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.

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Robert Tindol
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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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New Class of Reagents Developed by Caltech Chemical Biologists for In Vivo Protein Tracking

PASADENA, Calif.--One of the big problems in biology is keeping track of the proteins a cell makes, without having to kill the cell. Now, researchers from the California Institute of Technology have developed a general approach that measures protein production in living cells.

Reporting in the July 26 issue of the journal Chemistry and Biology, Caltech chemistry professor Richard Roberts and his collaborators describe their new method for examining "protein expression in vivo that does not require transfection, radiolabeling, or the prior choice of a candidate gene." According to Roberts, this work should have great impact on both cell biology and the new field of proteomics, which is the study of all the proteins that act in living systems.

"This work is a result of chemical biology—chemists, and biologists working together to gain new insights into a huge variety of applications, including cancer research and drug discovery," says Roberts.

"Generally, there is a lack of methods to determine if proteins are made in response to some cellular stimuli and what those specific proteins are," Roberts says. "These are two absolutely critical questions, because the behavior of a living cell is due to the cast of protein characters that the cell makes."

Facing this problem, the Roberts team tried to envision new methods that would enable them to decipher both how much and what particular protein a cell chooses to make at any given time. They devised a plan to trick the normal cellular machinery into labeling each newly made protein with a fluorescent tag.

The result is that cells actively making protein glow brightly on a microscope slide, much like a luminescent Frisbee on a dark summer night. Importantly, these tools can also be used to determine which particular protein is being made, in much the same way that a bar code identifies items at a supermarket checkout stand.

To demonstrate this method, the team used mouse white blood cells that are very similar to cells in the human immune system. These cells could be tagged to glow various colors, and the tagged proteins later separated for identification.

Over the next decade, scientists hope to better understand the 30,000 to 40,000 different proteins inside human cells. The authors say they are hopeful that this new approach will provide critical information for achieving that goal.

The title of the paper is "A General Approach to Detect Protein Expression In Vivo Using Fluorescent Puromycin Conjugates." For more information, contact Heidi Hardman at hhardman@cell.com.

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Robert Tindol
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Zewail Named to TIAA-CREF Board of Trustees

PASADENA, Calif.— Ahmed H. Zewail, Nobel laureate and the Linus Pauling Professor of Chemical Physics and professor of physics at the California Institute of Technology, has been named to the board of trustees of TIAA-CREF (Teachers Insurance and Annuity Association-College Retirement Equities Fund).

CREF is an investment company within the TIAA-CREF group of companies and Zewail will serve on the CREF board joining seven other renowned economists and leaders in the education and finance sectors.

"As a scientist I feel I'm also a citizen of the world and should make every effort to help our society. TIAA-CREF is a special institution charting the future of education and educators and I will do my best to aid in this noble mission," said Zewail.

"We are honored and delighted that Ahmed Zewail has joined our Board of Trustees. As one of the world's most eminent scholars and researchers, he is superbly qualified to help us fulfill our commitment to institutions and individuals in the not-for-profit community who contribute so much to our society," said TIAA-CREF chairman, president and CEO Herb Allison.

TIAA-CREF is a national financial services leader and the premier retirement system for education and research employees. It has $307 billion in assets and 2.9 million retirement system participants within 15,000 participating institutions.

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White House Names Three from Caltech Faculty as Presidential Early Career Award Winners

PASADENA, Calif.—Three members of the faculty at the California Institute of Technology have been named among the most recent winners of the prestigious Presidential Early Career Award for Scientists and Engineers (PECASE). The honor was announced today by the White House.

The three are Babak Hassibi, an electrical engineer who studies data transmission and wireless communications system; Mark Simons, a geophysicist who specializes in understanding the mechanical behavior of Earth using radar and other satellite observations of the motions of Earth's surface; and Brian Stoltz, an organic chemist who specializes in the synthesis of structurally complex, biologically active molecules.

Hassibi was cited by the White House for his "fundamental contributions to the theory and design of data transmission and reception schemes that will have a major impact on new generations of high-performance wireless communications systems. He has nurtured creativity in his undergraduate and graduate students by involving them in research and inspiring them to apply new approaches to communications problems."

An associate professor of electrical engineering at Caltech and a faculty member since 2001, Hassibi earned his bachelor's degree from the University of Tehran in 1989, and his master's and doctorate degrees from Stanford in 1993 and 1996, respctively. He is the holder or coholder of four patents for communications technology, and is the winner of several awards, including the 2002 National Science Foundation Career Award, the 1999 American Automatic Control Council O. Hugo Schuck Best Paper Award, the 2003 David and Lucille Packard Fellowship for Science and Engineering, and the 2002 Okawa Foundation Grant for Telecommunications and Information Sciences.

Simons, an associate professor of geophysics, combines satellite data with continuum mechanical models of Earth to study ongoing regional crustal dynamics, including volcanic and tectonic deformation in Iceland, crustal deformation and the seismic cycle in California, Chile, and Japan, and volcanic and tectonic deformation in and around Long Valley, California. He also uses the gravity fields of the terrestrial planets to study the large-scale geodynamics of mantle convection and its relationship to tectonics.

Simons earned his bachelor's degree at UCLA in 1989, and his doctorate from MIT in 1995. He was a postdoctoral scholar at Caltech for two years before joining the faculty in 1997.

Stoltz has been an assistant professor of chemistry at Caltech since 2000. He earned his bachelor's degree at Indiana University of Pennsylvania in 1993, his master's and doctorate degrees at Yale University in 1996 and 1997, respectively. Before joining the Caltech faculty he spent two years at Harvard University as a National Institutes of Health (NIH) Postdoctoral Fellow. His work is aimed at developing new strategies for creating complex molecules with interesting structural, biological, and physical properties. The goal is to use these complex molecules to guide the development of new reaction methodology to extend fundamental knowledge and to potentially lead to useful biological and medical applications.

Stoltz, an Alfred P. Sloan Fellow, is the recipient of a Research Corporation Cottrell Scholars Award, the Camille and Henry Dreyfus New Faculty Award, and the Pfizer Research Laboratories Creativity in Synthesis Award. Additionally, he was named as an Eli Lilly Grantee in 2003 and has won a number of young faculty awards from pharmaceutical companies such as Merck Research Laboratories, Abbott Laboratories, GlaxoSmithKline, Johnson & Johnson, Amgen, Boehringer Ingelheim, and Roche. At Caltech he won the 2001 Graduate Student Council Teaching Award and Graduate Student Council Mentoring Award.

The PECASE awards were created in 1996 by the Clinton Administration "to recognize some of the nation's most promising junior scientists and engineers and to maintain U.S. leadership across the frontiers of scientific research." The awards are made to those whose innovative work is expected to lead to future breakthroughs.

 

 

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Two Caltech Faculty Receive Franklin Medals

PASADENA—Two members of the California Institute of Technology faculty, chemist Harry Gray and biologist Seymour Benzer, are among this year's recipients of the prestigious Benjamin Franklin Medals.

The honor is bestowed annually by the Franklin Institute in Philadelphia to outstanding American scientists and technologists. Approaching its 180th anniversary, the Franklin Medal has been presented in the past to Albert Einstein, Samuel F. B. Morse, Alexander Graham Bell, Steven Hawking, Gordon Moore, Jane Goodall, and Noam Chomsky, among others. Past recipients have also won 103 Nobel Prizes through the years.

Gray, who is being recognized for his work in metalloproteins, is the Beckman Professor of Chemistry and founding director of the Beckman Institute at Caltech. A Caltech professor since 1966, he served as chair of the Division of Chemistry and Chemical Engineering from 1978 to 1984. He is a member of the National Academy of Sciences, received the National Medal of Science in 1986, and is also the recipient of the Wolf Prize and the Harvey Prize. Gray was named a foreign member of Great Britain's Royal Society, as well as a member of the American Philosophical Society.

Benzer is the Boswell Professor of Neuroscience, Emeritus, at Caltech, and a preeminent molecular biologist who has worked on phage genetics, nervous system development, and behavioral genetics of the fruit fly. He has been at Caltech since 1965. He is a member of the National Academy of Sciences. He received the National Medal of Science in 1983, and is also the recipient of the Lasker Award, the Wolf Prize, the Crafoord Prize, and the Harvey Prize. He is a member of the Royal Society and the American Philosophical Society.

Benzer and Gray will be honored in Philadelphia on April 29 at the annual Franklin Institute Awards Ceremony and Dinner, which is held in the Benjamin Franklin National Memorial.

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Robert Tindol
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Revolutionary Chemical Instrument Receives Historical Recognition

PASADENA, Calif. -- In the mid-1930s, Arnold O. Beckman, then an assistant professor of chemistry at the California Institute of Technology, solved a problem confronting the California citrus industry: how to get a rapid and accurate measure of the acidity of lemon juice. His pH meter--a faster and simpler acid and alkaline measuring device--revolutionized instrumentation.

On Wednesday, March 24, the development of the Beckman pH meter will be designated a National Historic Chemical Landmark in a special ceremony at Caltech. The American Chemical Society, the world's largest scientific society, is sponsoring the landmark program. Charles P. Casey, president of the society, will present the bronze plaque to David A. Tirrell, chair of the division of chemistry and chemical engineering at Caltech.

The Beckman pH meter was the first commercially successful electronic pH meter. Beckman soon discovered there was a market for the instrument, which he manufactured on the side while he continued his academic career. Strong sales led Beckman to leave his teaching post in 1939 and devote his full attention to the company.

Beckman Instruments went on to become a leader in manufacturing instruments used in medicine, industry, and scientific research. Now called Beckman Coulter, it is a multinational company with sales in excess of $2 billion last year.

Later in his long life (he will be 104 in April), Beckman turned to philanthropy. The Arnold and Mabel Beckman Foundation--established in 1977--has donated more than $350 million to support scientific research and education. The foundation provides ongoing research support to five Beckman centers and institutions in the United States, including one at Caltech (which is in addition to numerous other generous gifts by the Arnold and Mabel Beckman Foundation to Caltech).

The American Chemical Society established the chemical landmarks program in 1992 to recognize seminal historic events in chemistry and increase public awareness of the contributions of chemistry to society. The program will begin at 2 p.m. in the Beckman Institute auditorium on the Caltech campus. Speakers include John D. Roberts, institute professor of chemistry, emeritus, Caltech; Gerald Gallwas, the Arnold and Mabel Beckman Foundation; Arnold Thackray, the Chemical Heritage Foundation; and Harry Gray, Arnold O. Beckman Professor of Chemistry and the founding director of the Beckman Institute.

 

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Professor Harry Gray Awarded Wolf Prize

PASADENA, Calif. — Harry Gray still recalls the day in 1982 when, after eight years of research, he and his colleagues finally proved that electrons can literally jump from one molecule to another. "I was ecstatic," recalls the California Institute of Technology chemist. "My whole group was ecstatic." Gray is referring to electron transfer (ET), the process of moving an electron from one place to another, which is critical for life.

For his insight into ET, Gray, the Arnold O. Beckman professor of chemistry and the founding director of the Beckman Institute at Caltech, has been awarded the 2004 Wolf Prize in Chemistry. Specifically, the Wolf foundation is honoring Gray for his "pioneering work in bio-inorganic chemistry, unraveling novel principles of structure and long-range electron transfer in proteins." The prize includes an honorarium of $100,000.

"It is really special to be recognized for experimental work that's been done with students and other good friends," says Gray. "It has been so much fun."

Electron-transfer reactions are ubiquitous in the chemistry of biological systems. They are a fundamental process that, among other functions, are responsible for the generation of energy in a cell.

Gray studies the tiny bits of inorganic material in living molecules, such as iron or copper, which, within proteins, have long been known to transfer electrons. But conventional wisdom held that in order for such exchanges to take place, the molecules had to be physically close enough to interact. The puzzle was how the few metal atoms in proteins, surrounded by thousands of other atoms, could maneuver close enough for the exchange. Further, in biological systems the timing always has to be perfect in order to allow for such things as breaking down food and generating energy, conducting photosynthesis, or fixing nitrogen.

The answer, Gray and his colleagues discovered, is that in biological systems, electrons really do jump, and jump big-his work shows that electrons can leap across at least 30 atoms in a large protein molecule in less than one millionth of a second.

His insights could have practical applications in a number of areas. Because ET plays a role in the body's natural barriers against foreign substances, his work may influence the design of drugs to get around these barriers. It also has implications for computer miniaturization, energy storage, and the effort to develop an artificial counterpart to photosynthesis. Gray, a Caltech professor since 1966, is the recipient of numerous distinguished honors and awards. These include the National Medal of Science in 1986 and six national awards from the American Chemical Society, including the Priestley Medal, the Society's highest honor. Last year he received both the National Academy of Sciences Award in Chemical Sciences and an honorary degree from the University of Copenhagen that included an audience with Queen Margrethe II of Denmark.

The Wolf Prize was established in 1978 and is designed to promote science and art for the benefit of mankind. In presenting him the prize, the foundation noted "his ingenious chemistry, meticulously executed, has given us a real understanding, for the first time, of a biological process of great significance for life."

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Caltech engineers announce new, more promising type of electrolyte for fuel cells

PASADENA, Calif.—The quest for a cheap and robust fuel cell for future cars may be a bit closer this week to the "grail" moment. Scientists at the California Institute of Technology have announced that they're getting promising results with a new material that solves various limitations of previously tested fuel cells.

In an article published online November 20 by the journal Science on the Science Express Website, associate professor of materials science and chemical engineering Sossina Haile and her colleagues report that they have created a new phosphate-based electrolyte to go inside the fuel cells. The new substance, formally named cesium dihydrogen phosphate is, for a variety of reasons, better than the team's previously favored electrolyte, which was based on a sulfate.

"It's a whole new way of doing fuel cells that opens up tremendous possibilities for system simplification," says Haile, a leading authority on fuel cell technology. Haile's most spectacular results in recent years have been with the "solid acid" electrolytes, such as both the phosphate and the sulfate materials, that ferry current along the fuel cell in a way that minimizes the use of expensive parts that rapidly wear out.

Fuel cells have for some time been promoted as a way to help wean global society away from its addiction to gasoline and internal-combustion engines. Like a combustion engine, a fuel cell uses some sort of chemical fuel as its energy source, but like a battery, the chemical energy is directly converted to electrical energy, without a messy and inefficient combustion step.

The components in a fuel cell that make this direct electrochemical conversion possible are an electrolyte, a cathode, and an anode. In the simplest example hydrogen fuel is brought into the anode compartment and oxygen is brought into the cathode compartment. There is an overall chemical force driving the oxygen and the hydrogen to react to produce water.

In the fuel cell, however, the direct chemical reaction is prevented by the electrolyte that separates the fuel (H2) from the oxidant (O2). The electrolyte serves as a barrier to gas diffusion, but it will let protons migrate across it. In order for the reaction between hydrogen and oxygen to occur, the hydrogen molecules shed their electrons to become protons. The protons then travel across the electrolyte and react with oxygen atoms at the cathode, where they also pick up electrons to produce neutral water. An additional requirement for these electrochemical reactions to occur is that there be some external path through which the electrons migrate; it is precisely this electron motion that provides usable electricity from the fuel cell.

Traditional fuel cells, which utilize polymer electrolytes, are hampered by a number of problems. The most notable are the cells' inability to operate at high temperatures, their requirement for complicated water regulation systems, and their failure to control fuel diffusion.

Haile and her associates have addressed these shortcomings by creating a novel fuel cell with a solid-acid electrolyte. Solid acids have unique properties that lie between those of normal acids and normal salts. Importantly, solid acids are very efficient at conducting protons when they are heated to "warm" temperatures.

However, their use for any application was largely ignored because they are water-soluble and difficult to fabricate into useful forms. In previous work, Haile explored the applicability of the solid acid CsHSO4 as a fuel cell electrolyte and demonstrated the successful operation of such a fuel cell. She found that the key to creating a functional solid-acid fuel cell is an operation temperature above 100 degrees C, which ensures that water in the system, which would otherwise dissolve and leach away the solid acid, is present as harmless steam.

The CsHSO4 electrolyte fuel cell suffered from a serious problem that prohibited its use for power generation. Specifically, the output of the fuel cell decreased over time as the hydrogen fuel reacted with the solid acid in the presence of the catalyst. As reported in their Science paper, Haile and her colleagues circumvented this problem by replacing the CsHSO4 solid acid with CsH2PO4, which does not react with hydrogen.

According to Haile, they were initially hesitant to use this material because it decomposes via dehydration into a nonuseful salt. However, they found that humidifying the fuel cell anode and cathode chambers with a relatively low level of water vapor could prevent the dehydration reaction and thereby maintain the fuel cell for long-term power generation.

Haile's humidity-stabilized CsH2PO4 fuel cells solve several critical problems that have plagued polymer fuel cell development. First, these solid-acid fuel cells can be operated at higher temperatures than those built with polymer electrolytes, which are limited to temperatures less than 100 degrees C. Operation at "warm" temperatures, 100-–300 degrees C, brings a number of benefits to fuel cell technology. Most directly, catalyst activity is enhanced, resulting in higher-efficiency fuel cells and allowing one to use less of the expensive catalyst.

In addition, the susceptibility of the catalyst to poisoning from carbon monoxide contamination of the fuel decreases. As a consequence, the fuel stream need not be purified as thoroughly as for polymer fuel cells, reducing the overall system complexity. Perhaps most significantly, operation at warm temperatures opens up the possibility of using less-expensive base-metal catalysts, which are not active enough to be considered for low temperature applications.

Additional system simplifications come about from the fact that the radiator necessary for maintaining a fuel cell at about 200 degrees C is much smaller than the one required for maintaining a temperature of about 90 degrees C. This has significant implications for automotive applications. Warm-temperature operation can furthermore be easily integrated with onboard hydrogen-generation systems that produce hydrogen also at warm temperatures. For a polymer electrolyte fuel cell, the hydrogen stream from these generators has to be cooled before it can be introduced into the cell.

Solid-acid fuel cells can be operated in the temperature range of 100–300 degrees C because, unlike polymers, they do not rely on water molecules to transport protons from one side of the membrane to the other. This "dry" proton transport results in additional advantages. In particular, there is no longer a need to remove water that accumulates at the cathode and replenish it at the anode. As a consequence, the overall system is, again, significantly simplified.

In the case of CsH2PO4, a small amount of water partial pressure, equivalent to about 10 percent relative humidity at 100 degrees C, is required in order to prevent dehydration of the material, but no water recirculation is necessary. The dry, solid-acid electrolytes are furthermore much less corrosive than their hydrated, polymer counterparts. This allows for much more flexibility in the choice of materials for the other components of the fuel cell system.

Where solid-acid fuel cells have tremendous advantages over polymer electrolyte fuel cells is in the use of alcohol (e.g., methanol) fuels. Hydrogen "stored" as methanol results in a liquid fuel with a high energy density, which is much easier to transport, store, and carry on board than hydrogen, says Haile. Polymer-based fuel cells do not work well with alcohol fuels because the fuel diffuses across the electrolyte, consuming fuel without generating electrical output. The solid-acid electrolytes are entirely impermeable to methanol, which means very high power outputs are possible—much higher than from polymer fuel cells running on methanol.

While the solid-acid fuel cells solve many of the problems of polymer fuel cells, there are still a few obstacles standing in the way of extensive fuel cell use. A continuing problem of the solid-acid fuel cells is the water solubility of the electrolytes. Haile suggests that clever engineering could circumvent this drawback. However, she plans to solve this problem by developing new solid-acid materials that are water-insoluble.

In developing humidity-stabilizing CsH2PO4 fuel cells, Haile was assisted by the lead author Dane Boysen, a graduate student in materials science; and Tetsuya Uda and Calum Chisholm, both postdoctoral scholars in Haile's lab.

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Atmospheric scientists still acquire samples the old-fashioned way--by flying up and getting them

PASADENA, Calif.—Just as Ishmael always returned to the high seas for whales after spending time on land, an atmospheric researcher always returns to the air for new data.

All scientific disciplines depend on the direct collection of data on natural phenomena to one extent or another. But atmospheric scientists still find it especially important to do some empirical data-gathering, and the best way to get what they need is by taking up a plane and more or less opening a window.

At the California Institute of Technology, where atmospheric science is a major interest involving researchers in several disciplines, the collection of data is considered important enough to justify the maintenance of a specially equipped plane dedicated to the purpose. In addition to the low-altitude plane, several Caltech researchers who need higher-altitude data are also heavy users of the jet aircraft maintained by NASA for its Airborne Science Program--a longstanding but relatively unsung initiative with aircraft based at the Dryden Flight Research Center in California's Mojave Desert.

"The best thing about using aircraft instead of balloons is that you are assured of getting your instruments back in working order," says Paul Wennberg, professor of atmospheric chemistry and environmental engineering science. Wennberg, whose work has been often cited in policy debates about the human impact on the ozone layer, often relies on the NASA suborbital platforms (i.e., various piloted and drone aircraft operating at mid to high altitudes) to collect his data.

Wennberg's experiments typically ride on the high-flying ER-2, which is a revamped reconnaissance U-2. The plane has room for the pilot only, which means that the experimental equipment has to be hands-free and independent of constant technical attention. Recently, Wennberg's group has made measurements from a reconfigured DC-8 that has room for some 30 passengers, depending on the scientific payload, but the operating ceiling is some tens of thousands of feet lower than that of the ER-2.

"The airplane program has been the king for NASA in terms of discoveries," Wennberg says. "Atmospheric science, and certainly atmospheric chemistry, is still very much an observational field. The discoveries we've made have not been by modeling, but by consistent surprise when we've taken up instruments and collected measurements."

In his field of atmospheric chemistry, Wennberg says the three foundations are laboratory work, synthesis and modeling, and observational data--the latter being still the most important.

"You might have hoped we'd be at the place where we could go to the field as a confirmation of what we did back in the lab or with computer programs, but that's not true. We go to the field and see things we don't understand."

Wennberg sometimes worries about the public perception of the value of the Airborne Science Program because the launching of a conventional jet aircraft is by no means as glamorous or romantic as the blasting off of a rocket from Cape Canaveral. By contrast, his own data-collection would appear to most as bread-and-butter work involving a few tried-and-true jet airplanes.

"If you hear that the program uses 'old technology,' this refers to the planes themselves and not the instruments, which are state-of-the-art," he says. "The platforms may be old, but it's really a vacuous argument to say that the program is in any way old.

"I would argue that the NASA program is a very cost-effective way to go just about anywhere on Earth and get data."

Chris Miller, who is a mission manager for the Airborne Science Program at the Dryden Flight Research Center, can attest to the range and abilities of the DC-8 by merely pointing to his control station behind the pilot's cabin. On his wall are mounted literally dozens of travel stick-ons from places around the world where the DC-8 passengers have done research. Included are mementos from Hong Kong, Singapore, New Zealand, Australia, Japan, Thailand, and Greenland, to name a few.

"In addition to atmospheric chemistry, we also collect data for Earth imaging, oceanography, agriculture, disaster preparedness, and archaeology," says Miller. "There can be anywhere from two or three to 15 experiments on a plane, and each experiment can be one rack of equipment to half a dozen."

Wennberg and colleagues Fred Eisele of the National Center for Atmospheric Research and Rick Flagan, who is McCollum Professor of Chemical Engineering, have developed special instrumentation to ride on the ER-2. One of their new instruments is a selected-ion- chemical ionization mass spectrometer, which is used to study the composition of the atmospheric aerosols and the mechanisms that lead to its production.

Caltech's Nohl Professor and professor of chemical engineering, John Seinfeld, conducts an aircraft program that is a bit more down-to-earth, at least in the literal sense.

Seinfeld is considered perhaps the world's leading authority on atmospheric particles or so-called aerosols--that is, all the stuff in the air like sulfur compounds and various other pollutants not classifiable as a gas. Seinfeld and his associates study primarily atmospheric particles, their size, their composition, their optical properties, their effect on solar radiation, their effect on cloud formation, and ultimately their effect on Earth's climate.

"Professor Rick Flagan and I have been involved for a number of years in an aircraft program largely funded by the Office of Naval Research, and established jointly with the Naval Postgraduate School in Monterey. The joint program was given the acronym CIRPAS," says Seinfeld, explaining that CIRPAS, the Center for Interdisciplinary Remotely Piloted Aircraft Studies, acknowledges the Navy's interest in making certain types of environmental research amenable for drone aircraft like the Predator.

"The Twin Otter is our principal aircraft, and it's very rugged and dependable," he adds. "It's the size of a small commuter aircraft, and it's mind-boggling how much instrumentation we can pack in this relatively small aircraft."

Caltech scientists used the plane in July to study the effects of particles on the marine strata off the California coast, and the plane has also been to the Canary Islands, Japan, Key West, Florida, and other places. In fact, the Twin Otter can essentially be taken anywhere in the world.

One hot area of research these days, pardon the term, is the interaction of particulate pollution with radiation from the sun. This is important for climate research, because, if one looks down from a high-flying jet on a smoggy day, it becomes clear that a lot of sunlight is bouncing back and never reaching the ground. Changing atmospheric conditions therefore affect Earth's heat balance.

"If you change properties of clouds, then you change the climatic conditions on Earth," Seinfeld says. "Clouds are a major component in the planet's energy balance."

Unlike the ER-2, in which instrumentation must be contained in a small space, the Twin Otter can accommodate onboard mass spectrometers and such for onboard direct logging and analysis of data. The data are streamed to the ground in real time, which means that the scientists can sit in the hangar and watch the data come in. Seinfeld himself is one of those on the ground, leaving the two scientist seats in the plane to those whose instruments may require in-flight attention.

"We typically fly below 10,000 feet because the plane is not pressurized. Most of the phenomena we want to study occur below this altitude," he says.

John Eiler, associate professor of geochemistry, is another user of the NASA Airborne Research Program, particularly the air samples returned by the ER-2. Eiler is especially interested these days in the global hydrogen budget, and how a hydrogen-fueled transportation infrastructure could someday impact the environment.

Eiler and Caltech professor of planetary science Yuk Yung, along with lead author Tracey Tromp and several others, issued a paper on the hydrogen economy in June that quickly became one of the most controversial Caltech research projects in recent memory. Using mathematical modeling, the group showed that the inevitable leakage of hydrogen in a hydrogen-fueled economy could impact the ozone layer.

More recently Eiler and another group of collaborators, using samples returned by the ER-2 and subject to mass spectroscopy, have reported further details on how hydrogen could impact the environment. Specifically, they capitalized on the ER-2's high-altitude capabilities to collect air samples in the only region of Earth where's it's simple and straightforward to infer the precise cascade of reactions involving hydrogen and methane.

Though it seems contradictory, the Eiler team's conclusion from stratospheric research was that the hydrogen-eating microbes in soils can take care of at least some of the hydrogen leaked by human activity.

"This study was made possible by data collection," Eiler says. "So it's still the case in atmospheric chemistry that there's no substitute for going up and getting samples."

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