Caltech Chemists Develop Simple Technique to Visualize Atomic-Scale Structures

PASADENA, Calif.—Researchers at the California Institute of Technology (Caltech) have devised a new technique—using a sheet of carbon just one atom thick—to visualize the structure of molecules. The technique, which was used to obtain the first direct images of how water coats surfaces at room temperature, can also be used to image a potentially unlimited number of other molecules, including antibodies and other biomolecules.

A paper describing the method and the studies of water layers appears in the September 3 issue of the journal Science.

"Almost all surfaces have a coating of water on them," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech, "and that water dominates interfacial properties"—properties that affect the wear and tear on that surface. While surface coatings of water are ubiquitous, they are also very tough to study, because the water molecules are "in constant flux, and don't sit still long enough to allow measurements," he says.

Quite by accident, Heath and his colleagues developed a technique to pin down the moving molecules, under room-temperature conditions. "It was a happy accident—one that we were smart enough to recognize the significance of," he says. "We were studying graphene on an atomically flat surface of mica and found some nanoscale island-shaped structures trapped between the graphene and the mica that we didn't expect to see."

Graphene, which is composed of a one-atom-thick layer of carbon atoms in a honeycomb-like lattice (like chicken wire, but on an atomic scale), should be completely flat when layered onto an atomically flat surface. Heath and his colleagues—former Caltech graduate student Ke Xu, now at Harvard University, and graduate student Peigen Cao—thought the anomalies might be water, captured and trapped under the graphene; water molecules, after all, are everywhere.

To test the idea, the researchers conducted other experiments in which they deposited the graphene sheets at varying humidity levels. The odd structures became more prevalent at higher humidity, and disappeared under completely dry conditions, leading the researchers to conclude that they indeed were water molecules blanketed by the graphene. Heath and his colleagues realized that the graphene sheet was "atomically conformal"—it hugged the water molecules so tightly, almost like shrink wrap, that it revealed their detailed atomic structure when examined with atomic force microscopy. (Atomic force microscopes use a mechanical probe to essentially "feel" the surfaces of objects.)

"The technique is dead simple—it's kind of remarkable that it works," Heath says. The method, he explains, "is sort of like how people sputter carbon or gold onto biological cells so they can image them. The carbon or gold fixes the cells. Here, the graphene perfectly templates the weakly adsorbed water molecules on the surface and holds them in place, for up to a couple of months at least."

Using the technique, the researchers revealed new details about how water coats surfaces. They found that the first layer of water on mica is actually two water molecules thick, and has the structure of ice. Once that layer is fully formed, a second, two-molecule-thick layer of ice forms. On top of that, "you get droplets," Heath says. "It's truly amazing that the first two adsorbed layers of water form ice-like microscopic islands at room temperature," says Xu. "These fascinating structures are likely important in determining the surface properties of solids, including, for example, lubrication, adhesion, and corrosion."

The researchers have since successfully tested other molecules on other types of atomically flat surfaces—such flatness is necessary so the molecules don't nestle into imperfections in the surface, distorting their structure as measured through the graphene layer. "We have yet to find a system for which this doesn't work," says Heath. He and his colleagues are now working to improve the resolution of the technique so that it could be used to image the atomic structure of biomolecules like antibodies and other proteins. "We have previously observed individual atoms in graphene using the scanning tunneling microscope," says Cao. "Similar resolution should also be attainable for graphene-covered molecules."

"We could drape graphene over biological molecules—including molecules in at least partially aqueous environments, because you can have water present—and potentially get their 3-D structure," Heath says. It may even be possible to determine the structure of complicated molecules, like protein–protein complexes, "that are very difficult to crystallize," he says.

Whereas the data from one molecule might reveal the gross structure, data from 10 will reveal finer features—and computationally assembling the data from 1,000 identical molecules might reveal every atomic nook and cranny.

If you imagine that graphene draped over a molecule is sort of like a sheet thrown over a sleeping cat on your bed, Heath explains, having one image of the sheet-covered lump—in one orientation—"will tell you that it's a small animal, not a shoe. With 10 images, you can tell it's a cat and not a rabbit. With many more images, you'll know if it's a fluffy cat—although you won't ever see the tabby stripes."

The work in the paper, "Graphene Visualizes the First Water Adlayers on Mica at Ambient Conditions," was funded by the United States Department of Energy's Office of Basic Energy Sciences.

Kathy Svitil

"The Impact That Our Students Have on the World Is Remarkable"

A Q&A with Chemistry and Chemical Engineering Chair Jacqueline Barton

As a chemist, Jacqueline Barton appreciates the importance of bonds—between atoms to make molecules, of course, but also bonds forged between people, scientists, and scientific disciplines, all of which apply to Caltech's Division of Chemistry and Chemical Engineering (CCE), which she currently chairs. In that multifaceted interdisciplinary environment, says Barton, where cutting-edge research is under way on dozens of fronts, the strongest bonds are those created by graduate students—more than 300 of them, working with faculty and fellow students on research ranging from investigations into the molecular basis of disease to the quest for abundant clean energy. "Our graduate students are the lifeblood of the division," says Barton, "the essence of what we do."

That's why the Hanisch Memorial Professor and professor of chemistry has launched an ambitious, unprecedented campaign to raise $30 million to create 40 endowed graduate-student fellowships. "Competition for the top graduate students is keen," says Barton. "It's absolutely essential that we establish this permanent fellowship program if we are to continue to be the best."

In this Q&A Barton talks about the division and its graduate students, past, present—and future.

Why have you put such a high priority on raising new funds for graduate student fellowships?

Let me start with a little history. This is a truly outstanding division. Linus Pauling, one of our earliest division chairs, worked for 20 years in the office where we're sitting now. And the people who worked with him and who came after him have been extraordinary. On our own faculty, we currently have the largest number of Nobel laureates in a department of chemistry in the world, as well as faculty who have received the National Medal of Science.  

What's most impressive, and makes us all, I think, the most proud, is the quality of the students whom we train and the contributions that they go on to make through their own careers. If you look at the faculty at the top chemistry or chemical engineering departments in this country, you will find that an amazing number of them have spent time at Caltech, either as PhD students, undergrads, or postdocs. We are training the best and the brightest, who are now leaders in academia and industry across the country. The impact that our students have on the world after leaving Caltech is remarkable, particularly when you think about how small an institution we are.

So it's not surprising that our chemistry program is ranked first in the nation—and my job is to keep it that way.  And what makes us what we are and who we are, is, most importantly, our graduate students. They make the place run, and, quite frankly, they run the place.

What do an endangered sea slug and cancer patients have in common? A compound produced by the first may one day treat the second. In the lab of Professor Brian Stoltz, grad students Allen Hong, Nathan Bennett, and (in the back) Chris Gilmore are creating synthetic replicas of medicinal substances produced by plants and animals, some of them rare or endangered. This research could ultimately lead to large-scale production of potent new disease-fighting drugs.
Credit: Mike Rogers

They run the place?

They absolutely run the place. I think that's why we're so good. Our students are the heart of our division, they are at the heart of our research, they are an indispensable part of everything that we do. And our greatest challenge is to provide consistent support for them. That's a more complicated proposition than it once was, when we could count on more sustained federal funding. These days, funding goes up and funding goes down, but when you make a commitment to a student working toward his or her PhD, that's generally a five-year commitment.

What are some of the research areas that these students work in?  What key questions are they investigating?

Today, probably half of the division works on problems that are related to biological questions—questions at the biomedical frontiers. In the past 10 to 20 years, science has come up with the tools and techniques to ask biological questions at the molecular level—and that's chemistry. Chemists now have the unprecedented ability to probe biological systems at the fundamental level of molecules and their interactions, and our graduate students are an incredibly vital part of this research. They're looking at different aspects of biological signaling—how information is exchanged—in every important biological system, from nerve cells, to the genome, to the immune system. That information is chemical.  Whether it's finding innovative methods of drug delivery or engineering new proteins and new molecules to carry out new kinds of chemical reactions, that work is very much at the heart of what we do. Their research is leading to the development of new drugs and new diagnostic agents for a whole range of applications in medicine.

Another major research area, one that's of crucial importance not just to our nation but to the whole planet, is how we come up with alternative energy sources. That, too, is a problem in chemistry, and the solution requires chemical engineering. We have graduate students collaborating closely with faculty on ways to develop new methods for harnessing energy from the sun and converting it into clean fuels on a large scale. They'll be very much involved in all aspects of the work that goes on in the DOE's new Joint Center for Artificial Photosynthesis—which will be headquartered on the Caltech campus—and Caltech's Resnick Sustainability Institute, both of which will be working to develop novel and viable approaches to renewable energy technologies. We expect extraordinary things to come out of these programs.

Damage to cellular DNA lies at the root of many serious disorders, including cancer. From left, graduate students Pam Sontz, Anna Nordstrom, and Eric Olmon working in Professor Jackie Barton's lab, are conducting fundamental research into how specific proteins in the body recognize and initiate repairs to damaged DNA, and what causes this maintenance system to go awry. This work is shedding light on the origins of numerous diseases and could lead to the development of powerful new treatments.
Credit: Mike Rogers

So, as you can see, work in our division is very varied and highly interdisciplinary. Chemists like to say that chemistry is the central discipline, and that's never been more true than it is today, as we push the boundaries toward physics, toward biology, and use our discoveries to engineer new materials, new medicines, and new devices. And if you want to pursue and maintain a thriving interdisciplinary program, you need a critical mass of people who are working in all these different areas, exchanging information, and sharing new ideas and perspectives. For us, in large part, that's our graduate students. They are the glue that binds this cohesive effort together.

So, we have to preserve this treasure at the heart of our chemistry community—and that means taking care of our graduate students.

Can you talk about some of the exceptional people who received their PhDs from this division?

Sure. I like to start with Gordon Moore—everyone knows his name, but plenty of people are surprised to hear that he earned his Caltech PhD in physical chemistry. He cofounded Intel, he propounded Moore's Law, and he and his wife, Betty, have created one of this country's great philanthropic foundations, which supports all kinds of initiatives in education and the environment. Certainly, our world would be quite different without him.

Another Caltech chemist renowned as an innovator, industrialist, and philanthropist is, of course, Arnold Beckman. He started with the pH meter and went on to invent revolutionary instruments that led to new discoveries in biochemistry and medicine. He founded Beckman Instruments, and also established a foundation that has provided magnificent support for higher education. There's William Lipscomb, who studied here with Linus Pauling in the 1940s. He won the Nobel Prize in 1976 for his fundamental work on chemical bonding.

George Whitesides, who's been a professor at Harvard for many years, got his PhD here in 1964, and if you were to ask, what has he done, I would have to answer, What hasn't he done? He helped to move forward the field of nanoscience with his studies of how molecules arrange themselves on surfaces. He's opened whole new areas of research in developing innovative new tools and principles for surface science, molecular self-assembly, and nanotechnology. Students of his have come to Caltech as graduate students or postdocs, and vice versa, so he's also an excellent example of the cross-fertilization that we have going on with successive generations of graduate students.

We have alumni from this division who have become leaders in biotechnology, like Michael Hunkapiller, who for many years was president of the company Applied Biosystems. Richard Scheller is another. He's now the VP for Research at Genentech, and just this spring he shared the $1 million Kavli Prize in Neuroscience. The prize was for work that he did as a professor at Yale on how nerve cells communicate through molecular signaling, and it has its roots in research he began here at Caltech as a grad student in chemistry.

Other graduates have gone on to become major players in academic administration—for instance, Mark Wrighton, who spent five years as provost of MIT and has now been chancellor of Washington University in St. Louis for 15 years. This just gives you a sense of how productive our former students have been, and in so many different areas. 

What about more recent graduates?

We have so many of them working in exciting areas. I'll just mention a few who have graduated in the last decade or so. Justin Gallivan, who's now at Emory University in Atlanta, heads up a research group that is interested in reprogramming molecules like those in the bacterium E. coli, so that they can carry out tasks like environmental cleanup and energy conversion. At Harvard, another of our graduates, Ted Betley, is developing assemblies of molecules that mimic the action of plants in using sunlight to split water into oxygen and hydrogen to produce clean, cheap energy. In 2008, he was named one of the nation's leading young innovators by Technology Review.

The recruitment of gifted graduate students is indispensable to the future of chemistry and chemical engineering, says Caltech's Jackie Barton.
Credit: Bob Paz

And now so many of our outstanding graduate-student alumni are women—scientists like Melanie Sanford at the University of Michigan, who is also pioneering new approaches to green chemistry, making remarkably efficient catalysts for organic synthesis. One of my own former PhD students, Sarah Delaney, heads up a team at Brown that's investigating how different types of DNA damage are implicated in cancer and incurable inherited conditions like Huntington's disease.

These are all ambitious projects with incredible potential. The scientists who are working on them are precisely the kind of outstanding young people whom Caltech must continue to attract and to educate. That's why this fellowship support is so essential.

Let's take an "It's a Wonderful Life" approach for a moment, and imagine a CCE division at Caltech that has fewer graduate students because they didn't have access to these fellowships. What would happen?

We wouldn't be the best anymore. We wouldn't be able to attract the exceptional faculty that we do. We would lose our ability to attract the very best scientists in the world—from graduate students to senior professors—to come here and do science together. When you are the best, you can never take that status for granted—you have to work hard to stay that way. The outstanding science that we do here is rooted in our ability to gather together the remarkable people that we have. Caltech is an extraordinarily collaborative, interactive place, and that's how the best science comes to be.

Heidi Aspaturian
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Caltech-led Team Gets up to $122 Million for Energy Innovation Hub

Caltech will partner with Lawrence Berkeley Nat. Lab. and other CA institutions to develop method to produce fuels from sunlight

PASADENA, Calif.-As part of a broad effort to achieve breakthrough innovations in energy production, U.S. Deputy Secretary of Energy Daniel Poneman today announced an award of up to $122 million over five years to a multidisciplinary team of top scientists to establish an Energy Innovation Hub aimed at developing revolutionary methods to generate fuels directly from sunlight. 

The hub will be directed by Nathan S. Lewis, George L. Argyros Professor and professor of chemistry at the California Institute of Technology (Caltech). 

The Joint Center for Artificial Photosynthesis (JCAP), to be led by Caltech in partnership with the U.S. Department of Energy's (DOE) Lawrence Berkeley National Laboratory (Berkeley Lab), will bring together leading researchers in an ambitious effort aimed at simulating nature's photosynthetic apparatus for practical energy production. The goal of the hub is to develop an integrated solar energy-to-chemical fuel conversion system and move this system from the bench-top discovery phase to a scale where it can be commercialized.

"The Energy Innovation Hubs have enormous potential to advance transformative breakthroughs," says Deputy Secretary Poneman. "Finding a cost-effective way to produce fuels as plants do-combining sunlight, water, and carbon dioxide-would be a game changer, reducing our dependence on oil and enhancing energy security.  This Energy Innovation Hub will enable our scientists to combine their talents to tackle this bold and highly promising challenge."

Lewis, who will lead the multi-institutional team, says, "The sun is by far the largest source of energy available to man, but we must find a way to cheaply capture, convert, and store its energy if we are to build a complete clean energy system. Making fuels directly from sunlight presents an exciting opportunity to focus the efforts of teams of leading scientists onto developing the breakthroughs that are required to obtain a safe and secure energy future for all nations."

The hubs are large, multidisciplinary, highly collaborative teams of scientists and engineers working over a longer time frame to achieve a specific high-priority goal. They are managed by top teams of scientists and engineers with enough resources and authority to move quickly in response to new developments.

On the Caltech campus, the center will be housed in the Jorgensen Laboratory building.

"Caltech is honored to be chosen by the Department of Energy to lead its new Energy Innovation Hub, and I am confident that this bold public-private partnership envisioned by President Obama will ultimately help develop significant clean energy solutions and create green jobs," says Caltech President Jean-Lou Chameau. "Caltech's history of solving the most difficult, multidisciplinary, scientific problems, and the strong commitment to energy innovation through our new Resnick Sustainability Institute, make us uniquely suited to help make fuels from the sun an efficient and economical part of our nation's energy strategy."  

JCAP research will be directed at the discovery of the functional components necessary to assemble a complete artificial photosynthetic system: light absorbers, catalysts, molecular linkers, and separation membranes. The hub will then integrate those components into an operational solar fuel system and develop strategies to move from the laboratory toward commercial viability. The ultimate objective is to drive the field of solar fuels from fundamental research, where it has resided for decades, into applied research and technology development, thereby setting the stage for the creation of a direct solar fuels industry.   

Other members of the hub leadership team include: Bruce Brunschwig (Caltech); Peidong Yang (UC Berkeley/Berkeley Lab); and Harry Atwater, Caltech's Howard Hughes Professor, professor of applied physics and materials science, and director of the Resnick Institute, which will work in conjunction with the new center to foster transformational advances in energy science. Atwater and Lewis are both founding board members of the Kavli Nanoscience Institute based at Caltech.

The JCAP Proposal Leadership team included Heinz Frei and Elaine Chandler of Berkeley Lab, as well as Eric McFarland of the University of California, Santa Barbara and Jens Norskov of the SLAC National Accelerator Lab.  Also involved at Caltech will be Harry Gray, the Arnold O. Beckman Professor of Chemistry; Jonas Peters, the Bren Professor of Chemistry; and Michael Hoffman, the James Irvine Professor of Environmental Science.

In addition to the major partners, Caltech and Berkeley Lab, other participating institutions include SLAC, Stanford University; UC Berkeley; UC Santa Barbara; UC Irvine; and UC San Diego.

Selection was based on a competitive process using scientific peer review.  The selection process for the Fuels from Sunlight Hub was managed by the Department of Energy Office of Science, which will have federal oversight responsibilities for the artificial photosynthesis Hub.

The hub will be funded at up to $22 million this fiscal year.  The hub will then be funded at an estimated $25 million per year for the next four years, subject to congressional appropriations.  More information on the hubs can be found at:

Jon Weiner
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Something in the Air

For the past month, Caltech scientists have been zigzagging across the Los Angeles basin. Using an orange and white DeHavilland Twin Otter aircraft packed with instruments, the researchers have been sampling the air, measuring particles and pollutants to help policymakers improve air quality and dampen the impacts of climate change.

"We want to understand very thoroughly where these particles come from, what they're made of, how they evolve, and eventually how they're removed," says chemical engineer John Seinfeld, who leads the Caltech group. The flights are just one element of a project dubbed CalNex—the nexus of pollution and climate over California—run by the National Oceanic and Atmospheric Administration (NOAA).

CalNex is one of the largest air-quality experiments ever done, says Jose-Luis Jimenez, a professor at the University of Colorado and a former Caltech postdoc. The project involves three other aircraft—including NOAA's Lockheed WP-3D Orion, a plane with a 100-foot wingspan whose resume includes missions into dozens of hurricanes—and the Atlantis, a research vessel operated by the Woods Hole Oceanographic Institution. There are also two ground stations, one in Bakersfield and the other on the Caltech campus. (You may have noticed the main part of the Caltech station: two towers of scaffolding and the huddle of trailers on the vacant lot north of the Holliston parking structure.) Such studies are so expensive that they only occur about once a decade in southern California—the crew on campus alone includes more than 60 people from around the world.

Every morning in May, the Caltech team gathers at Ontario International Airport, checking their equipment for the day's four-hour flight. Typically carrying up to 20 passengers when it operates as a commuter plane, the twin-engine turboprop is so stuffed with gizmos and computers that there's only room for one researcher—usually a grad student—who monitors all the instruments, fixing them if needed.


"The best part is getting to see all the instruments in action," says Andrew Metcalf, one of the graduate students who got to fly. Because he can watch the data being collected in real time, he gets a better sense of what each data point on the screen means—important when trying to analyze the information later. For most flights, the plane heads west over Pasadena and toward Long Beach, then crisscrosses back east—occasionally going as far as Palm Springs and the Salton Sea—following the changing chemistry of the particles as they travel with the eastward wind. The plane usually flies at 1,000 feet—as low as the FAA will allow. To measure how the air changes with elevation, the pilot sometimes executes missed approaches—a maneuver in which the plane approaches the runway but doesn't land—over many of the small airports that dot the L.A. basin. On occasion, the plane flies north to Bakersfield and the San Joaquin Valley to see how the air differs from that above the Los Angeles basin.

An inlet pipe jutting from the front of the plane collects the air and channels it through tubes to the instruments, which are lined in racks on one side of the plane. The devices collect an assortment of data, such as the size distribution of particles and their chemical constituents.

Grad student Jill Craven gets to the airport at 6 a.m., having to boot up her mass spectrometer, a powerful but temperamental instrument. "When it breaks down, I get really stressed out," she says. "Field campaigns are wonderful because you're not in the lab. The hard part is that you're under pressure to perform in a month, because we only have four weeks to collect data for the entire year."

Airsickness can also be a challenge. "I flew the first flight and I got really sick," Metcalf recalls. As it happened, there was no airsickness bag on board that day, and one of the pilots had to sacrifice his lunch bag. "It was about a week and a half before I got up the nerve to try it again. Now I take motion-sickness drugs to help me out." Still, it's much more fun to be up in the air than cooped up in a lab, he says. "It's exciting to fly around and see exactly what's out there in the L.A. basin."

So what is out there? It will be years before scientists finish analyzing all the data. The results, however, will have a global impact. CalNex is designed to help untangle the complex ways in which particles affect air quality and climate. For example, tiny particles are bad for air quality, but they can also scatter sunlight, counteracting the warming effect of greenhouse gases. "If you go anywhere in the world," Seinfeld explains, "particles in the air are a mixture of the same kitchen sink of compounds. A large urban area like Los Angeles, with sources ranging from traffic, industry, and ships to vegetation, is the perfect staging area to study how such particles are formed and how they evolve."

Seinfeld, the Nohl Professor and professor of chemical engineering, leads the Caltech team, which includes Richard Flagan, the McCollum-Corcoran Professor of Chemical Engineering and professor of environmental science and engineering.

View our narrated slideshow of the Calnex plane and its instrumentation.

Marcus Woo
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Adaptable, New Building is Catalyst for Discovery

Caltech Opens the Schlinger Laboratory for Chemistry and Chemical Engineering

To facilitate the ever-evolving advancements in the chemical field today, the California Institute of Technology (Caltech) is opening the new Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering.

The state-of-the-art, sustainable Schlinger Laboratory will provide a custom-designed, adaptable facility for a number of Caltech's chemists and chemical engineers.  The laboratory will house research groups in synthetic chemistry and chemical engineering, enabling new research in catalysis, materials, and the atmosphere. 

The laboratory has been named in honor of Warren and Katharine Schlinger, benefactors of the Institute for more than 60 years. Support for the building and its research was provided by the Gordon and Betty Moore Foundation, Will and Helen Webster, Victor and Elizabeth Atkins, the John Stauffer Charitable Trust, Barbara Dickinson, and the Ralph M. Parsons Foundation.

Jacqueline Barton, chair of the Division of Chemistry and Chemical Engineering, and Arthur and Marian Hanisch Memorial Professor, states, "We are excited to bring together chemists and chemical engineers under one roof for new discovery and innovation.  This new laboratory is a realization of the vision of Warren and Katharine Schlinger to create a state-of-the-art facility linking chemists with chemical engineers."

The Science

Synthetic chemists Brian Stoltz, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry, and Sarah Reisman, assistant professor of chemistry, along with their research groups, will focus on the design of new catalysts and new routes to the preparation of pharmaceuticals.  Jonas Peters, the Bren Professor of Chemistry, and his group will conduct research designing new catalysts that may be critical in solar energy conversion. Richard Flagan, the Irma and Ross McCollum-William H. Corcoran Professor of Chemical Engineering and professor of environmental science and engineering, and John Seinfeld, the Louis E. Nohl Professor and professor of chemical engineering, will conduct research in atmospheric chemistry, focusing on aerosol processes and the control of air pollution.  Julia Kornfield, professor of chemical engineering, and her research group will characterize new polymers with broad applications in everything from liquid-crystal displays to intraocular lenses.  The Schlinger laboratory will also house the Center for Catalysis and Chemical Synthesis, led by Nobel laureate Robert Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry.

The Facility

The 62,300-square-foot, four-story Schlinger Laboratory blends innovative research design elements with contemporary and classic elements.  Expansive glass facades on north and south sides of the reinforced concrete structure are enhanced with one terracotta accent wall at the building's west entrance.  

The laboratory features a "green," eco-conscious design, furthering the campus-wide commitment to sustainability.  The facility is on target to obtain gold certification from the Leadership in Energy and Environmental Design (LEED) Green Building Rating System, which requires projects to meet stringent energy and water efficiency standards.  The Schlinger Laboratory has been designed with energy-conscious equipment and lighting, for a 28 percent reduction in energy usage and a 30 percent reduction in water usage.  The building utilizes locally derived and recycled building materials.

Maximizing the natural lighting in the new laboratory was an essential design element for the chemists.  Expansive, floor-to-ceiling windows illuminate 90 percent of the labs and conference rooms in the building and provide engaging, panoramic views.

Designed with flexible lab space, research areas can be adapted or reconfigured for specific uses.  Each of the highly specialized research areas was custom designed to meet the distinct specifications of the resident professors. The laboratory also offers an abundance of ventilated chemical fume hoods, providing a high ratio of workstations per student or researcher.

Throughout the building, contemporary stainless-steel components complement the classic maple cabinetry and millwork, much of which was custom built by Caltech carpenters.  Caltech painters also assisted on the project.  Recycled slate boards from the early 1900s were utilized as the main writing surfaces in the conference rooms.  Caltech electricians installed the computer network and data systems.

"The Institute is recognized for having made some of the most significant scientific achievements of the past century in chemistry and chemical engineering—with three Nobel laureates in chemistry currently in residence.  The Schlinger Laboratory will help to position Caltech for continued leadership in this critical area, helping to shape the future.  Warren and Katharine Schlinger's steadfast dedication and commitment to scientific achievement, particularly at Caltech, are exemplary and visionary," states Caltech president Jean-Lou Chameau.

The architectural firm of Bohlin Cywinski Jackson, known for leadership in sustainable design, was selected for this project.  The award-winning firm has designed diverse, high-end laboratories and academic facilities throughout the nation, ranging from biotechnology centers to software engineering institutes.

The building features

  • Six faculty offices within two faculty suites
  • Office space for over 100 postdoctoral and graduate students
  • A 50-person undergraduate teaching classroom/faculty conference room
  • Multiple interactive lounge areas
  • A central recycling room
  • Individual office climate control and auto-sensor lighting
  • A dual-glazed curtain wall system for window shading and reduced heat gain
  • 70 German-engineered Waldner fume hoods  (total capacity 110)
Deborah Williams-Hedges
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Young Caltech Innovators Recognized for Their Work in Advanced Disease Therapies

$30,000 Lemelson-MIT Collegiate Student Prizes Awarded to Students Nationwide; Four Leading Institutes Celebrate Winners

PASADENA, Calif.—California Institute of Technology (Caltech) graduate student Heather D. Agnew is the recipient of the 2010 $30,000 Lemelson-MIT Caltech Student Prize. 

Agnew was among the four $30,000 Lemelson-MIT Collegiate Student Prize winners announced Wednesday, March 3, 2010. She was recognized for her integral contributions to the development of innovative biochemical protocols that can be utilized for more stable, robust—and inexpensive—detection of diseases like cancer, HIV, or malaria.

The Lemelson-MIT Caltech Student Prize is supported through a partnership with the Lemelson-MIT Program, a nonprofit dedicated to celebrating innovation and inspiring youth. The Lemelson-MIT Student Prize has been awarded at the Massachusetts Institute of Technology since 1995 and at Rensselaer Polytechnic Institute and University of Illinois at Urbana-Champaign since 2007; in 2009, the program expanded with a similar award given to Caltech students. Caltech's Division of Engineering and Applied Science administers the Lemelson-MIT Caltech Student Prize. 

The Caltech selection committee also acknowledged a finalist, Yvonne Y. Chen, also a Caltech graduate student, who will receive a $10,000 award made possible through the support of Caltech alumnus Michael Hunkapiller.

Agnew, a graduate student in chemistry, has been working in the laboratory of James R. Heath, the Elizabeth W. Gilloon Professor and professor of chemistry.  Agnew contributed to the development of a progressive technique to create inexpensive, yet highly reliable and stable biochemical compounds that have the potential to replace antibodies (blood proteins produced in response to specific toxins or antigens) used in many standard medical diagnostic tests.  This antibody equivalent, or "protein capture agent" protocol, allows for more efficient, inexpensive diagnostics.

In her presentation, entitled "Protein Capture Agents for Improving the Performance and Stability of Point-of-Care Diagnostics," Agnew explained the stable and robust nature of the protein capture agents.  Their ability to withstand higher temperatures enhances their applications, paving the way for more reliable, inexpensive, and readily available medical diagnostic testing for use not only in the United States, but also in developing countries.

According to Heath, "Heather has led this project from start to finish, and it has involved innovation every step of the way.  In terms of public benefit, I believe that the stable, scalable protein capture agents truly have the chance to revolutionize in vitro diagnostics by putting them onto the path of increased capability at lower cost—similar to what has happened for genome sequencing."

Agnew was born and raised in Allentown, Pennsylvania.  She received dual undergraduate degrees in chemistry and in biochemistry and molecular biology from the Pennsylvania State University.  As a Gates Scholar, she received her master's degree in chemistry from the University of Cambridge.  Throughout her academic career, Agnew has received numerous honors and awards, and has continually volunteered as a research mentor and teacher for youth.  Agnew plans to continue her pursuit of biochemical solutions as a principal research investigator in a start-up commercialization venture.  Agnew may also pursue a teaching career at a leading research institution.

The Lemelson-MIT Caltech Student Prize finalist is Yvonne Y. Chen, a graduate student in chemical engineering at Caltech who worked in the lab of Christina D. Smolke, assistant professor of chemical engineering.  Chen will receive a $10,000 prize for her work on improving advanced, cell-based solutions for the treatment of certain incurable diseases, including various cancers and inoperable tumors. In her presentation, entitled "Improving Cell-Based Cancer Therapy with RNA Regulatory Systems," Chen describes an innovative T-cell (a type of white blood cell) therapy for treating aggressive, inoperable tumors.

Traditional chemotherapy and radiotherapy have often proved unable to eradicate diffusive tumors such as glioblastoma (the most common type of primary brain tumor in adults), and these therapies can have severe side effects.  And conventional immunotherapy, which enlists the body's immune system to fight diseases, while conceptually well suited to cancer treatment, has had limited success—efforts to improve its efficacy have raised safety concerns for leukemic growth. Chen's research has the potential to greatly increase both the safety and the efficacy of immunotherapy by controlling T-cell proliferation with regulatory systems based on engineered RNA (ribonucleic acid) devices—thus avoiding risks of uncontrolled T-cell proliferation and eventual leukemic side effects. Chen's novel RNA-based technology is a promising therapeutic candidate for clinical applications in the fight against cancer, and is adaptable to a wide range of disease treatment strategies. 

Chen was born in Taipei, Taiwan, and moved with her family to Rowland Heights, California, when she was 13 years old.  She earned her BS in chemical engineering from Stanford University and her MS in chemical engineering from Caltech.  Chen plans to pursue a career in academia as a researcher at a major institution or in public policy as it relates to scientific research.

According to Ares Rosakis, division chair and Theodore von Kármán Professor of Aeronautics and professor of mechanical engineering, "The Engineering and Applied Science Division is proud to support such real-world applications of science by student researchers at the Institute.  These innovations have the potential for creating significant advances in the future."

"This year's winners from the California Institute of Technology, Massachusetts Institute of Technology, Rensselaer Polytechnic Institute, and University of Illinois at Urbana-Champaign shine light on the significance of collegiate invention. They have the ability to transform seemingly implausible ideas into reality and are the true entrepreneurial leaders of their generation," states Joshua Schuler, executive director of the Lemelson-MIT Program. 

Lemelson-MIT Collegiate Student Prizes

In addition to Agnew's pioneering work, the other winners of the annual Lemelson-MIT Collegiate Student Prize were announced today at their respective universities:

·      Lemelson-MIT Illinois Student Prize winner Jonathan Naber and the Illini Prosthetics Team developed an affordable, durable, extremely functional prosthetic arm for people in underdeveloped countries, made from recycled materials.

·      Lemelson-MIT Student Prize winner Erez Lieberman-Aiden demonstrated creativity and innovation across several disciplines, most recently with his invention of "Hi-C", a three-dimensional genome sequencing method that will enable an entirely new understanding of cell state, genetic regulation and disease.

·      Lemelson-MIT Rensselaer Student Prize winner Javad Rafiee developed a new method for manufacturing and using graphene, an atom-thick sheet of carbon atoms arranged like a nanoscale chain-link fence, to store hydrogen at room temperature – opening the door to better and safer on-board fuel storage systems for hydrogen vehicles. 


Celebrating innovation, inspiring youth

The Lemelson-MIT Program recognizes the outstanding inventors and innovators transforming our world, and inspires young people to pursue creative lives and careers through innovation.

Jerome H. Lemelson, one of U.S. history's most prolific inventors, and his wife Dorothy founded the Lemelson-MIT Program at the Massachusetts Institute of Technology in 1994. It is funded by the Lemelson Foundation and administered by the School of Engineering. The Foundation sparks, sustains and celebrates innovation and the inventive spirit. It supports projects in the U.S. and developing countries that nurture innovators and unleash invention to advance economic, social and environmentally sustainable development. To date the Lemelson Foundation has donated or committed more than U.S. $150 million in support of its mission.

About the Lemelson-MIT Caltech Student Prize
Administered by the Caltech Division of Engineering and Applied Science, the Lemelson-MIT Caltech Student Prize is awarded to a student at Caltech who has demonstrated remarkable inventiveness and innovation.

Funded through a partnership with the Lemelson-MIT Program, the Lemelson-MIT Student Prize has recognized outstanding student inventors at MIT since 1995 (see: 

For more information, go to:

Lemelson-MIT Caltech Student Prize:

Deborah Williams-Hedges
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Caltech Receives More than $33 Million from American Recovery and Reinvestment Act

Neuroeconomics and the fundamentals of jet noise just some of the many projects supported

PASADENA, Calif.-Research in genomic sciences, astronomy, seismology, and neuroeconomics are some of the many projects being funded at the California Institute of Technology (Caltech) by the American Recovery and Reinvestment Act (ARRA).

As part of the federal government program of stimulating the economy, ARRA is providing approximately $21 billion for research and development. The goal is for the funding to lead to new scientific discoveries and to support jobs.

ARRA provides the funds to federal research agencies such as the National Institutes of Health, the National Science Foundation, and the Department of Energy, which then support proposals submitted by universities and other research institutions from across the country.

Caltech has received 82 awards to date, totaling more than $33 million. Spending from the grants began in the spring of 2009 and thus far has led to the support of 93 jobs at the Institute.

"This funding will help lead to substantive and important work here at Caltech," says Caltech president Jean-Lou Chameau. "We're grateful to have this opportunity to advance research designed to benefit the entire country."

For biologist Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator, the ARRA funds mean an opportunity to improve upon WormBase, an ongoing multi-institutional effort to make genetic information on the experimental animal C. elegans freely available to the world.

"All biological and biomedical researchers rely on publicly available databases of genetic information," says Sternberg. "But it has been expensive and difficult to extract information from scientific research articles. We have developed some tools to make it less expensive and less tedious to get the job done, for WormBase and many other groups."

Sternberg's ARRA funds-$989,492-will go towards developing a more efficient approach to extracting key facts from published biological-science papers.

Among the other diverse Caltech projects receiving ARRA funds are:

  • a catalog of jellyfish DNA;
  • improving the speed of data collection at Caltech's Center of Excellence in Genomic Science;
  • studies into the fundamentals of particle physics;
  • the California High School Cosmic Ray Observatory (CHICOS) program, which provides high school students access to cosmic ray research;
  • the search for new astronomical objects such as flare stars and gamma-ray bursts, and the means to make those discoveries accessible to the public; and
  • a $1 million upgrade of the Southern California Seismic Network.

Caltech Professor of Mechanical Engineering Tim Colonius received ARRA funds for research into better understanding how noise is created by turbulence in the exhaust of turbofan aircraft engines and what might be done to mitigate it. Jet noise is an environmental problem subject to increasingly severe regulation throughout the world.

"To meet the ambitious noise-reduction goals under discussion, a greatly enhanced understanding of the basic physics is needed," says Colonius. "Very large-scale computer simulations and follow-up analyses will bring us much closer to the goal of discovering the subtle physical mechanisms responsible for the radiation of jet noise and allow us to develop methods for suppressing it."

Colonius received $987,032 in ARRA funds from the National Science Foundation.

Colin Camerer, the Robert Kirby Professor of Behavioral Economics, received his ARRA funds to explore the application of neurotechnologies to solving real-life economic problems.

"Our project, with my Caltech colleague Antonio Rangel, will explore the psychological and neural correlates of value and decision-making and their use in improving the efficiency of social allocations," says Camerer.

Camerer and his colleagues previously found that they could use information obtained through functional magnetic resonance imaging measurements to develop solutions to economic challenges.

Rangel, an associate professor of economics, has a second ARRA-funded project to analyze the neuroeconomics of self-control in dieting populations.

"Funding of this nature is critical to much of the work we do here at Caltech," adds Chameau. "And with ARRA support, dramatic discoveries may be just around the corner."

For a complete list of ARRA projects, visit:

# # #

About Caltech:

Caltech is recognized for its highly select student body of 900 undergraduates and 1,200 graduate students, and for its outstanding faculty. Since 1923, Caltech faculty and alumni have garnered 32 Nobel Prizes and five Crafoord Prizes.

In addition to its prestigious on-campus research programs, Caltech operates the Jet Propulsion Laboratory (JPL), the W. M. Keck Observatory in Mauna Kea, the Palomar Observatory, and the Laser Interferometer Gravitational-Wave Observatory (LIGO). Caltech is a private university in Pasadena, California. For more information, visit

Jon Weiner
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Estate Gift of $3.9 Million Will Help Caltech Chemists Focus on Innovative Research

Gift comes from the estate of longtime Caltech supporters Edward and Ruth Hughes

PASADENA, CALIF. - A deep appreciation for the sciences has led to a gift of $3.9 million from the estate of Edward and Ruth Hughes to the California Institute of Technology (Caltech) and its Division of Chemistry and Chemical Engineering (CCE).

The funds will be used by the division to support highly innovative research proposals that might not otherwise be funded by traditional means.

The Hughes funds will help support eight graduate research fellowships. These fellowships will allow students to focus on challenging problems and find innovative solutions.

Helping support that goal is a matching gift of $2 million from the Gordon and Betty Moore Matching Program.

"This is an extraordinary gift from two special members of the CCE family, Ruth and Eddie Hughes," says Jackie Barton, chair of the division. "During their lives they made a difference to chemistry and to the Caltech community. Now, with this gift, they are going to make a difference to generations of graduate students trained in CCE."

The Division of Chemistry and Chemical Engineering currently has more than 40 faculty members and offers three degree programs. 

Edward Hughes passed away in 1987 and his wife, Ruth, in February 2009. Both were close friends of Caltech, though neither was an alumnus.

Edward was born in 1904, and first became enamored with chemistry in high school. In 1938, he came to Caltech at the invitation of Linus Pauling to help with the editing of Pauling's book, The Nature of the Chemical Bond and the Structure of Molecules and Crystals: An Introduction to Modern Structural Chemistry, and to conduct independent research in crystallography. During World War II he trained X-ray technicians and participated in research directed at isolating oxygen from the air at low pressure for high altitude use in bombers subject to enemy machine-gun fire. After working for the Shell Development Company, he returned to Caltech in 1946 as a Senior Research Associate in chemistry, a position he retained until 1974.  

Born in 1915 and educated in Germany, Ruth Hughes was unable to attend a university because of her Jewish heritage and instead trained as a nurse. Recognizing the dangers of staying in Germany, her family emigrated west in the late 1930s. Ruth was the last to leave, moving to London in 1939. It was after then moving to Boston that, coming from the hospital in a very bloody nursing uniform, she first met Edward. They were married on Halloween Day in 1951.

In September 1952, and after a stay at the Athenaeum, they bought a house within walking distance of the Caltech campus and became one of the most popular couples in the Caltech community, helping Pauling with his work and acting as hosts to visiting faculty.

An active member of the Caltech Women's Club, Ruth became a Life Member of the Caltech Associates in 1971, and in 1992 established a Summer Undergraduate Research Fellowship (SURF) endowment at Caltech in Edward's memory.

# # #

About Caltech:

Caltech is recognized for its highly select student body of 900 undergraduates and 1,200 graduate students, and for its outstanding faculty. Since 1923, Caltech faculty and alumni have garnered 32 Nobel Prizes and five Crafoord Prizes.

In addition to its prestigious on-campus research programs, Caltech operates the Jet Propulsion Laboratory (JPL), the W. M. Keck Observatory in Mauna Kea, the Palomar Observatory, and the Laser Interferometer Gravitational-Wave Observatory (LIGO). Caltech is a private university in Pasadena, California. For more information, visit

Jon Weiner
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Caltech Scientists Film Photons with Electrons

4D electron microscopy makes it possible to image photons of nanoscale structures and visualize their architecture

PASADENA, Calif.—Techniques recently invented by researchers at the California Institute of Technology (Caltech)—which allow the real-time, real-space visualization of fleeting changes in the structure of nanoscale matter—have been used to image the evanescent electrical fields produced by the interaction of electrons and photons, and to track changes in atomic-scale structures.

Papers describing the novel technologies appear in the December 17 issue of Nature and the October 30 issue of Science.

Four-dimensional (4D) microscopy-the methodology upon which the new techniques were based-was developed at Caltech's Physical Biology Center for Ultrafast Science and Technology. The center is directed by Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at Caltech, and winner of the 1999 Nobel Prize in Chemistry. 

Zewail was awarded the Nobel Prize for pioneering the science of femtochemistry, the use of ultrashort laser flashes to observe fundamental chemical reactions occurring at the timescale of the femtosecond (one-millionth of a billionth of a second). The work "captured atoms and molecules in motion," Zewail says, but while snapshots of such molecules provide the "time dimension" of chemical reactions, they don't give the dimensions of space of those reactions-that is, their structure or architecture.

Zewail and his colleagues were able to visualize the missing architecture through 4D microscopy, which employs single electrons to introduce the dimension of time into traditional high-resolution electron microscopy, thus providing a way to see the changing structure of complex systems at the atomic scale. (See

In the research detailed in the Science paper, Zewail and postdoctoral scholar Aycan Yurtsever were able to focus an electron beam onto a specific nanoscale-sized site in a specimen, making it possible to observe structures within that localized area at the atomic level.

In electron diffraction, an object is illuminated with a beam of electrons. The electrons bounce off the atoms in the object, then scatter and strike a detector. The patterns produced on the detector provide information about the arrangement of the atoms in the material. However, if the atoms are in motion, the patterns will be blurred, obscuring details about small-scale variations in the material.

The new technique devised by Zewail and Yurtsever addresses the blurring problem by using electron pulses instead of a steady electron beam. The sample under study-in the case of the Science paper, a wafer of crystalline silicon-is first heated by being struck with a short pulse of laser light. The sample is then hit with a femtosecond pulse of electrons, which bounce off the atoms, producing a diffraction pattern on a detector. 

Since the electron pulses are so incredibly brief, the heated atoms don't have time to move much; this shorter "exposure time" produces a sharp image. By adjusting the delay between when the sample is heated and when the image is taken, the scientists can build up a library of still images that can be strung together into a movie.

"Essentially all of the specimens we deal with are heterogeneous," Zewail explains, with varying compositions over very small areas. "This technique provides the means for examining local sites in materials and biological structures, with a spatial resolution of a nanometer or less, and time resolution of femtoseconds."

The new diffraction method allows the structures of materials to be mapped out at an atomic scale. With the second technique-introduced in the Nature paper, which was coauthored by postdoctoral scholars Brett Barwick and David Flannigan-the light produced by such nanostructures can be imaged and mapped. 

The concept behind this technique involves the interaction between electrons and photons. Photons generate an evanescent field in nanostructures, and electrons can gain energy from such fields, which makes them visible in the 4D microscope.

Photons imaged in nanoscale structures (carbon nanotubes) using pulsed electrons at very high speed. Shown are the evanescent fields for two time frames and for two polarizations.
Credit: Zewail/Caltech

In what is known as the photon-induced near-field electron microscopy (PINEM) effect, certain materials-after being hit with laser pulses-continue to "glow" for a short but measurable amount of time (on the order of tens to hundreds of femtoseconds).

In their experiment, the researchers illuminated carbon nanotubes and silver nanowires with short pulses of laser light as electrons were being shot past. The evanescent field persisted for femtoseconds, and the electrons picked up energy during this time in discrete amounts (or quanta) corresponding to the wavelength of the laser light. The energy of an electron at 200 kilo-electron volts (keV) increased by 2.4 electron volts (eV), or by 4.8 eV, or by 7.2 eV, etc.; alternatively, an electron might not change in energy at all. The number of electrons showing a change is more striking if the timing is just right, i.e., if the electrons are passing the material when the field is at its strongest.

The power of this technique is that it provides a way to visualize the evanescent field when the electrons that have gained energy are selectively identified, and to image the nanostructures themselves when electrons that have not gained energy are selected.

"As noted by the reviewers of this paper, this technique of visualization opens new vistas of imaging with the potential to impact fields such as plasmonics, photonics, and related disciplines," Zewail says. "What is interesting from a fundamental physics point of view is that we are able to image photons using electrons. Traditionally, because of the mismatch between the energy and momentum of electrons and photons, we did not expect the strength of the PINEM effect, or the ability to visualize it in space and time."

The work in the Nature paper, "Photon-Induced Near-Field Electron Microscopy," and the Science paper, "4D Nanoscale Diffraction Observed by Convergent-Beam Ultrafast Electron Microscopy," was supported by the National Science Foundation, the Air Force Office of Scientific Research, and the Gordon and Betty Moore Foundation at the Center for Physical Biology at Caltech.

Kathy Svitil

Caltech Scientists Show How Ubiquitin Chains are Added to Cell-Cycle Proteins

Findings could one day lead to the development of targeted cancer therapies

PASADENA, Calif.—Researchers from the California Institute of Technology (Caltech) have been able to view in detail, and for the first time, the previously mysterious process by which long chains of a protein called ubiquitin are added by enzymes called ubiquitin ligases to proteins that control the cell cycle. Ubiquitin chains tag target proteins for destruction by protein-degrading complexes in the cell.

"We found that ubiquitin ligases build ubiquitin chains very rapidly by transferring ubiquitins one at a time," says Raymond Deshaies, professor of biology at Caltech and Howard Hughes Medical Institute investigator.

Their findings, and the innovative process by which they were obtained, are described in this week's issue of the journal Nature.

Ubiquitin is one of nature's most unusual proteins. Unlike most of its protein brethren, ubiquitin has to be physically attached to other proteins to do its job.

“As its name implies, ubiquitin is found in essentially every kind of eukaryotic cell," says Caltech graduate student Nathan Pierce, the Nature paper's lead author.

In their Nature paper, the Caltech team looked at the process of ubiquitylation, the method by which ubiquitin and ubiquitin chains are added to target proteins. The target proteins used in the study, cyclin E and β-Catenin, are both involved in controlling the cell cycle.

It was already known, Pierce explains, that the addition of a chain of four or more ubiquitins to a target protein marks that protein for annihilation.

The destruction of cyclin E is critical for the accurate replication of DNA, while the degradation of β-Catenin keeps cells from dividing during development at the wrong time. If β-Catenin is not degraded, cells proliferate excessively and become predisposed to tumorigenesis. Meanwhile, cells that don't degrade cyclin E accumulate DNA damage and mutations, which can help fuel the unchecked growth of a tumor.

It was also already known that ubiquitin chains are added to the protein using three different enzymes, dubbed E1, E2, and E3. Simply put, E1 activates ubiquitin for transfer, then passes it over to E2. E3 then gets into the act. A form of E3 called a RING ligase (RING stands for "really interesting new gene") plays a key role in the tagging of cyclin E and β-Catenin; according to Pierce, the RING ligase  "simultaneously binds to E2 and the target protein (like cyclin E), and then causes E2 to transfer the ubiquitin to the target protein."

Despite all of this knowledge, one question has remained: is the chain transferred to the protein in an already assembled form, or are the ubiquitins moved over one at a time?

"The process is so complicated and so fast," Pierce notes, "that we weren't able to see how the chain is actually built."

To address that issue, Pierce created a sort of biological stop-motion animation that allowed the Caltech team to watch every step in the transfer of ubiquitin from E2 onto the cyclin E protein substrate.

"We devised methods to take snapshots of ubiquitin ligase reactions at a rate of up to 100 'pictures' every second," says Deshaies. "This enables us to see things that would normally evade detection. "

Previous studies had looked at the reaction on the scale of seconds or minutes, Pierce adds. But through an innovative use of a laboratory tool called a quench-flow machine—a machine that allows for extreme precision in the stopping, or "quenching," of a reaction—the team was able to look at what was going on over intervals of just 10 milliseconds in both yeast and human proteins.

"Prior methods did not have sufficient time resolution to see what was going on," says Deshaies. "It's as if you gave an ice-cream cone to a kid and took pictures every minute. You would see the ice cream disappear from the first photo to the next, but since the pictures are too far apart in time, you would have no idea whether the child ate the ice cream one bite at a time, or swallowed the entire scoop in one gulp."

The new method revealed the biological equivalent of small, single bites of ice cream. "Using our approach," Deshaies says, "we could see that our ubiquitin ligase builds ubiquitin chains one ubiquitin at a time."

"Once we knew what the steps were, we calculated the rates at which they occur," adds Pierce. "And from those rates, we were able to really describe the biology of how this system works."

The quest doesn't stop there, of course. "One thing we have to understand now is, how do ubiquitin ligases achieve the speeds that they do?" asks Deshaies. "What special mechanisms do they have to enable them to build chains rapidly? And the flip side of the coin: What sets the speed limit? Why can't our ubiquitin ligase work even faster?"

A recent paper published in the journal Cell by Gary Kleiger, a postdoctoral scholar in the Deshaies lab, answered some of these speed-related questions. By measuring the rates at which E2 and E3 interacted with one another, Kleiger was able to demonstrate their unusually fast association—faster than predicted for normal proteins. E2 and E3 use oppositely-charged surfaces to attract each other, thereby speeding up the formation of a functional complex of the two proteins. This helps explain how the rapid sequential additions of ubiquitin described in the Nature paper are possible.

Gaining these kinds of insights into the ubiquitin system is important, Deshaies says, because ubiquitin ligases play a critical role in a number of human diseases, including cancer, due to their role in the regulation of the cell cycle.

"Once we understand these aspects of how ubiquitin ligases work, and what limits their speed, we will be in an excellent position to think about how we might develop drugs that attack the ligase's Achilles' heel, to make its slowest step even slower," he says. "If we can slow down ubiquitin ligases enough, they may become too slow to get their job done—to build chains—in the time available to them to do so. Being able to develop drugs to block their function would open up a new frontier in medicine."

"We were able to invent HIV therapeutics because we understand how reverse transcriptase works," adds Pierce. "The same applies here. We need to understand how these enzymes work if we're ever going to be able to target them with therapeutics."

In addition to Pierce and Deshaies, other researchers involved in the study included Kleiger and Shu-ou Shan, assistant professor of chemistry at Caltech.

The work described in the Nature paper, "Detection of Sequential Polyubiquitylation on a Millisecond Time-Scale," was funded by a Gordon Ross Fellowship, National Institutes of Health training and research grants, and the Howard Hughes Medical Institute.

Lori Oliwenstein


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