Six Caltech Professors Awarded Sloan Research Fellowships

PASADENA, Calif.— Six Caltech professors recently received Alfred P. Sloan Research Fellowships for 2003.

The Caltech recipients in the field of chemistry are Paul David Asimow, assistant professor of geology and geochemistry, Linda C. Hsieh-Wilson, Jonas C. Peters, and Brian M. Stoltz, assistant professors of chemistry. In mathematics, a Sloan Fellowship was awarded to Danny Calegari, associate professor of mathematics, and in neuroscience, to Athanassios G. Siapas, assistant professor of computation and neural systems.

Each Sloan Fellow receives a grant of $40,000 for a two-year period. The grants of unrestricted funds are awarded to young researchers in the fields of physics, chemistry, computer science, mathematics, neuroscience, computational and evolutionary molecular biology, and economics. The grants are given to pursue diverse fields of inquiry and research, and to allow young scientists the freedom to establish their own independent research projects at a pivotal stage in their careers. The Sloan Fellows are selected on the basis of "their exceptional promise to contribute to the advancement of knowledge."

From over 500 nominees, a total of 117 young scientists and economists from 50 different colleges and universities in the United States and Canada, including Caltech's six, were selected to receive a Sloan Research Fellowship.

Twenty-eight former Sloan Fellows have received Nobel prizes.

"It is a terrific honor to receive this award and to be a part of such a tremendous tradition of excellence within the Sloan Foundation," said Stoltz. Asimow commented that he will use his Sloan Fellowship to "support further investigation into the presence of trace concentrations of water in the deep earth... I'm pleased because funds that are unattached to any particular grant are enormously useful for seeding new and high-risk projects that are not quite ready to turn into proposals." On his research, Peters said, "The Sloan award will provide invaluable seed money for work we've initiated in the past few months regarding nitrogen reduction using molecular iron systems."

The Alfred P. Sloan Research Fellowship program was established in 1955 by Alfred P. Sloan, Jr., who was the chief executive officer of General Motors for 23 years. Its objective is to encourage research by young scholars at a time in their careers when other support may be difficult to obtain. It is the oldest program of the Alfred P. Sloan Foundation and one of the oldest fellowship programs in the country.

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

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Caltech Professor Receives Award for Research into Mechanisms of Memory Formation

PASADENA, Calif.— How do we form short-term and long-term memories in the brain? A California Institute of Technology professor will try to answer this question and others. Athanassios Siapas, assistant professor of computation and neural systems, has been awarded a $445,120 grant by the James S. McDonnell Foundation for his project "Network Mechanisms of Memory Formation."

The establishment of long-term memories is a gradual process that involves intricate interactions across distributed networks of neurons in the brain. Until recently, the direct experimental observation of such interactions was not technically feasible. Using techniques that enable monitoring of the simultaneous activity of large numbers of single neurons across multiple brain areas, Siapas's research group will study the mechanisms that orchestrate memory formation in distributed brain circuits.

Understanding the fundamental principles that underlie memory formation and learning may offer insights into neurological disorders that affect memory, such as Alzheimer's disease, and may aid in finding a cure for such debilitating illnesses.

Siapas joined Caltech in January 2002, after conducting postdoctoral work at the Center for Learning and Memory at the Massachusetts Institute of Technology. Siapas also earned his PhD from MIT.

Founded in 1950 by aerospace pioneer James S. McDonnell, the James S. McDonnell Foundation was established to improve the quality of life, and has done so by contributing to the generation of new knowledge through its support of research and scholarship. In 2002 the foundation awarded approximately $16 million in grants. Since its inception, the McDonnell Foundation has awarded over $264 million in grants.

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

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Caltech, Italian Scientists Find Human Longevity Marker

"A very short one." Oldest known living person in 1995, Jeanne Calment, of France, then 120, when asked what sort of future she anticipated having. Quoted in Newsweek magazine, March 6, 1995.

PASADENA, Calif. – Even though Jeanne Louise Calment died in 1997 at the age of 122, we envy her longevity. Better, perhaps, to envy her mother's lineage, suggest scientists at the California Institute of Technology.

In a study of nonrelated people who have lived for a century or more, the researchers found that the centenarians had something in common: each was five times more likely than the general population to have the same mutation in their mitochondrial DNA (mtDNA).

That mutation, the researchers suggest, may provide a survival advantage by speeding mtDNA replication, thereby increasing its amount or replacing that portion of mtDNA which has been battered by the ravages of aging

The study was conducted by Jin Zhang, Jordi Asin Cayuela, and Yuichi Michikawa, postdoctoral scholars; Jennifer Fish, a research scientist; and Giuseppe Attardi, the Grace C. Steele Professor of Molecular Biology, all at Caltech, along with colleagues from the Universities of Bologna and Calabria in Italy, and the Italian National Research Center on Aging. It appears in the February 4 issue of the Proceedings of the National Academy of Sciences, and online at the PNAS website (

Mitochondrial DNA is the portion of the cell DNA that is located in mitochondria, the organelles which are the "powerhouses" of the cell. These organelles capture the energy released from the oxidation of metabolites and convert it into ATP, the energy currency of the cell. Mitochondrial DNA passes only from mother to offspring. Every human cell contains hundreds, or, more often, thousands of mtDNA molecules.

It's known that mtDNA has a high mutation rate. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and other colleagues found what Attardi described as a "clear trend" in mtDNA mutations in individuals over the age of 65. In fact, in the skin cells the researchers examined, they found that up to 50 percent of the mtDNA molecules had been mutated.

Then, in another study two years ago, Attardi and colleagues found four centenarians who shared a genetic change in the so-called main control region of mtDNA. Because this region controls DNA replication, that observation raised the possibility that some mutations may extend life.

Now, by analyzing mtDNA isolated from a group of Italian centenarians, the researchers have found a common mutation in the same main control region. Looking at mtDNA in white blood cells of a group of 52 Italians between the ages of 99 and 106, they found that 17 percent had a specific mutation called the C150T transition. That frequency compares to only 3.4 percent of 117 people under the age of 99 who shared the same C150T mutation.

To probe whether the mutation is inherited, the team studied skin cells collected from the same individuals between 9 and 19 years apart. In some, both samples showed that the mutation already existed, while in others, it either appeared or became more abundant during the intervening years. These results suggest that some people inherit the mutation from their mother, while others acquire it during their lifetime.

Confirmation that the C150T mutation can be inherited was obtained by looking at mtDNA samples from 20 monozygotic (that is, derived from a single egg) twins and 18 dizygotic (from separate eggs) twins between 60 and 75 years of age. To their surprise, the investigators found that 30 percent of the monozygotic twins and 22 percent of the dizygotic twins shared the C150T mutation.

"The selection of the C150T mutation in centenarians suggests that it may promote survival," says Attardi. "Similarly, it may protect twins early in life from the effects of fetal growth restriction and the increased mortality associated with twin births.

"We found the mutation shifts the site at which mtDNA starts to replicate, and perhaps that may accelerate its replication, possibly, allowing the lucky individual to replace damaged molecules faster." Attardi says the study is the first to show a robust difference in an identified genetic marker between centenarians and younger folks. Their next goal, he says, is to find the exact physiological effect of this particular mutation.

The researchers who contributed to the paper in Italy were Massimiliano Bonafe, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, and Claudio Franceschi.

Contact: Mark Wheeler (626) 395-8733

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Research shows that shear force of blood flowis crucial to embryonic heart development

In a triumph of bioengineering, an interdisciplinary team of California Institute of Technology researchers has imaged the blood flow inside the heart of a growing embryonic zebrafish. The results demonstrate for the first time that the very action of high-velocity blood flowing over cardiac tissue is an important factor in the proper development of the heart—a result that could have profound implications for future surgical techniques and even for genetic engineering.

In the January 9, 2003 issue of the journal Nature, the investigators report on two interrelated advances in their work on Danio rerio, an animal reaching only two inches in length as an adult but a model of choice for research in genetic and developmental biology. First, the team was able to get very-high-resolution motion video, through the use of confocal microscopy, of the tiny beating hearts that are less than the diameter of a human hair. Second, by surgically blocking the flow of blood through the hearts, the researchers were able to demonstrate that a reduction in "shear stress," or the friction imposed by a flowing fluid on adjacent cells, will cause the growing heart to develop abnormally.

The result is especially important, says co-lead author Jay Hove, because it shows that more detailed studies of the effect of shear force might be exploited in the treatment of human heart disease. Because diseases such as congestive heart failure are known to cause the heart to enlarge due to constricted blood flow, a better understanding of the precise mechanisms of the blood flow could perhaps lead to advanced treatments to counteract the enlargement.

Also, Hove says, a better understanding of genetic factors involving blood flow in the heart—a future goal of the team's research—could eventually be exploited in the diagnosis of prenatal heart disease for early surgical correction, or even genetic intervention.

Hove, a bioengineer, along with Liepmann Professor of Aeronautics and Bioengineering Morteza Gharib, teamed with Scott Fraser, who is Rosen Professor of Biology, and Reinhardt Köster, a postdoctoral scholar in Fraser's lab, to study the heart development of zebrafish. Gharib, a specialist on fluid flow, has worked on heart circulation in the past, and Fraser is a leading authority on the imaging of cellular development in embryos. The new results are thus an interdisciplinary marriage of the fields of engineering, biology, and optics.

"Our research shows that the shape of the heart can be changed during the embryonic stage," says Hove. "The results invite us to consider whether this can be related to the roots of heart failure and heart disease."

The researchers keyed their efforts on the zebrafish because the one-millimeter eggs and the embryos inside them are nearly transparent. With the addition of a special chemical to further block the formation of pigment, the team was able to perform a noninvasive, in vivo "optical dissection." To do this, they used a technique known as confocal microscopy, which allows imaging of a layer of tissue. The images are two-dimensional, but they can be "stacked" for a three-dimensional reconstruction.

Concentrating on two groups of embryos—one group 36 hours after fertilization and the other at about four days—the researchers discovered that their deliberate interference with the blood flow through the use of carefully placed beads had a profound effect on heart development. When the shear force was reduced by 90 percent, the tiny hearts did not form valves properly, nor did they "loop," or form an outflow track properly.

Because the early development of an embryonic heart is thought to proceed through several nearly identical stages for all vertebrates, the researchers say the effect should also hold true for human embryos. In effect, the research demonstrates that the shear force should also be a fundamental influence on the formation of the various structures of the human heart.

The next step for the researchers is to attempt to regulate the restriction of shear force through new techniques to see how slight variations affect structural development, and to look at how gene expression is involved in embryonic heart development. " What we learn will give us directions to go and questions to ask about other vertebrates, particularly human beings," Hove says.

In addition to the lead authors Hove and Köster and professors Gharib and Fraser, the team also included Caltech students Arian S. Forouhar and Gabriel Acevedo-Bolton.

The paper is available on the Nature Web site at

Contact: Robert Tindol (626) 395-3631


Caltech, UCLA Researchers Create a New Gene Therapy for Treatment of HIV

PASADENA, Calif.— California Institute of Technology and UCLA researchers have developed a new gene therapy that is highly effective in preventing the HIV virus from infecting individual cells in the immune system. The technique, while not curative, could be used as a significant new treatment for people already infected by reducing the HIV-infected cells in their bodies.

Also, the new approach could be used to fight other diseases resulting from gene malfunctions, including cancer.

Reporting in the current issue of the Proceeding s of the National Academy of Sciences (PNAS), Caltech biologist David Baltimore and his UCLA collaborators announce that the new technique works by using a disabled version of the AIDS virus as a sort of "Trojan horse" to get a disruptive agent inside the human T-cells, thereby reducing the likelihood that a potent HIV virus will be able to successfully invade the cell. Early laboratory results show that more than 80 percent of the T-cells may be protected.

"To penetrate a cell, HIV needs two receptors that operate like doorknobs and allow the virus inside," says Baltimore, who is president of Caltech. "HIV grabs the receptor and forces itself into the cell. If we can knock out one of these receptors, we hope to prevent HIV from infecting the cell."

The receptors in question are called the CCR5 and the CD4. The human immune system can't get along without the CD4, but about 1 percent of the Caucasian population is born without the CCR5. In fact, these people are known to have a natural immunity to AIDS.

Therefore, the researchers' strategy was to disrupt the CCR5 receptor. They did this by introducing a special double-stranded RNA known as "small interfering RNA," or siRNA, into the T-cell. To do so, they engineered a disabled HIV virus to carry the siRNA into the T-cell. Thus, the T-cell was invaded, but the disabled virus has no ability to cause disease. Once inside the T-cell, the siRNA knocks out the CCR5 receptor.

Laboratory results show that human T-cells thus protected are then quite resistant to infection by the HIV virus. When the T-cells were put in a petri dish and exposed to HIV, less than 20 percent of the cells were actually infected.

"Synthetic siRNAs are powerful tools," says Irvin S.Y. Chen, one of the authors of the paper and director of the UCLA AIDS Institute. "But scientists have been baffled at how to insert them into the immune system in stable form. You can't just sprinkle them on the cells."

The other two authors of the paper are Xiao-Feng Qin, a postdoctoral researcher at Caltech; and Dong Sung An, a postdoctoral researcher at UCLA. The two contributed equally to the work.

The technique should become a significant new means of treating people already infected with HIV, Baltimore and Chen say.

"Our findings raise the hope that we can use this approach or combine it with drugs to treat HIV in people—particularly in persons who have not experienced good results with other forms of treatment," says Baltimore.

The technique can also potentially be used for other diseases when a specific gene needs to be knocked out, such as the malfunctioning genes associated with cancer, Chen says. "We can easily make siRNAs and use the carrier to deliver them into different cell types to turn off a gene malfunction," he says.

In addition, the technique could be used to prevent certain microorganisms from invading the body, Baltimore adds.

The research is supported by the National Institute of Allergy and Infectious Diseases and the Damon Runyon-Walter Winchell Fellowship.

[Note to editors: UCLA is also issuing a news release on this research. Contact Elaine Schmidt at (310) 794-2272;]

Robert Tindol

Caltech Professor Receives McKnight Award for Brain Disease Research

PASADENA, Calif. — The McKnight Endowment Fund for Neuroscience will award $300,000 over three years to California Institute of Technology biology professor Paul H. Patterson for research he is conducting on mental illness.

Patterson is one of seven researchers nationally who are each being awarded the same amount in order to further their studies into diagnosing, preventing, and treating injuries or diseases affecting the brain and spinal cord.

Patterson's research is "A Mouse Viral Model for Study of the Pathogenesis and Prevention of Mental Illness." It is based on the knowledge that when a pregnant mother contracts influenza at a certain stage of pregnancy, there is an increase in the chance that her child will be schizophrenic, or possibly autistic. Patterson uses a mouse model to determine how maternal infection causes defects in fetal brain development, and to attempt to prevent the brain abnormalities.

Other McKnight Neuroscience of Brain Disorders Awards will go to U.S. scientists investigating Alzheimer's disease, epilepsy, mood disorders, schizophrenia, and spongiform encephalopathies.

The McKnight Endowment Fund created the Neuroscience of Brain Disorders Awards to help translate basic laboratory discoveries in neuroscience into clinical benefits for patients. The first such awards were given in 2001.

"Neuroscience has made tremendous progress over the last few decades, and that progress is reflected in the research proposals we see," said Larry R. Squire, chair of the awards committee. Dr. Squire is a professor of psychiatry, neurosciences, and psychology at the University of California at San Diego School of Medicine, and research career scientist at the Veterans Affairs Medical Center, San Diego. "Scientists not only are exploring fundamental questions about the structure and function of the nervous system but are finding applications for their work in the clinical arena," he said.

The McKnight Endowment Fund for Neuroscience is an independent organization funded solely by the McKnight Foundation of Minneapolis, Minnesota, and led by a board of prominent neuroscientists from around the country. The McKnight Foundation has supported neuroscience research since 1977. The foundation established the Endowment Fund in 1986 to carry out one of the intentions of founder William L. McKnight (1887-1979). One of the early leaders of the 3M Company, he had a personal interest in memory and its diseases and wanted part of his legacy used to help find cures.

The Endowment Fund makes three types of awards each year. In addition to the McKnight Neuroscience of Brain Disorders Awards, they are the McKnight Technological Innovations in Neuroscience Awards, providing seed money to develop technical inventions to advance brain research; and the McKnight Scholar Awards, supporting neuroscientists in the early stages of their research careers.

Caltech Contact: Jill Perry, Media Relations Director (626) 395-3226

McKnight Foundation Contact: Kathleen Rysted

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Caltech Biologist Pamela BjorkmanWins Max Planck Research Prize

Pamela Bjorkman, professor of and executive officer for biology at the California Institute of Technology, has been awarded the Max Planck Research Prize by the Max Planck Society in Germany. She joins 11 other outstanding international researchers in this year's honor.

The award is presented each year to "individual foreign and German researchers who lead their respective fields with regard to outstanding, internationally recognized scientific achievements," according to the society's official Website. The award carries a cash prize of up to $125,000 euros (approximately $125,000), and enables winners to collaborate intensively and on a long-term basis with partners from around the world.

Bjorkman, a specialist in the mechanisms of the immune system, has been a member of the Caltech faculty since 1989. She also holds an appointment as a full investigator with the Howard Hughes Medical Institute. She is a graduate of Harvard University.

In naming Bjorkman to the honor, the society cited her work in determining how the human immune system fights disease at the molecular level, especially in the differentiation between endogenous and alien proteins.

"Bjorkman has contributed greatly to elucidating these mechanisms with the help of molecular immunology—particularly by determining the crystal structure of the MHC complex," according to the award citation. "It is the differences between the MHC molecules in each individual person which are responsible for the rejection reaction occurring in organ transplantations. And these differences also play a role in the detection of diseased cells.

"Bjorkman was able to show that the MHC molecules not only present alien but also endogenous peptides. If the latter are misidentified by the T cells as alien peptides, healthy cells and tissues are destroyed. Thus it became clear where the reasons for autoimmune diseases may be found."

Contact: Robert Tindol (626) 395-3631

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Cellular choreography, not molecular prepattern, creates repeated segments of vertebrate embryo

In a study that combines state-of-the-art biological imaging with gene expression analysis, scientists at the California Institute of Technology have uncovered a fundamental insight into the way embryonic cells and tissue move about to form key structures along the vertebrate axis. The study, which could lead to a better understanding of human development, takes advantage of the accessibility of chick embryos to embryonic manipulation.

The study by Caltech biologists Scott Fraser and Paul Kulesa, appearing in the November 1 issue of the journal Science, centers on segments known as somites, which form along either side of the future spinal cord of an embryo. Somites give rise to mature structures such as ribs, individual vertebrae, and even skin. The key role of somite segmentation in the patterning of the nervous system and the vertebral column has been long known. But the question of precisely how an individual somite buds off from a block of tissue in a pattern that is repeated all along the animal's torso, from head to tail, is poorly understood.

"Developmental biologists have had a difficult time getting a handle on how cell movements and gene expression patterns are coordinated to form complex structures, in this case the segmented units called somites," says Kulesa, a postdoctoral scholar in Fraser's lab and lead author of the paper. "The problems have been due to limitations in obtaining cellular resolution of tissue deep within living vertebrate embryos and difficulty in coordinating the cell movements and tissue shaping in living tissue with gene expression patterns typically obtained at one time point from fixed, non-living tissue."

The new insight of the paper is that the factors that determine the embryo's ultimate form as well as the eventual position of its cells involve a complicated set of motions of the cells themselves. Previous models of embryonic patterning had suggested that there was a molecular prepattern that subdivided the tissues, somewhat like a "paint-by-numbers" piece of art. The study thus shows the action of a more complex coordination between physical forces within the tissue and gene expression patterns that determine where an embryonic cell will go and what type of structure it will help form.

Kulesa and Fraser's study is made possible with a new culture technique combined with confocal time-lapse microscopy, an advanced form of imaging that allows the tissue of a living, developing embryo to be studied in intricate detail at the cellular level. Time-lapse imaging involves, first, labeling the tissue so that it will fluoresce when exposed to laser light, then passing a laser through the tissue, then reconstructing the fluorescent patterns of individual cells to form a three-dimensional microscopic image. The laser scans over the tissue of the developing embryo every minute or so, which allows the researchers to gather the hundreds of images taken during a several-hour run into a time-lapse video.

Using fertilized eggs, the researchers placed an embryo into a specially designed chamber to allow for high-resolution time-lapse imaging, and afterwards performed gene expression analyses on the same embryo. Thus, they were both videotaping cell movements for 6-to-12 hours as well as analyzing the expression of several genes, including EphA4 and c-Meso1, both thought to play a role in determining future somite boundary sites.

The results showed that the straight-line patterns of gene expression, which were thought to correlate with a simple, periodic slicing of the tissue into blocks, did not predict the complex cell movements. Time-lapse imaging showed that a ball-and-socket separation of tissue takes places in a series of six repeatable steps.

"It turns out that a somite pulls apart from the block of tissue, and cells move in anterior and posterior directions near the forming somite boundary," Kulesa says. "This is contrary to many models of somite segmentation which assume that gene expression boundaries that correlate with presumptive somite boundaries allocate cells into a particular block with very little cell movement.

"This study tells us that we have to be careful about assuming that gene expression patterns strictly determine a cell's fate and position."

Kulesa says the next step is to do the work in mouse embryos, which pose considerably more difficult challenges for developmental imaging, but have a tremendous advantage over chick-embryo imaging in attempting to isolate the role of key genes through gene manipulation.



Robert Tindol

Caltech Professor Awarded Wilson Medal for Insights Into the Life Cycle of Cells

Ubiquitin is the Swiss Army knife of proteins. Long known to be ubiquitous in all organisms (hence the name, of course), it plays important roles in cell growth, division, and death, in DNA repair, and in the body's response to stress.

For his discovery of the ubiquitin system and its crucial physiological functions, the California Institute of Technology's Alexander Varshavsky has been named the co-recipient of the 2002 E. B. Wilson Medal, the highest scientific honor given by the American Society for Cell Biology (ASCB).

Varshavsky, the Smits Professor of Cell Biology, will share the award with Avram Hershko of the Technion—Israel Institute of Technology. Working separately, the pair made complementary discoveries of ubiquitin's many unique functions.

Ubiquitin is a small protein that attaches itself to other proteins within a cell that have outlived their usefulness, marking them for destruction. Hershko's initial studies uncovered ubiquitin's role in protein degradation in extracts derived from whole cells. Then, using cells from mice and baker's yeast as model organisms, Varshavsky proved that it is indeed ubiquitin that's essential for this natural process to take place. His laboratory also discovered that the ubiquitin system plays major roles in a number of biological processes, including cell growth and division, DNA repair, and responses to stress.

Subsequent work by numerous laboratories uncovered many other functions of this remarkable system, including its multiple roles in the functioning of the brain (for example, memory formation), in the development of most organs in the body, and in the regulation of general metabolism.

Scientists are now striving to understand the role of ubiquitin in many human diseases, including cancer, bacterial and viral infections, and neurodegenerative syndromes like Parkinson's and Alzheimer's diseases. Varshavsky's work on the ubiquitin system was instrumental in making possible the current efforts to devise new classes of drugs to attack such diseases.

Varshavsky is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society. He has received many of the top international prizes in biology and medicine, including the Wolf Prize, the Horwitz Prize, and the Merck Award, (all in 2001), the 2000 Sloan Prize from the General Motors Cancer Research Foundation, the 2000 Albert Lasker Award, and the 1999 Gairdner Award.

The ASCB's E. B. Wilson Medal, named for an early 20th-century pioneer of American biology who advocated the chromosomal theory of inheritance, is awarded by scientific peers to those who have made highly significant and far-reaching contributions to cell biology over the course of a career. The society will present its award to Varshavsky and Hershko on December 15 in San Francisco, during the 42nd ASCB Annual Meeting.

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Humans and chimps have 95 percent DNA compatibility, not 98.5 percent, research shows

Genetic studies for decades have estimated that humans and chimpanzees possess genomes that are about 98.5 percent similar. In other words, of the three billion base pairs along the DNA helix, nearly 99 of every 100 would be exactly identical.

However, new work by one of the co-developers of the method used to analyze genetic similarities between species says the figure should be revised downward to 95 percent.

Roy Britten, a biologist at the California Institute of Technology, reports in the current issue of the journal Proceedings of the National Academy of Sciences that the large amount of sequencing that has been done in recent years on both the human and chimp genomes—and improvements in the techniques themselves—allow for the issue to be revisited. In the article, he describes the method he used, which involved writing a special computer program to compare nearly 780,000 base pairs of the human genome with a similar number from the chimp genome.

To describe exactly what Britten did, it is helpful to explain the old method as it was originally used to determine genetic similarities between two species. Called hybridization, the method involved collecting tiny snips of the DNA helix from the chromosomes of the two species to be studied, then breaking the ladder-like helixes apart into strands. Strands from one species would be radioactively labeled, and then the two strands recombined.

The helix at this point would contain one strand from each species, and from there it was a fairly straightforward matter to "melt" the strands to infer the number of good base pairs. The lower the melting temperature, the less compatibility between the two species because of the lower energy required to break the bonds.

In the case of chimps and humans, numerous studies through the years have shown that there is an incidence of 1.2 to 1.76 percent base substitutions. This means that these are areas along the helix where the bases (adenine, thymine, guanine, and cytosine) do not correspond and hence do not form a bond at that point.

The problem with the old studies is that the methods did not recognize differences due to events of insertion and deletion that result in parts of the DNA being absent from the strands of one or the other species. These are different from the aforementioned substitutions. Such differences, called "indels," are readily recognized by comparing sequences, if one looks beyond the missing regions for the next regions that do match.

To accomplish the more complete survey, Britten wrote a Fortran program that did custom comparisons of strands of human and chimp DNA available from GenBank. With nearly 780,000 suitable base pairs available to him, Britten was able to better infer where the mismatches would actually be seen if an extremely long strand could be studied. Thus, the computer technique allowed Britten to look at several long strands of DNA with 780,000 potential base pairings.

As expected, he found a base substitution rate of about 1.4 percent—well in keeping with earlier reported results—but also an incidence of 3.9 percent divergence attributable to the presence of indels. Thus, he came up with the revised figure of 5 percent.

As for the implications, Britten says the new work should help biologists with future work on precisely how species branch off from each other, and why. "The basic question you would like to answer is what makes the chimp different from humans—what were the basic changes in the genome that mattered.

"A large number of these 5 percent of variations are relatively unimportant. But what matters, according to everyone's idea, is regulation of the genes, which is controlled by the genes that are actually expressed. So to address this issue, you first have to know how different the genomes are, and second, where the differences are located.

The article is available from PNAS by contacting Jill Locantore, the public information officer, at, or by calling 202-334-1310.

Contact: Robert Tindol (626) 395-3631



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