Four from Caltech Named to National Academy of Sciences

PASADENA-Three members at the California Institute of Technology faculty and one former faculty who is now a visiting associate are among the 72 new members and 18 foreign associates being named to the National Academy of Sciences today. The election was announced during the 142nd annual meeting of the Academy in Washington, D.C.

Caltech's newest members are Richard Andersen, the Boswell Professor of Neuroscience; James Eisenstein, the Roshek Professor of Physics; and Wallace Sargent, the Bowen Professor of Astronomy. Roger Blandford, a former Caltech faculty member and current visiting associate in physics, is also among the electees.

Membership in the National Academy of Sciences is considered one of the most important honors that a scientist can achieve. In addition to the 1,976 active members of the academy following today's election, 360 foreign associates are also listed in the organization's roster as nonvoting members.

The National Academy of Sciences is a private organization of scientists and engineers dedicated to the furtherance of science and its use for the general welfare. It was established in 1863 by a congressional act of incorporation signed by Abraham Lincoln that calls on the Academy to act as an official adviser to the federal government, upon request, in any matter of science or technology.

Andersen is a neuroscientist who has garnered considerable attention in recent years for his progress toward the goal of controlling prosthetic devices with brain signals. Much of his current work focuses on severely paralyzed human patients who can think about making movements, but due to brain lesions from trauma, stroke, or peripheral neuropathies, can no longer make movements. His approach is to create brain-implant technology that will act as an interface between a patient's thoughts for movement and artificial limbs, computers, or other devices, that would "read out" the patient's desires.

Eisenstein is a specialist in condensed-matter physics, which involves the exploration of the fundamental laws of nature as they apply to atoms and molecules that comprise solid matter. His most significant research accomplishment in the last year has been his demonstration that unusual particles known as "excitons" can inhabit solid semiconductor materials in such a way that each exciton loses its individual identity and, in certain ways, a large collection of excitons becomes a single quantum entity.

Sargent is particularly well-known in the astrophysical community for his work in spectroscopy. His research in extragalactic spectroscopy provided the first evidence for a black hole in galaxy M87, and his work on intergalactic gas has led to new insights on the primeval materials of the early universe. His work in the stellar spectroscopy of A-type stars led to the discovery of the He3 isotope in the star 3 Centauri.

Blandford is a former faculty member in the Division of Physics, Mathematics and Astronomy at Caltech. He is currently a visiting associate in physics at Caltech and the Pehong and Adele Chen Professor of Physics and Stanford Linear Accelerator Center at Stanford University, where he is also director of the Kavli Institute for Astrophysics and Cosmology.

Today's election brings the total number of Caltech faculty members of the National Academy of Sciences to 70.

Robert Tindol
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Five from Caltech Faculty Elected to American Academy of Arts and Sciences

PASADENA, Calif.-Five faculty members at the California Institute of Technology are among this year's newly elected fellows of the American Academy of Arts and Sciences. They join 191 other Americans and 17 foreign honorees as the 225th class of fellows of the prestigious institution that was cofounded in 1780 by John Adams.

This year's new Caltech inductees are Barry Barish, the Linde Professor of Physics and director of the Laser Interferometer Gravitational-Wave Observatory (LIGO); Andrew Lange, the Goldberger Professor of Physics; Barry Simon, the IBM Professor of Mathematics and Theoretical Physics; David Tirrell, chair of the Division of Chemistry and Chemical Engineering and McCollum-Corcoran Professor and professor of chemistry and chemical engineering; and William Bridges, the Braun Professor of Engineering, Emeritus.

The five from Caltech join an illustrious list of fellows, both past and present. Other inductees in the 225th class include Supreme Court Chief Justice William Rehnquist, Angels in America author Tony Kushner, Academy Award-winning actor Sidney Poitier, former NBC Nightly News anchor Tom Brokaw, Washington Post CEO Donald Graham, and Pulitzer Prize-winning cartoonist Art Spiegelman. Past fellows have included George Washington, Benjamin Franklin, Ralph Waldo Emerson, Albert Einstein, and Winston Churchill.

According to the academy's president, Patricia Meyer Spacks, the fellows were chosen "through a highly competitive process that recognizes individuals who have made preeminent contributions to their disciplines and to society at large."

"Throughout its history, the Academy has convened the leading thinkers of the day, from diverse perspectives, to participate in projects and studies that advance the public good," said Executive Officer Leslie Berlowitz.

The academy is an independent policy research center that focuses on complex and emerging problems such as scientific issues, global security, social policy, the humanities and culture, and education.

The new fellows and foreign honorary members will be formally recognized at the annual induction ceremony on October 8 at the academy's headquarters in Cambridge, Massachusetts.


Robert Tindol
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HHMI Investigator's Approach Could Lead to Novel Drug Design, New Way to Generate Energy

PASADENA, Calif.--For anyone suffering from cystic fibrosis or AIDS, the bacterium Pseudomonas aeruginosa is bad news. While the organism is found everywhere--including in sediment on the ocean floor--it can cause lung infections in those with weak immune systems.

California Institute of Technology researcher Dianne Newman thinks her laboratory work could lead to ways of neutering the organism's threat to patients--and, at the same time, perhaps even hijack the microbe's internal chemistry for a novel method of energy generation.

This unlikely marriage of medical application and environmental engineering has won Newman one of this year's prestigious funding awards from the Howard Hughes Medical Institute. Newman, who is Caltech's Luce Assistant Professor of Geobiology and Environmental Science and Engineering, joins 42 other leading American researchers as this year's new crop of HHMI Investigators.

One of the most prestigious honors in the country for scientists involved in biomedicine, the grant is designed to provide a select group of individuals "with the freedom and flexibility they need in order to make lasting contributions to mankind," says Thomas R. Cech, the HHMI president.

Newman's approach toward the microbe is to exploit the manner in which it must generate energy through electron transfer reactions in order to survive. Scientists know the fine details of electron transfer about a few proteins involved in cellular energy generation, but not about the processing of redox-active small molecules produced by organisms such as Pseudomonas aeruginosa, Newman says. Progress could lead toward new insights about the function of these molecules in biofilms.

For the biomedical application, the work could determine if other discoveries in Newman's lab can be applied to understanding how electrons shuttle about in the course of the microbe's carrying on its life functions, and how these processes could be interfered with for novel treatments. With the new HHMI funding, Newman says she will be able to take full advantage of her collaborative work at the Jet Propulsion Laboratory--work that has already led to her codesigning a special apparatus for studying electron shuttling in biofilms.

A possible outcome of the research would be the demonstration that electron shuttles work in such a way that the human pathogen Pseudomonas aeruginosa could be attacked through rational drug design. In other words, new drugs might be specifically created to interfere with the way that electrons move around in the course of the bacterium's doing what it needs to do to remain alive. Such a drug would be a new type of antibiotic.

"It's hard to treat these bacterial infections with conventional antibiotics," Newman says. "Hopefully we can learn something about what these organisms need to live, and can develop a new way to interfere with it."

A fuller understanding of the bacterium's electron shuttling mechanism could also perhaps lead to a new type of energy production with a novel device called a "sediment fuel cell." These are devices that are planted in ocean sediment, with the anode side (the side from which electrons flow) buried beneath the surface, and the cathode side (to which electrons flow) above the sediment surface.

Because the Pseudomonas aeruginosa bacterium has been found in significant numbers in biofilms developing on marine cathodes, the fuel cell could possibly be designed in such a way that the organism's life functions could be tapped to catch the energy from the current flow. This research is already receiving DARPA funding, and Newman says that the additional HHMI funding should provide her with greater flexibility to understand the basic biology needed to make the fuel cells work.

Such a fuel cell would work like an underwater battery, with the bacteria ultimately providing a source of current by carrying on their life processes.

A nonprofit medical research organization, HHMI was established in 1953 by the aviator-industrialist Howard Hughes. The Institute, headquartered in Chevy Chase, Maryland, is one of the largest philanthropies in the world with an endowment of $12.8 billion at the close of its 2004 fiscal year. HHMI spent $573 million in support of biomedical research and $80 million for support of a variety of science education and other grants programs in fiscal 2004.


Robert Tindol
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McKnight Awards Go to Two from Caltech

PASADENA, Calif.--Richard Andersen, Boswell Professor of Neuroscience, and Kai Zinn, professor of biology, both of the California Institute of Technology, have each received a 2005 McKnight Neuroscience of Brain Disorder Award.

Andersen's work focuses on severely paralyzed human patients. These patients can think about making movements, but due to brain lesions from trauma, stroke, or peripheral neuropathies, can no longer make movements. The McKnight funding will allow Andersen's group to further their research in creating brain-implant technology that will interface between a patient's thoughts for movement and artificial limbs, computers, and other devices that will "read out" the patient's desires.

Zinn's work on prions, which are commonly known to the public as the cause of mad cow disease, addresses the mechanisms involved in the accumulation of these proteins. Aggregates composed of prion proteins are known to cause fatal human brain diseases. Through his study of prion propagation, in Drosophila and yeast, Zinn hopes to uncover how prions are formed and whether prions might have functions in the normal brain.

The Research Projects Award from the McKnight Foundation, established in 1977, and its Endowment Fund for Neuroscience, established in 1986, will provide $300,000 each to the Caltech professors over three years to further their work in neuroscience.

Robert Tindol
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Toward a Longer, Healthier Life

PASADENA, Calif. - The Spanish explorer Ponce de Leon spent a fair amount of his time in 1513 looking for the fountain of youth. The upside was that he discovered Florida. The downside was that the fountain was a myth. Now in two separate awards from the Ellison Medical Foundation, two scientists from the California Institute of Technology are taking a much more scholarly approach to the ravages of aging. Harry Gray, a chemist, has been awarded $970,000 to reveal the structure of a protein and a peptide that underlie two age-related diseases, Alzheimer's and Parkinson's, while biologist Alexander Varshavsky has been awarded $972,000 to conduct a systematic investigation of the genetics and biochemistry of aging.

Gray, the Arnold O. Beckman Professor of Chemistry, notes that approximately one million Americans suffer from Parkinson's, while 4.5 million have Alzheimer's. In order to design a drug to combat these two diseases, a key step is to understand the critical structural differences between normal proteins and the malignant proteins that comprise these diseases.

Both Alzheimer's and Parkinson's are associated with the accumulation in the brain of aggregates of proteins known as fibrils. In Parkinson's, the fibrils are composed of the protein alpha-synuclein, while in Alzheimer's, the fibrils or plaques are composed of the AB amyloid peptide. Alpha-synuclein and AB amyloid peptide are known as "disordered biopolymers," meaning that they do not have well-defined structures. Because of this lack of structure, the traditional tools used by chemists, such as x-ray crystallography and nuclear magnetic resonance spectroscopy, are virtually useless. They are only effective if the peptides and proteins being studied have well-defined structures in crystals or solutions.

Instead, Gray and his colleagues plan to use laser spectroscopic methods developed in Caltech's Beckman Institute to gain new insights into the structures, dynamics, and misfolding of malignant proteins and peptides. One of the most powerful methods they will use will employ an ultrafast camera to obtain distances between atoms in disordered structures that are constantly changing.

"We're very excited about the possibility of applying our laser methods to study proteins and peptides that are involved in disease in older people," says Gray. "We have a chance to identify toxic species that lead to these diseases, and point the way to successful interventions."

For Alexander Varshavsky, the Howard and Gwen Laurie Smits Professor of Cell Biology, it is the causes and alterations of the aging process that interest him. Every cell contains within it a molecular machine to eventually destroy its own proteins, he notes. The mechanisms and functions of this so-called regulated protein degradation became (mostly) understood over the last 25 years, in large part through discoveries in Varshavsky's lab. When a protein called ubiquitin is linked to another protein in a cell, that protein is marked for destruction. The molecular machines inside a cell that link ubiquitin to other proteins, and the intracellular machinery that "recognizes" ubiquitin-linked proteins and destroys them, are elaborate and complex. "Detailed understanding of these protein-destruction pathways will have a profound impact on the practice of medicine," says Varshavsky, "because all kinds of things that go wrong with us, from cancer and infectious diseases, to neurodegenerative syndromes and even normal aging, have a lot to do with either inherent imperfections of the ubiquitin system, or with an overt damage to it in a specific disease." Many clinical drugs of the future, he notes, will be designed to suppress, enhance, or otherwise modify various aspects of the ubiquitin system.

In this research Varshavsky will overexpress, selectively and in a controlled manner, specific components of the mouse ubiquitin system in intact mice, in order to determine the effects of such alterations on the rate of aging. He also plans to use analogous approaches with a much simpler organism, S. cerevisiae, common baker's yeast. His aim is to discover the molecular circuits that contribute to normal aging, and also to see whether some of the alterations that he plans to introduce could slow down the aging process.

The Ellison Medical Foundation is a nonprofit corporation that was established by a gift from Mr. Lawrence J. Ellison to support basic biomedical research to understand aging processes and age-related diseases and disabilities. Through various award mechanisms, including the Senior Scholar and New Scholar award programs, the foundation fosters research by means of grants-in-aid to investigators at universities and laboratories within the United States.

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Scientists Discover What You Are Thinking

PASADENA, Calif. - By decoding signals coming from neurons, scientists at the California Institute of Technology have confirmed that an area of the brain known as the ventrolateral prefrontal cortex (vPF) is involved in the planning stages of movement, that instantaneous flicker of time when we contemplate moving a hand or other limb. The work has implications for the development of a neural prosthesis, a brain-machine interface that will give paralyzed people the ability to move and communicate simply by thinking.

By piggybacking on therapeutic work being conducted on epileptic patients, Daniel Rizzuto, a postdoctoral scholar in the lab of Richard Andersen, the Boswell Professor of Neuroscience, was able to predict where a target the patient was looking at was located, and also where the patient was going to move his hand. The work currently appears in the online version of Nature Neuroscience.

Most research in this field involves tapping into the areas of the brain that directly control motor actions, hoping that this will give patients the rudimentary ability to move a cursor, say, or a robotic arm with just their thoughts. Andersen, though, is taking a different tack. Instead of the primary motor areas, he taps into the planning stages of the brain, the posterior parietal and premotor areas.

Rizzuto looked at another area of the brain to see if planning could take place there as well. Until this work, the idea that spatial processing or movement planning took place in the ventrolateral prefrontal cortex has been a highly contested one. "Just the fact that these spatial signals are there is important," he says. "Based upon previous work in monkeys, people were saying this was not the case." Rizzuto's work is the first to show these spatial signals exist in humans.

Rizzuto took advantage of clinical work being performed by Adam Mamelak, a neurosurgeon at Huntington Memorial Hospital in Pasadena. Mamelak was treating three patients who suffered from severe epilepsy, trying to identify the brain areas where the seizures occurred and then surgically removing that area of the brain. Mamelak implanted electrodes into the vPF as part of this process.

"So for a couple of weeks these patients are lying there, bored, waiting for a seizure," says Rizzuto, "and I was able to get their permission to do my study, taking advantage of the electrodes that were already there." The patients watched a computer screen for a flashing target, remembered the target location through a short delay, then reached to that location. "Obviously a very basic task," he says.

"We were looking for the brain regions that may be contributing to planned movements. And what I was able to show is that a part of the brain called the ventrolateral prefrontal cortex is indeed involved in planning these movements." Just by analyzing the brain activity from the implanted electrodes using software algorithms that he wrote, Rizzuto was able to tell with very high accuracy where the target was located while it was on the screen, and also what direction the patient was going to reach to when the target wasn't even there.

Unlike most labs doing this type of research, Andersen's lab is looking at the planning areas of the brain rather than the primary motor area of the brain, because they believe the planning areas are less susceptible to damage. "In the case of a spinal cord injury," says Rizzuto, "communication to and from the primary motor cortex is cut off." But the brain still performs the computations associated with planning to move. "So if we can tap into the planning computations and decode where a person is thinking of moving," he says, then it just becomes an engineering problem--the person can be hooked up to a computer where he can move a cursor by thinking, or can even be attached to a robotic arm.

Andersen notes, "Dan's results are remarkable in showing that the human ventral prefrontal cortex, an area previously implicated in processing information about objects, also processes the intentions of subjects to make movements. This research adds ventral prefrontal cortex to the list of candidate brain areas for extracting signals for neural prosthetics applications."

In Andersen's lab, Rizzuto's goal is to take the technology they've perfected in animal studies to human clinical trials. "I've already met with our first paralyzed patient, and graduate student Hilary Glidden and I are now doing noninvasive studies to see how the brain reorganizes after paralysis," he says. If it does reorganize, he notes, all the technology that has been developed in non-paralyzed humans may not work. "This is why we think our approach may be better, because we already know that the primary motor area shows pathological reorganization and degeneration after paralysis. We think our area of the brain is going to reorganize less, if at all. After this we hope to implant paralyzed patients with electrodes so that they may better communicate with others and control their environment."

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Potential New Approach to Fighting Cancer

PASADENA, Calif. - The immune system is a remarkable defense mechanism, able to defend the body against a lifetime's worth of pathogens and pathogen attractors--bacteria and viruses, toxins and parasites, splinters and cuts--everything, that is, except cancer. Although the immune system handles most of these disease-causing organisms and insults well, it does a poor job of suppressing the growth of tumors.

A major goal of cancer immunotherapy has been to bolster the immune system by generating large numbers of white blood cells (T cells) that could specifically seek and destroy cancer cells. Now, two scientists from the California Institute of Technology have come up with a novel and promising approach to antitumor immunotherapy. Reporting in the online edition of the Proceedings of the National Academy of Sciences (, Lili Yang, a postdoctoral scholar, and David Baltimore, professor of biology, Caltech president, and Nobel Prize recipient, have developed a new methodology they are calling "instructive immunotherapy" that someday may fight human cancer.

In mice and humans, hematopoietic stem cells (HSC) form both red blood cells and immune system cells. In mice, Yang and Baltimore succeeded in altering some HSCs so that they would generate specific kinds of T cells that aggressively attack and destroy specific cancer cells. Once the mouse immune system received this enhancement, it became able to generate its own cancer-specific T cells on a long-term basis. When helped by dendritic cells (another type of immune system cell) carrying a piece of the tumor's marker protein, the methodology achieved the complete elimination of large, established tumors. While the work is preliminary and was done with mice, says Baltimore, instructive immunotherapy could eventually be used for controlling the growth of tumors in humans.

"We've achieved something that could one day prove important," says Baltimore, who was awarded the 1975 Nobel Prize in Physiology or Medicine, "but the first caveat is that this is all with mice, and mice are often not predictive of behavior in humans." Still, he notes, "everything we have done is in principle possible to do in humans, so we plan to try to develop a system for optimizing the ability to program human stem cells."

Yang, a former graduate student of Dr. Baltimore, says current cancer strategies fall into two categories: developing a cancer vaccine, or developing a drug that can be given when cancer is diagnosed. "Our strategy is threefold," she says, "a combination of gene therapy, stem cell therapy, and immunotherapy. When these three methodologies work together, it is possible to provide life-long immunity."

In addition to making billions of new blood cells each day, HSCs are responsible for providing immune protection of every cell type in the body. In fact, HSC transplants are routinely used to treat patients with cancers. In their case, Yang and Baltimore chose to manipulate HSCs for three reasons--because HSCs normally make T cells, they make them by the billions, and they exist in humans through their lifetime.

The first step was to design a retrovirus vector that could deliver genes for both chains of the T cell receptor to HSCs. This was actually the key to the whole study. For this work, two vectors delivering two sets of genes were developed. The HSCs then gave rise to both of the major types of T cells known as CD4 helper cells and CD8 killer cells. Together, these two cell types can recognize the foreign nature of the test cancer cells used in the study and can kill them. The researchers were successful in programming up to a quarter of the mouse's T cells to react to the model tumor. Even better, once modified, the mouse's immune system continued to produce these antigen-specific T cells on its own. However, with this method alone, Yang and Baltimore found that mice were only partially resistant to the tumor cells.

To achieve complete protection required boosting the animal's immune system with dendritic cells carrying a fragment of the tumor cell's marker protein. These dendritic cells are thought to use their long tentacle-like branches (called dendrites) to stimulate the T cells and make them more active. With this combination, Yang and Baltimore were able to achieve the complete shrinkage and suppression of even large, well-established tumors.

Dr. Yang recalled her reaction to the first positive results: "It was a great surprise that the method worked so well. This level of efficacy makes us believe that the method may have real therapeutic potential."

The next step, says Yang, will be to repeat the experiment, this time using conditions that more closely approximate human tumors. After that, if things hold up, the next step will be to start thinking about human trials.

"Producing a state of antitumor immunity has been a dream of immunologists for years, but has been unrealized in humans," says Baltimore. "Here we've developed a methodology that provides a new opportunity to realize this goal. We certainly hope that it will prove to be effective in humans."

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Caltech computer scientists embed computation in a DNA crystal to create microscopic patterns

PASADENA, Calif.--In a demonstration that holds promise for future advances in nanotechnology, California Institute of Technology computer scientists have succeeded in building a DNA crystal that computes as it grows. As the computation proceeds, it creates a triangular fractal pattern in the DNA crystal.

This is the first time that a computation has been embedded in the growth of any crystal, and the first time that computation has been used to create a complex microscopic pattern. And, the researchers say, it is one step in the dream of nanoscientists to master construction techniques at the molecular level.

Reporting in the December issue of the journal Public Library of Science (PLoS) Biology, Caltech assistant professor Erik Winfree and his colleagues show that DNA "tiles" can be programmed to assemble themselves into a crystal bearing a pattern of progressively smaller "triangles within triangles," known as a Sierpinski triangle. This fractal pattern is more complex than patterns found in natural crystals because it never repeats. Natural crystals, by contrast, all bear repeating patterns like those commonly found in the tiling of a bathroom floor. And, because each DNA tile is a tiny knot of DNA with just 150 base pairs (an entire human genome has some 3 billion), the resulting Sierpinski triangles are microscopic. The Winfree team reports growing micron-size DNA crystals (about a hundredth the width of a human hair) that contain numerous Sierpinski triangles.

A key feature of the Caltech team's approach is that the DNA tiles assemble into a crystal spontaneously. Comprising a knot of four DNA strands, each DNA tile has four loose ends known as "sticky ends." These sticky ends are what binds one DNA tile to another. A sticky end with a particular DNA sequence can be thought of as a special type of glue, one that only binds to a sticky end with a complementary DNA sequence, a special "anti-glue''. For their experiments, the authors just mixed the DNA tiles into salt water and let the sticky ends do the work, self-assembling the tiles into a Sierpinski triangle. In nanotechnology this "hands off" approach to manufacturing is a desirable property, and a common theme.

The novel aspect of the research is the translation of an algorithm--the basic method underlying a computer program--into the process of crystal growth. A well-known algorithm for drawing a Sierpinski triangle starts with a sequence of 0s and 1s. It redraws the sequence over and over again, filling up successive rows on a piece of paper, each time performing binary addition on adjacent digits.

The result is a Sierpinski triangle built out of 0s and 1s. To embed this algorithm in crystal growth, the scientists represented written rows of binary "0s" and "1s" as rows of DNA tiles in the crystal--some tiles stood for 0, and others for 1. To emulate addition, the sticky ends were designed to ensure that whenever a free tile stuck to tiles already in the crystal, it represented the sum of the tiles it was sticking to.

The process was not without error, however. Sometimes DNA tiles stuck in the wrong place, computing the wrong sum, and destroying the pattern. The largest perfect Sierpinski triangle that grew contained only about 200 DNA tiles. But it is the first time any such thing has been done and the researchers believe they can reduce errors in the future.

In fact the work is the first experimental demonstration of a theoretical concept that Winfree has been developing since 1995--his proposal that any algorithm can be embedded in the growth of a crystal. This concept, according to Winfree's coauthor and Caltech research fellow Paul W. K. Rothemund, has inspired an entirely new research field, "algorithmic self-assembly," in which scientists study the implications of embedding computation into crystal growth.

"A growing group of researchers has proposed a series of ever more complicated computations and patterns for these crystals, but until now it was unclear that even the most basic of computations and patterns could be achieved experimentally," Rothemund says.

Whether larger, more complicated computations and patterns can be created depends on whether Winfree's team can reduce the errors. Whether the crystals will be useful in nanotechnology may depend on whether the patterns can be turned into electronic devices and circuits, a possibility being explored at other universities including Duke and Purdue.

Nanotechnology applications aside, the authors contend that the most important implication of their work may be a better understanding of how computation shapes the physical world around us. "If algorithmic concepts can be successfully adapted to the molecular context," the authors write, "the algorithm would join energy and entropy as essential concepts for understanding how physical processes create order."

Winfree is an assistant professor of computation and neural systems and computer science; Rothemund is a senior research fellow in computer science and computation and neural systems. The third author is Nick Papadakis, a former staff member in computer science.


Robert Tindol

A "Smoking Gun" For Nicotine Addiction

Embargoed for Release at 11 a.m. PST, Thursday, November 4, 2004

PASADENA, Calif. - Nicotine is responsible for more than four million smoking-related deaths each year. Yet people still smoke. Why? One reason is the stranglehold of addiction, started when nicotine enhances the release of a neurotransmitter called dopamine, a chemical messenger that induces a feeling of pleasure. That's what smoking, presumably, is all about.

Knowing specifically which receptor molecules are activated by nicotine in the dopamine-releasing cells would be a promising first step in developing a therapeutic drug to help people kick the habit. But that's a challenging goal, since there are many cell receptor proteins, each in turn comprising a set of "subunit proteins" that may respond to nicotine, or instead, to a completely different chemical signal. Reporting in the November 5 issue of the journal Science, California Institute of Technology postdoctoral scholar Andrew Tapper, Professor Allan Collins of the University of Colorado, seven other colleagues, and Henry A. Lester, the Bren Professor of Biology at Caltech, have determined that when receptors with a specific subunit known as alpha4 are activated by nicotine, it's sufficient for some addiction-related events, such as pleasure response, sensitization, and tolerance to repeated doses of nicotine. This research suggests that alpha4, and the molecules that are triggered in turn by alpha4, may prove to be useful targets for addiction therapies.

When cells communicate in the brain, nerve impulses jump chemically across a gap between two nerve cells called the synapse, using a neurotransmitter such as acetylcholine. Acetylcholine activates specific receptors on the post-synaptic nerve cell. This starts the firing of electrical impulses and, in cells that manufacture dopamine, that pleasure-inducing messenger is released as well. Having completed its task, acetylcholine is then rapidly broken down by an enzyme called acetylcholinesterase. It's a clever and wondrous biological machine, says Lester. But, he says, "nicotine is clever too, because it mimics acetylcholine." Worse, nicotine is not broken down by acetylcholinesterase. "So it persists at the synapse for minutes rather than milliseconds, and excites the post-synaptic neurons to fire rapidly for long periods, releasing large amounts of dopamine. Most scientists believe that's a key reason why nicotine is so addictive."

Previous work in several laboratories in the 1990s had suggested that, of the many so-called nicotinic acetylcholine receptors, one consisting of subunits called alpha4 and beta2 was important for nicotine addiction. This had been determined by the use of so-called "knockout" mice. In this method, scientists identify a gene that may affect a behavior, then interrupt or knock it out in a specially bred strain of mice. In this case, the effects of nicotine on the knockout mice and normal mice were compared, and the mice without the beta2 subunit lacked some responses to nicotine.

In work to identify receptor subunits that were sufficient to cause nicotine dependence, Lester's group examined the "partner" subunit, alpha4. But instead of experimenting with a knockout mouse, they developed "hypersensitive knock-in" mice. Lester's group replaced a naturally occurring bit of DNA with a mutation that changed a single amino acid in a single gene among the mouse's 30,000 genes. That change was enough to make the alpha4 subunit highly sensitive to nicotine.

Lester's group first selected the proper mutation with tests in frog eggs and cultures, then bred the strain of mice. As they hypothesized, the mice with the re-engineered alpha4 receptor proved to be highly sensitive even to very small doses of nicotine that didn't activate other nicotinic receptor types. This finding shows the alpha4 subunit is a prime candidate to be studied at the molecular and cellular level, says Lester, "and it may be a possible target for developing a medication that would reduce the release of dopamine caused by nicotine, and hopefully reduce nicotine's addictive grip."

Knockout mice leave nothing to measure, explains Lester. Knock-in mice have the advantage, he says, of isolating and amplifying the "downstream" chain of molecular signals within nerve cells that occur after nicotine activates its receptors. These signals, when repeatedly stimulated by nicotine, eventually cause the-as-yet unknown, long-term changes in nerve cells that are presumably the biological basis of addiction. Lester and his colleagues are now tracking down those signals, molecules, and newly activated genes, using their hypersensitive mice. The eventual hope: one of those signals might provide a molecular target that can be specifically blocked, providing a therapy against addiction. This strategy would resemble modern cancer drugs, such as Gleevec, which block only specific signaling molecules needed by proliferating cancer cells. Hypersensitive knock-in mice may also prove useful in gaining further insight into diseases such as epilepsy and Parkinson's disease.

Lester is optimistic about ultimately defeating nicotine's addictive power. "It's a complicated pathway that still must be broken down into individual steps before we can understand it fully," he says, "but I personally believe that nicotine addiction will be among the first addictions to be solved, because we already have so many tools to study it."

This research was supported by the California Tobacco-Related Disease Research Program, the W. M. Keck Foundation, the Plum Foundation, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse.

MEDIA CONTACT: Mark Wheeler (626) 395-8733


Caltech Biologists Pursue Promising New Approach in Treatment of HIV/AIDS and Cancer

PASADENA, Calif.—In response to the arduously slow progress in finding cures for AIDS and cancer, Caltech researchers are now investigating a promising new approach in the treatment of these diseases.

With a $1.5 million matching grant from the Skirball Foundation in New York, Caltech biologists have established the Engineering Immunity project, designed to create a novel immunological approach to treating–and even some day preventing–HIV infection and some cancers like melanoma.

The immune system provides humans with a powerful defense against infectious diseases–but sometimes, it fails. Utilizing an innovative, integrated approach, the Engineering Immunity project will combine gene therapy, stem cell biology, and immunotherapy to arm the immune system; this integrative methodology offers groundbreaking potential for treatment of these diseases and others for which the immune system currently fails to provide defense.

Caltech President David Baltimore, who won the Nobel Prize in 1975 for his work in virology and cancer research, stated, "The Engineering Immunity project advocates a new approach to therapy for AIDS and cancer with revolutionary implications for the treatment of these and many other diseases. It is an innovative research project that holds special significance for the future of biomedical sciences."

In the fight against HIV, the virus that causes AIDS, T-cell immunity and T-cell-focused therapies and vaccines have been methods widely investigated and pursued. However, antibodies often provide the best protection against viruses, and virtually all vaccines for other viral diseases are designed to elicit antibody-based immunity. Antibodies against HIV do appear during HIV infections, but heretofore, they had not been able to provide therapeutic advantage to most patients. Rare neutralizing antibodies have been identified, but have not proven valuable because a general way to elicit their production in all patients has not been found. Moreover, most of them are effective only at very high concentrations that are hard to maintain in a person by conventional means. Thus, early attempts to elicit antibody-based immunity against HIV have largely failed.

The Engineering Immunity integrated methodology involves utilizing retroviruses, which are natural carriers of genes. Retrovirus vectors will be produced that encode antibodies found to be effective against HIV. Utilizing retroviruses, the Baltimore Laboratory at Caltech, in collaboration with Caltech structural biologist Pamela Bjorkman, will introduce specific genes into stem cells. These genes will encode specificity molecules on the immune cells, thereby arming the immune cells to kill selected agents or cells, i.e., the cells that are growing HIV or particular cancer cells.

The Engineering Immunity initiative will provide a new route to the production of antibodies with therapeutic, and even protective, ability for a potential cure of AIDS, melanoma, and other diseases ultimately.

The Skirball Foundation, an independent foundation created in 1950 by Jack H. Skirball, is dedicated primarily to medical research and care, educational and social needs of disadvantaged children, and advancing the highest values of the Jewish heritage. Among the many institutions that the Foundation has supported are the Skirball Cultural Center, the Salk Institute, the Venice Family Clinic, the Jewish Childcare Association in New York City, and the Skirball Institute of Biomolecular Medicine at New York University.


Contact: Deborah Williams-Hedges (626) 395-3227

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