Volume 4, Issue 33 November/December
Brightening Science's Future
Physics professor Roger Falcone is director of the Advanced Light Source at Lawrence Berkeley National Laboratory and a co-faculty director Cal Teach at Berkeley. Photo courtesy of Roger Falcone
The minute you opened your eyes this morning, the curtain of pigments at the back of your eye began changing at a breakneck pace. Every photon that hits your rods and cones twists those pigments into new and temporary shapes. It is these new shapes, or isomers, that ultimately generate the sensation of vision in your brain.
According to Berkeley physics professor Roger Falcone, ultrafast processes like those underlying vision are everywhere: plants performing photosynthesis, hemoglobin shuttling oxygen to your cells, sunlight converting pollutants into smog. "Most chemical reactions have many fast and complicated steps in between, and those are what we're trying to unravel," Falcone says.
To observe these brief phenomena, Falcone uses the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory. Housed in a cavernous circular building high above campus, this machine produces beams of x-ray light a billion times brighter than radiation from the sun.
Together with a team of scientists and engineers at the ALS, including his colleague Robert Schoenlein, Falcone helped develop an instrument that converts x-rays from the ALS into extremely rapid bursts. Just as a strobe light freezes a pitcher's high-speed throw into a series of incremental movements, these x-ray pulses can capture fleeting events in the movements of two passing molecules. These snapshots can illuminate the steps within the fastest chemical reactions.
Falcone became director of the ALS last year. His primary job at the light source is to enable the more than 2,000 researchers who visit the lab each year from around the world to conduct their experiments smoothly. Their ALS projects range from visualizing protein structures via x-ray crystallography, to analyzing the chemical composition of dust from the 9/11 World Trade Center disaster.
Falcone is also helping to lay the groundwork for a next-generation light source at the lab. Envisioned to be the most powerful x-ray light source in the world, the new instrument could take as long as ten years and cost as much as $1 billion to complete.
The Advanced Light Source, the circular building at center.
The current light source at the ALS can image the structure and bonds of almost any material and observe the motions of molecules. The new instrument, an x-ray free electron laser, could resolve how clouds of electrons-the glue that binds atoms and molecules together- adjust in the instant before a chemical reaction or a change in the structure of a solid, such as melting. By allowing scientists to observe such events, which occur at orders of magnitude shorter than can be visualized with the present light source, the new machine, says Falcone, "would take the tools to observe nature's pathways, microscopically, to a whole new level."
With this new instrument, scientists could test the computer simulation models they use to predict the behaviors of countless enzymes and nanomaterials, evaluate and refine the performance of chemical catalysts, and even observe why atoms in superconductors produce capabilities that are more than the sum of their parts.
Although the ALS occupies most of Falcone's time, he remains involved in undergraduate education. Falcone is a faculty co-director and instructor for Cal Teach, a UC-wide effort to encourage undergraduates in math and science to become K-12 teachers in these fields. Cal Teach students complete their normal undergraduate course requirements while taking additional courses that provide training in education. Upon graduation, the students will be eligible for an intern teaching credential.
Falcone believes Cal Teach also fulfills a need on campus for what he calls "pre-ed." He says, "We have very clear pre-med and pre-law programs on campus, with associated student organizations, clear course requirements, and faculty advisers. But there hasn't been a commensurate program where people can tell you what courses to take to become a teacher. CalTeach is a parallel pre-ed program with the goal of allowing students to get jobs as teachers right after earning their bachelor's degree."
Falcone views the research and teaching aspects of his work as supporting the University's scholarship goal. He says, "Whether you're a student searching for skills or insights in a field, or a researcher investigating brand new concepts, it's all about the same goal-the search for knowledge."
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Making History in Math
UC Berkeley professor of mathematics Ken Ribet Photo credit: Jenny Shi Wen
Talk to Ken Ribet about mathematics, and it's clear he has a great regard for history as well as numbers. A Berkeley professor of mathematics and expert in number theory, he discusses the work of scholars from ancient Rome and Enlightenment France as easily as he would contemporary research. But this respect for his professional forebears is actually quite fitting: Ribet is headed for a place in math's hall of fame himself. A number of important theorems and mathematical objects bear his name.
Ribet is best known, however, for his role in solving modern mathematics' most famous problem. Known as Fermat's Last Theorem, it is based on a brief note scribbled by a seventeenth-century French lawyer in the margins of an ancient math text. In the centuries that followed, attempts to solve it have frustrated legions of brilliant mathematicians. Ribet's work ultimately sparked a solution to the problem in 1993.
As math problems go, Fermat's Last Theorem is deceptively easy to describe. For one thing, it bears a great resemblance to the Pythagorean theorem so familiar from basic geometry. According to Pythagorus, the squares of two sides of a right triangle, added together, should equal the square of its hypoteneuse, or x2 + y2 = z2. The great mathematician Diophantus of Alexandria discussed this problem in detail in his seminal third century work Arithmetica.
More than 1,300 years later, Pierre de Fermat, a distinguished mathematician in his own right, took this idea one step further. He asked, in his copy of Arithmetica, what happens if the exponent is an integer of three or greater instead of two? Can the equation be solved if neither x nor y is zero? Fermat then claimed he could prove the problem has no answer-but left behind no further explanation.
His tantalizing statement fueled more than three centuries of effort to develop a proof. But the puzzle's seeming simplicity belied the fiendish difficulty of the solution. "A whole cottage industry of people who were invested in the theorem developed," Ribet says. "They developed more and more intricate and sophisticated techniques to chip away at the problem."
A 2001 French postage stamp commemorated the 400th anniversary of mathematician Pierre de Fermat's birth. Image credit: La Poste Francaise
A crucial insight to the problem came in the early 1980s. German mathematician Gerhard Frey proposed that Fermat's Last Theorem could be linked to problems involving elliptic curves. Previous research had suggested that such curves were, surprisingly, related to a completely different branch of mathematics called modular forms.
"I and others stepped in because we were experts in both and wanted to see if it was really possible to link these two together," Ribet says.
But Ribet was the one who moved the problem forward. He proved that Frey's prediction was true. In doing so, he provided the link needed to show that Fermat's Last Theorem was true.
Ribet's work galvanized Princeton mathematician Andrew Wiles into action. Wiles saw Ribet's finding as a way to transform Fermat's Last Theorem from an insurmountable enigma into a solvable problem. In 1993, after seven years of laboring in secrecy, Wiles announced he had a proof of Fermat's longstanding puzzle.
By linking elliptic curves to modular curves, Ribet laid the cornerstone for the proof of Fermat's Last Theorem. Image credit: Wikipedia
The achievement, Ribet says, "turned me overnight into a historical figure, which is an amusing situation to be in."
All of the practice he gained fielding press calls about the theorem, Ribet says, has turned him in to a much better communicator about math. He has since participated in a number of forums designed to make high-level math more accessible to the public. These include a sold-out event at San Francisco's Palace of Fine Arts celebrating the proof of Fermat's Last Theorem, a BBC documentary on the same topic, and symposia on campus and elsewhere on other aspects of number theory.
"It's been incredibly validating that mathematics was able to have this concrete success," Ribet says. "It was really a big shot in the arm for mathematics as a whole."
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Signaling an End to TB
Tom Alber, professor of molecular biology and biochemistry, is also a QB3 faculty affiliate. Photo by Melanie Brewer
HIV, SARS, and ebola may get the headlines, but among public health officials, tuberculosis is the pathogen to watch. Once routinely treated with cheap antibiotics, TB is poised to make a terrifying comeback.
More and more, doctors in developing nations are finding patients infected with strains of TB invulnerable to all but a handful of extremely expensive, exotic drugs. Worldwide, TB already infects one in every three people and sickens one in ten. Without new methods to stop the spread of drug-resistant strains, the cost of treating this ancient human pathogen could bankrupt even the most prosperous economies.
The environmental sensing enzymes in tuberculosis turn on when joined together. This mechanism activates the pathogen's defenses against the immune system. Image courtesy of Tom Alber
At Berkeley, Tom Alber is working to forestall this dire scenario. A professor of biochemistry and molecular biology, Alber is characterizing a class of enzymes TB uses to sense and adapt to its environment. Called protein phosphatases and protein kinases, they are essential components of the bacterium's invasion arsenal. By learning to subvert this system, Alber is developing a means to thwart even the most stubborn strains of TB.
So far, Alber has described the three-dimensional structure of more than a dozen of TB kinases and phosphatases. This has allowed him to piece together how these enzymes operate. He's found that their target molecules join two of the enzymes on the cell's exterior. Inside the cell, the lower halves of the enzymes lock together, too. "That's like shaking hands. All of a sudden they change shape, and that turns them on," Alber says.
The shape change triggers far-reaching shifts in the microbe's physiology. Activating one type of phosphate kinase, Alber has found, alters the expression of nearly 150 microbial genes.
The sensing enzymes in TB can trigger many changes in the bacterium's physiology. These include altering the expression of hundreds of genes as shown on this gene array chip. Image courtesty of Tom Alber
In addition to telling the bacterium whether it's in the water, languishing in soil, or inside a body, these enzymes also help TB to evade the immune system. In humans, the bacilli take up residence within the very cells out to kill them-the white blood cells, or macrophages, of the lungs. Normally, macrophages alert other cells to the presence of an invader. But TB, Alber discovered, pumps a phosphatase into the macrophage that seems to silence this alarm. For this reason, Alber says, "TB over decades can live in a macrophage and prevent it from ever knowing it's infected."
The same cloaking strategy could be at work in other pathogens. "Both TB and HIV live in immune system cells and may subvert the same molecules," says Alber, who has recently begun work on the virus that causes AIDS to see if there are commonalities between the two cloaking mechanisms.
More than 60 human pathogens, including deadly listeria and staphylococcus microbes, possess kinase and phosphatase enzymes, some of which are necessary for the microbes to cause disease. Alber's findings could lead to new classes of antibiotics for these pathogens as well.
After noticing commonalities in the defense mechanisms of HIV and TB, Alber expanded his research to include HIV. Photo courtesy of Tom Alber
Alber is now finding ways to inhibit these enzymes. Kinases and phosphatases are built along the same lines in both bacteria and humans. That means the vast libraries of molecules assembled to search for diabetes, pain, and cancer drugs could yield compounds that interfere with TB.
TB could, in theory, develop resistance to this new class of drugs, too. But Alber thinks he can skew the odds to favor humans. Identifying a drug capable of knocking out several TB enzymes at once could make it next to impossible for the bacterium to evolve resistance on multiple fronts.
Though TB is a daunting foe, Alber remains confident about the prospects of beating the disease. "As a bacterium, it should be easier to treat than HIV or malaria. Those kinds of diseases-caused by viruses and protozoans-we generally don't know how to cure," Alber says. "From a scientific perspective, TB is a simpler problem."
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