salk Institute for Biological Studies.
This venture is built upon the previously established and highly successful
La Jolla Interfaces in Science program, an interdisciplinary training
program founded by the same investigators four years ago that has to date
supported the studies of more than 40 graduate students and post-graduate
fellows. The program is generously supported by the Burroughs Wellcome
Fund.
The CTBP will bring together theoreticians and experimentalists from
around the world to advance research and educate scientists using an interdisciplinary
approach to be carried out jointly by physicists, chemists, mathematicians,
and biologists.
The center represents the first time that the Physics Division of the
National Science Foundation is providing, through its Physics Frontier
Center program, substantial support for biological physics. Additional
funds will come from the science foundation's Information Technology Resource
program, designed to support "visionary work" that could lead to major
advances in information technology and its applications.
"It is very satisfying that our long-running efforts in establishing
a paradigm for research and training at the interdisciplinary interface
of physics and biology are being recognized and supported by the NSF,"
notes Brooks. "[The NSF's] forward-looking initiative to establish the
CTBP should provide a model for other funding agencies as we seek a more
quantitative understanding of biology."
No Other Place like It
Other researchers involved in the center include José N. Onuchic,
a professor of physics at UCSD; Kim Baldridge, a UCSD chemistry and biochemistry
professor working at the San Diego Supercomputer Center; UCSD physics
professors Henry Abarbanel, Terrance Hwa, and David Kleinfeld; UCSD physicist
Wouter-Jan Rappel; UCSD chemistry and biochemistry professors J. Andrew
McCammon and Peter Wolynes; UCSD mathematics professor Michael Holst;
David Case, a professor in the Department of Molecular Biology at TSRI;
Terrence Sejnowski, a neurobiologist at Salk and adjunct professor of
physics and biology at UCSD; and Charles Stevens, a neurobiologist at
Salk.
Even though the center is in the very early stages, there is a lot of
enthusiasm among the researchers about the collaborative spirit in which
the work will proceed.
Onuchic says the computational resources of the San Diego Supercomputer
Center combined with the intellectual resources of UCSD, TSRI, and Salk
make this a unique center, one that will allow biological physics to advance
and gain influence within the traditional disciplines of biology and physics.
"No other place in the world has as many top people working in this field,"
he says.
"I am really enthusiastic about the increased interactions in the La
Jolla area," says Case, a professor in TSRI's Department of Molecular
Biology. "This will be broader and go beyond [anything we have done in
the past]."
Over the past several years, adds Brooks, the interface between physics
and biology has come of age—particularly in La Jolla, where many
people who do the sorts of studies that the center will foster have been
moving.
"It was time for a center for biological physics," adds Brooks. "And
this is probably the best place in the world to have it."
The Structure of Viruses
Brooks and Case also collaborate on a National Institutes of Health
(NIH) center to develop multi-scale modeling tools for structural biology
and to make these tools available to the scientific community for free.
"Our mandate is to build tools to help structural biologists better
interrogate, explore, and understand structural models," says Brooks,
who is director of the NIH center.
One of the center's objectives is to develop tools that might be used
for genome-scale modeling and structure prediction. As more and more genomes
are solved and annotated with gene prediction algorithms and proteomic
techniques, the number of proteins of unknown structure and function is
growing, which is creating a great demand for computational tools that
can predict the structures—or partial structures—of these proteins.
Brooks and Case work on tools for problems including protein folding
prediction and homology modeling—where the structure of a protein
is predicted based on the similarity of its amino acid sequence to another,
known protein—and test these tools for their ability to predict the
fold of unknown proteins. The computations that they use are sometimes
very intensive.
"We recently ran a calculation in which we used 2,500 nodes (processors)
at the Pittsburgh Computing Center together with about 500 nodes of San
Diego's machine and hundreds of nodes as a site in Virginia," says Brooks.
"They were all working at once for one computation for a period of 24
to 48 hours."
That particular calculation, says Brooks, involved exploring a protein-folding
landscape for a protein that is known to fold very quickly in order to
understand how the sequence of amino acids in the chain determines the
three dimensional structure of the folding protein.
In another area of research at the NIH center, Brooks and Case aim to
make connections between atomic-level descriptions of molecules obtained
from crystallography and NMR and lower-resolution pictures obtained with
other techniques, such as electron microscopy (EM).
This is important because in solving structures, crystallographers and
NMR spectroscopists often can only solve a small piece of a large structure,
while EM can handle large structures, but not at high-resolution. Reconciling
the two allows them to fit high-resolution pieces together, jigsaw-like,
in order to obtain a complete picture with more atomic detail than would
be possible using only one technique or the other.
They then take this still-static picture and make a sophisticated model
out of it, modeling the dynamics of the molecule at a larger scale.
"Generally, the reason for doing this," says Case, "is to get biologically
interesting states that are not observable at high resolution.
They have also worked in collaboration with TSRI Professor Jack Johnson
to study the assembly of viruses—a subject that Johnson has been
studying with x ray crystallography for a number of years.
"We're looking at understanding, at a molecular level, the process that
swells and shrinks the particles," says Brooks.
Virus particles are dynamic in solution and undergo large structural
changes throughout their "lifetime," and some of these changes are interesting
biologically because they may be related to such issues as how the virus
particle gets its genetic information into a cell that it infects. However
not all the changes may be accessible experimentally, since the transition
states may be unstable and therefore impossible to crystallize or study
with NMR.
Brooks and Case are also trying to understand how nucleic acids are
packaged in viruses. "Usually that cannot be seen at high resolution,"
says Case, "because the DNA or RNA is too disordered."
Still, he adds, the problem is not so simple computationally either.
The insides of a virus are incredibly crowded, which makes computing difficult.
Some of the work they do involves figuring out how to remove atomic detail
from the structures so that they do not have to take it into account.
Case, for instance is working on how to model a protein or DNA in continuum
solvent to simplify the calculations.
"You keep an atomic-level protein or DNA model, but you remove all the
atomic level descriptions of the water or ions," he explains.
The Fluctuating Ribosome
Brooks is particularly interested in the workings of the large molecular
machines that carry out much of the work of the cell, such as the ribosome
or actin/myosin.
"Nature effectively exploits the shape of these objects to provide robustness
in the motions that they have to undergo," says Brooks.
In the case of the ribosome, the starting point for the study of these
motions are the near atomic-resolution and atomic-resolution molecular
structures that have been solved in the last couple of years using EM
and x ray crystallography.
Brooks is working to create atomic-level models using these structures
that give dynamic movement to them. He, with his postdoctoral collaborator
Florence Tama, is building an elastomechanical model that captures the
shape of molecular "objects" and allows dynamic behavior to emerge from
normal vibrations and rotations associated with the atoms in the molecule.
These dynamic movements may be the key to some of the molecules' most
complex behavior. In the model of the ribosome, the collective fluctuations
may give rise to a ratchet-like motion that is involved with the phenomenon
known as translocation.
Translocation is an important part of the ribosome function because
it involves moving tRNA molecules loaded with amino acids from the site
on the ribosome where the anticodon of the tRNA is paired with the codon
of the mRNA to the site on the ribosome that catalyzes the formation of
the peptide bond between the amino acid loaded on the tRNA and the growing
protein chain. A major motion of the ribosome is associated with this
movement from one location on the ribosome to another after an "effector"
molecule binds to the ribosome.
In Brooks' dynamic model of the ribosome, the movement occurs quite
naturally, as one of the "normal modes" of vibration. Physicists describe
normal modes as fluctuations about a local energy minimum (preferred vibration)
for simple harmonic oscillations—between two adjacent atoms, for
instance. More collective motions in large molecular assemblies like the
ribosome may describe functionally important dynamics.
"[The translocation] is happening only because of the shape of the molecule,"
says Brooks. "It seems as though nature somehow engineers these shapes
so that it is a single mode that is functionally relevant."
These models are promising because they may be the only way to access
atomic-level structural information about transition states of large structures
like the ribosome. Such transition states may be inherently unstable and
completely inaccessible to experimental techniques but nevertheless important
to the operational cycle of these cellular machines—in other words,
they may hold some of the secrets of life.
And perhaps of physics as well.
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