Caltech Researchers Achieve First Electrowetting of Carbon Nanotubes

PASADENA, Calif.—If you can imagine the straw in your soda can being a million times smaller and made of carbon, you pretty much have a mental picture of a carbon nanotube. Scientists have been making them at will for years, but have never gotten the nanotubes to suck up liquid metal to form tiny wires. In fact, conventional wisdom and hundreds of refereed papers say that such is not even possible.

Now, with the aid of an 1875 study of mercury's electrical properties, researchers from the California Institute of Technology have succeeded in forcing liquid mercury into carbon nanotubes. Their technique could have important applications, including nanolithography, the production of nanowires with unique quantum properties, nano-sized plumbing for the transport of extremely small fluid quantities, and electronic circuitry many times smaller than the smallest in existence today.

Reporting in the December 2 issue of the journal Science, Caltech assistant professor of chemistry Patrick Collier and associate professor of chemical engineering Konstantinos Giapis describe their success in electrowetting carbon nanotubes. By "electrowetting" they mean that the voltage applied to a nanotube immersed in mercury causes the liquid metal to rise into the nanotube by capillary action and cling to the surface of its inner wall.

Besides its potential for fundamental research and commercial applications, Giapis says that the result is an opportunity to set the record straight. "We have found that when measuring the properties of carbon nanotubes in contact with liquid metals, researchers need to take into account that the application of a voltage can result in electrically activated wetting of the nanotube.

"Ever since carbon nanotubes were discovered in 1991, people have envisioned using them as molds to make nanowires or as nanochannels for flowing liquids. The hope was to have the nanotubes act like molecular straws," says Giapis.

However, researchers never got liquid metal to flow into the straws, and eventually dismissed the possibility that metal could even do so because of surface tension. Mercury was considered totally unpromising because, as anyone knows who has played with liquid mercury in chemistry class, a glob will roll around a desktop without wetting anything it touches.

"The consensus was that the surface tension of metals was just too high to wet the walls of the nanotubes," adds Collier, the co-lead author of the paper. This is not to say that researchers have never been able to force anything into a nanotube: in fact, they have, albeit by using more complex and less controllable ways that have always led to the formation of discontinuous wires.

Collier and Giapis enter the picture because they had been experimenting with coating nanotubes with an insulator in order to create tiny probes for future medical and industrial applications. In attaching nanotubes to gold-coated atomic force microscope tips to form nanoprobes, they discovered that the setup provided a novel way of making liquid mercury rise in the tubes by capillary action.

Casting far beyond the nanotube research papers of the last decade, the researchers found an 1875 study by Nobel Prize-winning physicist Gabriel Lippmann that described in detail how the surface tension of mercury is altered by the application of an electrical potential. Lippmann's 1875 paper provided the starting point for Collier and Giapis to begin their electrowetting experiments.

After mercury entered the nanotubes with the application of a voltage, the researchers further discovered that the mercury rapidly escaped from the nanotubes immediately after the voltage was turned off. "This effect made it very difficult to provide hard proof that electrowetting occurred," Collier said. In the end, persistence and hard work paid off as the results in the Science paper demonstrate.

Giapis and Collier think that they will be able to drive various other metals into the nanotubes by employing the process at higher temperature. They hope to be able to freeze the metal nanowires in the nanotubes so that they remain intact when the voltage is turned off.

"We can pump mercury at this point, but it's possible that you could also pump nonmetallic liquids," Giapis says. "So we now have a way of pumping fluids controllably that could lead to nanofluidic devices. We envision making nano-inkjet printers that will use metal ink to print text and circuitry with nanometer precision. These devices could be scaled up to operate in a massively parallel manner. "

The paper is titled "Electrowetting in Carbon Nanotubes." In addition to Collier and Giapis, the other authors are Jinyu Chen, a postdoctoral scholar in chemistry, and Aleksandr Kutana, a postdoctoral scholar in chemical engineering.

Robert Tindol
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Researchers uncover new details about how signals are transmitted in the brain

PASADENA, Calif.—An international team of scientists has announced a new breakthrough in understanding the molecular details of how signals move around in the human brain. The work is basic research, but could help pharmacologists design new drugs for treating a host of neurological disorders, as well as drugs for reducing alcohol and nicotine craving.

Reporting in the November 11 issue of the journal Nature, researchers from the California Institute of Technology and the University of Cambridge explain how they have learned to force a protein known as the 5-HT3 receptor to change its function by chemically changing the shape of one of the amino acids from which it is built. Using a technique developed at Caltech known as "unnatural amino mutagenesis," the researchers altered a proline amino acid in the 5-HT3 protein in order to modulate the receptor's ion channel. This gave the researchers control of the "switch" that is involved in neuron signaling.

According to Dennis Dougherty, lead author of the paper and the Hoag Professor of Chemistry at Caltech, the new research solves a 50-year-old mystery of how a neuroreceptor is changed by a chemical signal. Scientists have long known that signaling in the brain is a chemical process, in which a chemical substance known as a neurotransmitter is released into the synapse of a nerve and binds to a neuroreceptor, which is a protein that is found in the surface membranes of neurons. The action of the neurotransmitter changes the neuroreceptor in such a way that a signal is transmitted, but the precise nature of the structural change was unknown until now.

"The key is that we've identified the switch that has to get thrown when the neuroreceptor sends a signal," Dougherty says. "This switch is a proline."

The 5-HT3 receptor is one of a group of molecular structures in the brain cells that are known as Cys-loop receptors, which are associated with Parkinson's disease, schizophrenia, and learning and attention deficit disorders, as well as alcoholism and nicotine addiction. For treatments of some of these conditions, pharmacologists already custom-design drugs that have a general effect on the Cys-loop receptors. But the hope is that better design at the molecular level will lead to much better treatments that address more precisely the underlying signaling problems.

Dougherty says the work required the collaboration of organic chemists, molecular biologists, electrophysiologists and computer modelers. His Caltech group worked closely with the research group of Caltech biologist Henry Lester, and with the group at Cambridge headed by Sarah Lummis, to establish how proline changes its structure to open an ion channel and launch a neuron signal.

"This is the most precise model of receptor signaling yet developed, and it provides valuable insights into the nature of neuroreceptors and the drugs that modulate them," Dougherty says.

"The promise for pharmacology is that precise control of the signaling could lead to new ways of dealing with receptors that are malfunctioning," says Lester, Caltech's Bren Professor of Biology. "The fundamental understanding of how this all works is of value to people who want to manipulate the signaling."

The 5-HT3 receptor is also involved in the enjoyment people derive from drinking alcohol. If the 5-HT3 receptors are blocked, then alcoholics no longer get as much pleasure from drinking. Therefore, better control of the signaling mechanism could lead to more potent drug interventions for alcoholics. The nicotine receptors are also related, so progress could also lead to better ways of reducing the craving for nicotine.

In addition to Dougherty, Lester, and Lummis, the other authors of the paper are Caltech graduate students Darren Beene (now graduated) and Lori Lee, and Cambridge researcher William Broadhurst.

The research is supported by the National Institute of Neurological Disorders and Stroke.

Robert Tindol

Caltech Chemist Robert Grubbs Wins Nobel Prize

PASADENA, Calif.--Robert Grubbs, an organic chemist whose work on catalysis has led to a wide variety of applications in medicine and industry, has won the 2005 Nobel Prize in chemistry. The announcement was made this morning by the Royal Swedish Academy of Sciences in Stockholm.

Grubbs and this year's other two winners were cited specifically "for the development of the metathesis method in organic synthesis." Metathesis is an organic reaction in which chemists selectively strip out certain atoms in a compound and replace them with atoms that were previously part of another compound. The end result is a custom-built molecule that has specialized properties that can lead to better drugs for the treatment of disease, or better electrical conducting properties for specialized plastics, for example.

In particular, Grubbs has worked on olefin metathesis. Prior to Grubbs's work, metathesis was poorly understood and of limited value to scientists. Grubbs developed powerful new catalysts for metathesis that enabled custom synthesis of valuable molecules, such as pharmaceuticals and new polymers with novel materials properties.

According to the Nobel citation, metathesis has already led to industrial and pharmaceutical methods that are more efficient and less wasteful, simpler, and more environmentally friendly. "This represents a great step forward for 'green chemistry,' reducing potentially hazardous waste through smarter production," the Royal Swedish Academy announced.

"Metathesis is an example of how important basic science has been applied for the benefit of man, society, and the environment," the citation continued.

Grubbs is currently spending a month at the University of Canterbury in Christchurch, New Zealand, as an Erskine Fellow. In an e-mail message, he singled out his students and collaborators and said that he was especially pleased that the Nobel committee had chosen to recognize the research that had taken place at Caltech.

"I'm excited for all the outstanding students and postdoctoral fellows who have contributed to this work over the years," Grubbs wrote.

Grubbs added that he has been swamped with calls since the announcement was made earlier today, and that his son--a physician currently serving a residency at the USC Medical School--has been swamped with calls as well.

"Sometime when I'm more rested and I'm available in person, I'll be happy to sit down and discuss the work this award represents," he wrote.

Grubbs' award was an especially welcomed going-away present for Caltech president David Baltimore, who just Monday announced his pending retirement. Baltimore, himself a Nobel laureate, said he was pleased that the Nobel committee had recognized a Caltech researcher whose work had so direct an impact on biomedicine.

"Bob's work shows that basic chemical research continues to have importance to pharmaceuticals and industry, and it also shows that the sometimes highly esoteric work young people do in the lab is a huge contribution to society," said Baltimore. "I congratulate Bob on joining Caltech's growing list of Nobel laureates, and I envy his young students for the elation they're feeling today."

Grubbs is a native of Kentucky who earned his bachelor's and master's degrees at the University of Florida. After completing his doctorate in chemistry at Columbia University, he spent a year at Stanford University as a postdoctoral fellow, and then joined the Michigan State University faculty in 1969. He came to Caltech in 1978 with full tenure as a professor, and has been the Victor and Elizabeth Atkins Professor of Chemistry since 1990.

Grubbs has been a member of the National Academy of Sciences since 1989, and was the 2000 recipient of the Benjamin Franklin Medal.

Today's award brings to 32 the total number of prizes won by 31 Caltech faculty and alumni through the years (Linus Pauling won awards in both chemistry and peace).


Scientists Uncover Rules that Govern the Rate of Protein Evolution

PASADENA, Calif.--Humans and insects and pond scum-and all other living things on Earth-are constantly evolving. The tiny proteins these living things are built from are also evolving, accumulating mutations mostly one at a time over billions of years. But for reasons that hitherto have been a mystery, some proteins evolve quickly, while others take their sweet time-even when they reside in the same organism.

Now, a team of researchers at the California Institute of Technology, applying novel data-mining methods to the now-completed sequence of the yeast genome, have uncovered a surprising reason why different proteins evolve at different rates.

Reporting in the September 19 edition of the journal Proceedings of the National Academy of Sciences (PNAS), lead author Allan Drummond and his coauthors from Caltech and the Keck Graduate Institute show that the evolution of protein is governed by their ability to tolerate mistakes during their production. This finding disputes the longstanding assumption that functionally important proteins evolve slowly, while less-important proteins evolve more quickly.

"The reason proteins evolve at different rates has been a mystery for decades in biology," Drummond explains. But with the recent flood of sequenced genomes and inventories of all the pieces and parts making up cells, the mystery deepened. Researchers discovered that the more of a protein that was produced, the slower it evolved, a trend that applies to all living things. But the reason for this trend remained obscure, despite many attempts to explain it.

Biologists have long known that the production machinery that translates the genetic code into proteins is sloppy. So much so, in fact, that on average about one in five proteins in yeast is mistranslated, the equivalent of translating the Spanish word "Adios" as "Goofbye." The more copies of a protein produced, the more potential errors. And mistakes can be costly: some translation errors turn proteins into useless junk that can even be harmful (like miscopying a digit in an important phone number), while other errors can be tolerated. So the more protein copies per cell, the more potential harm-unless those abundant proteins themselves can evolve to tolerate more errors.

"That was the 'Aha!'" says Drummond. "We knew from our experiments with manipulating proteins in the lab that some had special properties that allowed them to tolerate more changes than other proteins. They were more robust." So, what if proteins could become robust to translation errors? That would mean fewer harmful errors, and thus a more fit organism.

To test predictions of this hypothesis, the team turned to the lowly baker's yeast, a simple one-celled organism that likes to suck up the nutrients in bread dough, and then expels gas to give baked bread its fluffy texture. Baker's yeast is not only a simple organism, it is also extraordinarily well understood. Just as biologists have now sequenced the human genome, they have also sequenced the yeast genome. Moreover, the numbers of every type of protein in the yeast cell have been painstakingly measured.

For example, there's a protein in the yeast cell called PMA1 that acts as a transformer, converting stored energy into more useful forms. Since nothing living can do without energy, this is a very fundamental and important component of the yeast cell. And every yeast cell churns out about 1.26 million individual PMA1 molecules, making it the second-most abundant cellular protein.

The old assumption was that PMA1 changed slowly because its energy-transforming function was so fundamental to survival. But the Caltech team's new evidence suggests that the sheer number of PMA1 molecules produced is the reason that the protein doesn't evolve very quickly.

"The key insight is that natural selection targets the junk proteins, not the functional proteins," says Drummond. "If translation errors turned 5 percent of the PMA1 proteins in a yeast cell into junk, those junk proteins would be more abundant than 97 percent of all the other proteins in the cell. That's a huge amount of toxic waste to dispose of."

So instead, Darwinian evolution favors yeast cells with a version of PMA1 that continues to function despite errors, producing less junk. That version of PMA1 evolves slowly because the slightest changes destroy its crucial ability to withstand errors.

Consider two competing computer factories. Both make the same number of mistakes on their assembly lines, but one company's computers are designed such that the inevitable mistakes result in computers that still work, while with the other company's design, one mistake and the computer must be tossed on the recycling heap. In the cutthroat marketplace, the former company, with lower costs and higher output, will quickly outcompete the latter.

Likewise, viewing yeast cells as miniature factories, the yeast whose most-abundant proteins are least likely to be destroyed by production mistakes will outcompete its less-efficient rivals. The more optimized those high-abundance proteins are--the more rigid the specifications that make them so error-resistant-the slower they evolve. Hence, high abundance means slow evolution.

The team is now exploring other predictions of this surprising hypothesis, such as what specific chemical changes allow proteins to resist translation errors. "It's the tip of the iceberg," Drummond says.

Drummond is a graduate student in Caltech's interdisciplinary Computation and Neural Systems program. The other authors of the paper include his two advisors: Frances Arnold, the Dickinson Professor of Chemical Engineering and Biochemistry at Caltech, and Chris Adami, an expert in population genetics who is now at the Keck Graduate Institute in Claremont, California. The other authors are Jesse D. Bloom, a graduate student in chemistry at Caltech; and Claus Wilke, a former postdoctoral researcher of Adami's who has recently joined the University of Texas at Austin as an assistant professor.

The title of the PNAS paper is "Why highly expressed proteins evolve slowly."


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Caltech, MIT Chemists Look for Better Waysto Use Chemical Bonds to Store Solar Energy

PASADENA, Calif.-With gasoline prices hovering at $3 per gallon, probably few Americans need convincing that another energy crisis is imminent. But what precisely is to be done about our future energy needs is still a puzzle. There's talk about a "hydrogen economy," but hydrogen itself poses some formidable challenges.

The key challenge is, of course, how to make the hydrogen in the first place. The best and cheapest methods currently available involve burning coal or natural gas, which means more greenhouse gases and more pollution. Adopting the cheapest method by using natural gas would merely result in replacing our dependence on foreign oil with a dependence on foreign gas.

"Clearly, one clean way to get hydrogen is by splitting water with sunlight," says Harry Gray, who is the Beckman Professor of Chemistry at the California Institute of Technology.

Gray is involved with several other Caltech and MIT chemists in a research program they call "Powering the Planet." The broadest goal of the project is to "pursue efficient, economical ways to store solar energy in the form of chemical bonds," according to the National Science Foundation (NSF). With a new seed grant from the NSF and the possibility for additional funding after the initial three-year period, the Caltech group says they now have the wherewithal to try out some novel ideas to produce energy cheaply and cleanly.

"Presently, this country spends more money in 10 minutes at the gas pump than it puts into a year of solar-energy research," says Nathan S. Lewis, the Argyros Professor and professor of chemistry. "But the sun provides more energy to the planet in an hour than all the fossil energy consumed worldwide in a year."

The reason that Gray and Lewis advocate the use of solar energy is that no other renewable resource has enough practical potential to provide the world with the energy that it needs. But the sun sets every night, and so use of solar energy on a large scale will necessarily require storing the energy for use upon society's demand, day or night, summer or winter, rain or shine.

As for non-renewable resources, nuclear power plants would do the job, but 10,000 new ones would have to be built. In other words, one new nuclear plant would have to come on-line every other day somewhere in the world for the next 50 years.

The devices used in a simple experiment in the high school chemistry lab to make hydrogen by electrolysis are not currently the cheapest ones to use for mass production. In fact, the tabletop device that breaks water into hydrogen and oxygen is perfectly clean (in other words, no carbon emissions), but it requires a platinum catalyst. And platinum has been selling all year for more than $800 per ounce.

The solution? Find something cheaper than platinum to act as a catalyst. There are other problems, but this is one that the Caltech group is starting to address. In a research article now in press, Associate Professor of Chemistry Jonas Peters and his colleagues demonstrate a way that cobalt can be used for catalysis of hydrogen formation from water.

"This is a good first example for us," says Peters. "A key goal is to try to replace the current state-of-the-art platinum catalyst, which is extremely expensive, with something like cobalt, or even better, iron or nickel. We have to find a way to cheaply make solar-derived fuel if we are to ever really enable widespread use of solar energy as society's main power source."

"It's also a good example because it shows that the NSF grant will get us working together," adds Gray. "This and other research results will involve the joint use of students and postdocs, rather than individual groups going it alone."

In addition to the lab work, the Caltech chemists also have plans to involve other entities outside campus--both for practical and educational reasons. One proposal is to fit out a school so that it will run entirely on solar energy. The initial conversion would likely be done with existing solar panels, but the facility would also serve to provide the researchers with a fairly large-scale "lab" where they can test out new ideas.

"We'd build it so that we could troubleshoot solar converters we're working on," explains Gray.

The ultimate lab goal is to have a "dream machine with no wires in it," Gray says. "We visualize a solar machine with boundary layers, where water comes in, hydrogen goes out one side, and oxygen goes out the other."

Such a machine will require a lot of work and a number of innovations and breakthroughs, but Lewis says the future of the planet depends on moving away from fossil fuels.

"If somebody doesn't figure this out, and fast, we're toast, both literally and practically, due to a growing dependence on foreign oil combined with the increasing projections of global warming."

The NSF grant was formally announced August 11 as a means of funding a new group of chemical bonding centers that will allow research teams to pursue problems in a manner "that's flexible, tolerant of risk, and open to thinking far outside the box." The initial funding to the Caltech and MIT group for the "Powering the Planet" initiative is $1.5 million for three years, with the possibility of $2 to $3 million per year thereafter if the work of the center appears promising.

In addition to Gray, Lewis, and Peters, the other Caltech personnel include Jay Winkler and Bruce Brunschwig, both chemists at Caltech's Beckman Institute. The two faculty members from MIT involved in the initiative are Dan Nocera and Kit Cummins.

Jonas Peters's paper will appear in an upcoming issue of the journal Chemical Communications. In addition to Peters and Lewis, the other authors are Brunschwig, Xile Hu, a postdoctoral researcher in chemistry at Caltech, and Brandi Cossairt, a Caltech undergraduate.


Robert Tindol

All-Female Chemical Engineering Graduating Class at Caltech This Year

PASADENA, Calif.-"I am not a novelty. . . It is not amazing that girls are engineers-it's normal," says Victoria Loewer, a member of the class of 2005 at the California Institute of Technology. Loewer is referring to the fact that she is a member of the first all-female chemical engineering graduating class at Caltech, a significant milestone in the history of the Institute.

This graduating class reflects a change in today's scientific, technological, and academic environments. More than 30 percent of the undergraduate students now attending Caltech are female.

Loewer is joined by Maryam Ali, Michelle Giron, Haluna Gunterman, Shannon Lewis, and Joan Karen Sum Ping. And these graduates do not see their unprecedented accomplishment as anything special.

Gunterman, from Placerville, was a little put off by the attention placed on the students' gender. She says, "I doubt if any of us thought much about sitting in chemical engineering classes that were 100 percent female as opposed to 35 percent for most other courses; it felt no different. Ironically, this may have been true especially because we are at Caltech, where the gender stereotype of women not being in science fields is turned on its head; hence, there were no preconceived notions about what we-as students admitted by the same standards-could or could not do. And while we may think nothing of it, there is some fun in being able to see people's shocked expressions when they hear of a 100 percent female graduating class, in [chemical] engineering of all majors, at Caltech of all places." Gunterman intends to pursue a PhD in chemical engineering at UC Berkeley this fall.

Loewer, from Arlington, Virginia, who took the environmental engineering track as a Caltech chemical engineering undergraduate, is contemplating focusing on materials when she enters the chemical engineering PhD program at MIT in the fall.

Maryam Ali is from Islamabad, Pakistan. Her area of interest is biomaterials. She plans to attend graduate school in chemical engineering at Auburn University.

Michelle Giron, from Los Angeles, is particularly interested in materials. She plans on attending Cornell University to pursue a PhD in chemical engineering.

Hailing from Alexandria, Virginia, Shannon Lewis focused on materials while at Caltech. Lewis will enter the PhD program in materials science and engineering at the University of Texas at Austin in the coming year.

Joan Karen Sum Ping is from Tombeau Bay, Mauritius. At Caltech as a chemical engineering undergraduate, she took the environmental engineering track. She plans to pursue a JD at George Washington University Law School.

The executive officer for chemical engineering, McCollum-Corcoran Professor of Chemical Engineering and professor of environmental science and engineering Richard Flagan, says, "This is the first group of Caltech students to graduate under a revised chemical engineering curriculum that was designed to be more responsive to increasing job diversity in industry, and allowed students to emphasize one of the many different areas in which chemical engineers are now working. Today's chemical engineers are no longer just involved in fuels or chemicals processing; their jobs now include environmental engineering, materials, biochemistry, microelectronics, consulting on Wall Street, and working in corporate law firms. We broadened and diversified the chemical engineering curriculum at Caltech, and have attracted women into a profession that was previously male dominated; this group of graduates is significant in the sense that it shows that we are making progress and have finally turned the corner in bringing women into a discipline that, heretofore, has had relatively small numbers of women. We are extremely proud of these students."

And while the current number of women in science still may not be adequate, it is significantly increasing. According to the U.S. Department of Education, as of 2003, the U.S. population is 50.8 percent female, with more than 56 percent of all undergraduate students being women. And according to the same data, in 1970 the percentage of bachelor's degrees conferred on females in engineering was 1 percent; as of 2001, the percentage was 20 percent. In the physical sciences in 1970, 14 percent of bachelor's degrees were conferred on females; in 2001, the percentage increased to 41 percent. In 1970, 37 percent of mathematics degrees went to women; in 2001, 48 percent. And in computer and information science, women earned 13 percent of the degrees in 1970, and 28 percent in 2001. (Source: U.S. Department of Education, National Center for Education Statistics, 2004.)

The Caltech Division of Chemistry and Chemical Engineering describes its discipline as "the science of change," and says that chemists and chemical engineers are involved not just in understanding, but in changing the material world around us. These words could also describe the impact of this graduating class

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Caltech Chemical Biologist SpecializingIn Brain Chemistry Named HHMI Investigator

PASADENA, Calif.--California Institute of Technology chemical biologist Linda Hsieh-Wilson has been named one of this year's new Howard Hughes Medical Institute Investigators. Hsieh-Wilson's research integrates chemistry and neurobiology to understand how the cells of the brain communicate with one another.

Hsieh-Wilson, an assistant professor of chemistry at Caltech, joins 42 other American researchers in the new coterie of HHMI Investigators. The prestigious grant is presented to researchers who have shown particularly high promise in their first four to 10 years as independent scientists.

"These scientists are on the rapidly rising slope of their careers and have made surprising discoveries in a short period of time," says Thomas R. Cech, the president of HHMI. "We have every reason to believe that they will use their creativity to extend the boundaries of scientific knowledge for many years to come."

For Hsieh-Wilson, a major focus of her research is to understand how the structure of carbohydrates and other molecules impacts the function of proteins in the brain. In so doing, she is breaking down boundaries between fields and extending an understanding of how the brain works at the molecular and even atomic level.

"The HHMI award gives us greater freedom and flexibility," says Hsieh-Wilson, who arrived at Caltech four and a half years ago. " We can take risks, explore new areas, and take our science to the next level."

The HHMI's biography of Hsieh-Wilson sums up her current research as the quest to discover how "the right chemistry keeps the brain working properly." To investigate the role of carbohydrates on proteins, for example, she has created new chemical tools for studying a chemical process known as glycosylation, which is thought to be important for functions such as learning, memory, and motor control. Hsieh-Wilson's research also has an important medical component in that she is studying how glycosylation may have a role in the molecular basis of diseases such as diabetes, Alzheimer's, and cancer.

Hsieh-Wilson is also the winner of an Alfred P. Sloan Research Fellowship, a Beckman Young Investigator Award, and a National Science Foundation Faculty Early Development (CAREER) Program award. A graduate of Yale with a bachelor's degree in chemistry, she earned her doctorate in bioorganic chemistry at UC Berkeley before joining Rockefeller University to do research in neurobiology.

The election of Hsieh-Wilson and Dianne Newman, Caltech's other new HHMI Investigator, brings the total number of HHMI Investigators in residence on campus to nine.

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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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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Systems Biology Could Augur New Age for Predictive and Preventive Medicine

PASADENA, Calif./SEATTLE--The dream of monitoring a patient's physical condition through blood testing has long been realized. But how about detecting diseases in their very early stages, or evaluating how they are responding to treatment, with no more to work with than a drop of blood?

That dream is closer to realization than many of us think, according to several leading experts advocating a new approach known as systems biology. Writing in the current issue of the journal Science, Institute for Systems Biology immunologist and technologist Leroy Hood and California Institute of Technology chemist Jim Heath and their colleagues explain how a new approach to the way that biological information is gathered and processed could soon lead to breakthroughs in the prevention and early treatment of a number of diseases.

The lead author of the Science article is Leroy Hood, a former Caltech professor and now the founding director of the Institute for Systems Biology in Seattle. According to Hood, the focus of medicine in the next few years will shift from treating disease--often after it has already seriously compromised the patient's health--to preventing it before it even sets in.

Hood explains that systems biology essentially analyzes a living organism as if it were an electronic circuit. This approach requires a gigantic amount of information to be collected and processed, including the sequence of the organism's genome, and the mRNAs and proteins that it generates. The object is to understand how all of these molecular components of the system are interrelated, and then predict how the mRNAs or proteins, for example, are affected by disturbances such as genetic mutations, infectious agents, or chemical carcinogens. Therefore, systems biology should be useful for diseases resulting from genetics as well as from the environment.

"Patients' individual genome sequences, or at least sections of them, may be part of their medical files, and routine blood tests will involve thousands of measurements to test for various diseases and genetic predispositions to other conditions," Hood says. "I'll guarantee you we'll see this predictive medicine in 10 years or so."

"In this paper, we first describe a predictive model of how a single-cell yeast organism works," Heath explains, adding that the model covers a metabolic process that utilizes copious amounts from data such as messenger RNA concentrations from all the yeast's 6,000 genes, protein-DNA interactions, and the like.

"The yeast model taught us many lessons for human disease," Heath says. "For example, when yeast is perturbed either genetically or through exposure to some molecule, the mRNAs and proteins that are generated by the yeast provide a fingerprint of the perturbation. In addition, many of those proteins are secreted. The lesson is that a disease, such as a very early-stage cancer, also triggers specific biological responses in people. Many of those responses lead to secreted proteins, and so the blood provides a powerful window for measuring the fingerprint of the early-stage disease."

Heath and his colleagues write in the Science article that, with a sufficient number of measurements, "one can presumably identify distinct patterns for each of the distinct types of a particular cancer, the various stages in the progression of each disease type, the partition of the disease into categories defined by critical therapeutic targets, and the measurement of how drugs alter the disease patterns. The key is that the more questions you want answered, the more measurements you need to make. It is the systems biology approach that defines what needs to be measured to answer the questions."

In other words, the systems biology approach should allow therapists to catch diseases much earlier and treat them much more effectively. "This allows you to imagine the pathway toward predictive medicine rather than reactive medicine, which is what we have now," Heath says.

About 100,000 measurements on yeast were required to construct a predictive network hypothesis. The authors write that 100,000,000 measurements do not yet enable such a hypothesis to be formulated for a human disease. In the conclusion of the Science article, the authors address the technologies that will be needed to fully realize the systems approach to medicine. Heath emphasizes that most of these technologies, ranging from microfluidics to nanotechnologies to molecular-imaging methods, have already been demonstrated, and some are already having a clinical impact. "It's not just a dream that we'll be diagnosing multiple diseases, including early stage detection, from a fingerprick of blood," Heath says.

"Early-stage versions of these technologies will be demonstrated very soon."

The other authors of the paper are Michael E. Phelps of the David Geffen School of Medicine at UCLA, and Biaoyang Lin of the Institute for Systems Biology.

Robert Tindol

Chemists at Caltech devise new, simpler wayto make carbohydrates

PASADENA, Calif.--Chemists at the California Institute of Technology have succeeded in devising a new method for building carbohydrate molecules in a simple and straightforward way that requires very few steps. The new synthesis strategy should be of benefit to scientists in the areas of chemistry and biology and in the pharmaceutical industry.

In an article published online August 12 by the journal Science on the Science Express Website, Caltech chemistry professor David MacMillan and his graduate student Alan Northrup describe their new method of making carbohydrates in two steps. This is a major improvement over current methods, which can require up to a dozen chemical steps.

"The issue with carbohydrate utilization is that, for the last 100 years, scientists have needed many chemical reactions to differentiate five of the six oxygen atoms present in the carbohydrate structure," explains MacMillan, a specialist in organic synthesis. "We simplified this to two steps by the invention of two new chemical reactions that are based on an old but powerful chemical transformation known as the aldol reaction. Furthermore, we have devised methods to selectively build oxygen differentiated glucose, mannose, or allose in just two chemical steps."

MacMillan has also demonstrated that this new method for carbohydrate synthesis allows easy access to unnatural carbohydrates for use in medicinal chemistry and glycobiology as well as in a number of diagnostic techniques. One application involves a rare form or carbon known as carbon-13, which is easier to identify with magnetism-based analytical methods.

By using the readily available and inexpensive 13C-labeled form of ethylene glycol, MacMillan and Northrup have been able to construct the all-13C-labeled versions of carbohydrates in only four chemical steps. For comparison, the previous total synthesis of this all-13C-labeled carbohydrate was accomplished in 44 chemical steps.

"Carbohydrates are essential to human biology, playing key roles in everything from our growth and development to our immune system and brain functions," says John Schwab, a chemist at the National Institute of General Medical Sciences, which supported the research. "They also play critical roles in plants, bacteria, and viruses, where they have huge implications for human health. But because they are so difficult to work with, carbohydrates are not nearly as well understood as DNA and proteins.

"MacMillan's technique will allow scientists to more easily synthesize and study carbohydrates, paving the way for a deeper understanding of these molecules, which in turn may lead to new classes of drugs and diagnostic tools," Schwab adds.

"One of the central goals of chemical synthesis is to design new ways to build molecules that will greatly benefit other scientific fields and ultimately society as a whole," MacMillan says. "We think that this new chemical sequence will help toward this goal; however, there is a bounty of new chemical reactions that are simply waiting to be discovered that will greatly impact many other areas of research in the biological and physical sciences."

The title of the paper is "Two Step Synthesis of Carbohydrates by Selective Aldol Reactions." The paper will be published in the journal Science at a later date.



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