Volume 1, Issue 4
Flipping The Switch On Cancer
Four years ago, a new weapon in the war on cancer made it to clinical trials accompanied by headlines and hope. Gleevec, a drug manufactured by Novartis, appeared to selectively turn off a specific cancer-causing protein like a light switch, stopping the progress of a severe form of leukemia in its tracks. The odd thing is that nobody really knew how the drug knocked out the leukemia-causing cells while leaving healthy proteins alone. Just seven months before the FDA approved Gleevec in May 2001, Professor John Kuriyan announced that he had solved the puzzle.
"Our lab studies protein molecules that are produced by certain genes, normal or not," says Kuriyan, a professor of molecular and cell biology and chemistry at UC Berkeley. "By determining how the atoms are arranged in three dimensions, we try to figure out what goes wrong as a result of particular mutations. That can help drug companies learn how a compound might flip the switch one way or another."
John Kuriyan is also affiliated with the California Institute for Quantitative Biomedical Research, a cooperative effort among UC Berkeley, UC Santa Cruz, and UC San Francisco.
At the time of his discovery, Kuriyan was head of the Laboratory of Molecular Biophysics at Rockefeller University and an investigator at the Howard Hughes Medical Institute (HHMI). Since arriving at Berkeley, Kuriyan has continued his cancer-related research with HHMI support. Most recently, he's helped determine why some patients develop a resistance to Gleevec.
Gleevec's ability to fight chronic myelogenous leukemia (CML) first emerged from drug discovery techniques based on trial-and-error. Pharmaceutical companies commonly screen myriad compounds and then use organic chemistry to optimize those that show promise as potential drugs.
When Gleevec came on the scene, it was well known that CML is caused when a single molecule called the Abelson kinase (Abl) is activated. The tyrosine kinase family, of which Abl is a member, play a key role in regulating cell growth and division. When genetic mutations occur that disrupt the normal switching function of Abl, the cells divide out of control, leading to cancer.
"The switch is not statically locked on or off, but the disease is caused when it's on much more often than it's off," says Kuriyan, also a faculty scientist at Lawrence Berkeley National Laboratory.
Drugs work by binding to the protein and disrupting its function. However, the human genome codes for about 500 protein kinases that are virtually identical. Flipping the right switch is tricky.
"When the kinases are ready to work, they all look the same," Kuriyan says. "That's because they bring to bear the same machinery to carry out their chemical reactions."
As a result, it's extremely difficult to find a drug candidate that targets a certain type of a protein kinase--Abl, in the case of chronic myelogenous leukemia--and not other normal kinases. But Gleevec did just that. The big question was how.
Kuriyan and his colleagues are masters of X-ray crystallography, a method used to reconstruct a three-dimensional image of a molecule. This kind of visual analysis revealed that Gleevec didn't recognize the "on" state of the protein but rather the "off" state. When the proteins are "on," they do indeed look alike. But when "off," the differences are dramatic.
This model, built from X-ray diffraction data, depicts the crystal structure of the Abelson kinase in complex with the Gleevec molecule.
"Evolution has specialized these switching devices so they all come into the same shape when they turn on," Kuriyan says. "But when they turn off in response to the presence or absence of a certain input signal, they're structurally quite different. Gleevec takes advantage of that to bind to just a few of the kinases it encounters instead of all 500."
Since unraveling the secret of Gleevec's power, Kuriyan and his colleagues continue to explore the intricate workings of the molecular switches. For example, Gleevec is entirely ineffective for a growing number of patients. Certain mutations, Kuriyan says, entirely block the drug from binding to the kinase.
"Unfortunately what we're realizing is that the property that gives these compounds their specificity is also an Achilles' Heel for the drug," he says. "To evade the drug, all the protein has to do is destabilize the inactive state."
To that end, Kuriyan, in collaboration with HHMI investigator Charles L. Sawyers at the University of California, Los Angeles, is examining new "sloppier inhibitors" that aren't quite as dependent on recognizing Abl's "off" state to work. So far, one new drug, developed by Bristol-Myers Squibb, has proven effective in mice and is undergoing FDA Phase I clinical trials.
"We hope to understand the origins of resistance," Kuriyan says. "Perhaps the very basic information we provide will help the pharmaceutical companies design the next generation of anti-cancer drugs."
http://www.boingboing.net/images/Abl.jpg This model, built from X-ray diffraction data, depicts the crystal structure of the Abelson kinase in complex with the Gleevec molecule.Related Web Sites
Think Molecularly, Act Globally
When NASA's ER-2 stratospheric aircraft returns from another trip to 70,000 feet above the earth, it may be carrying a special payload back for UC Berkeley professor Kristie Boering. The small canister inside the modified spy plane provides Boering, an assistant professor of chemistry and earth and planetary science, with clues into the human impact on global climate and how the ozone layer may recover over the next century. Amazingly, the canister appears to be empty. That's because Boering's understanding of atmospheric chemistry comes from studying the air up there.
Kristie Boering also studies the atmosphere of Mars to help scientists determine if the Red Planet could ever have supported life.
"We combine measurements on air samples collected in the stratosphere with physical chemistry experiments in our lab and computer models of the atmosphere," Boering says. "It's really a combination of molecular and global scale research."
Boering's goal is to tease apart the coupling of chemistry and air circulation to understand climate change and ozone depletion on monthly to millennial time scales.
"You'd think we'd know everything about how the air circulates from the lower atmosphere where we live, up into the stratosphere, and back down again," she says. "But we're really still working on quantifying it."
The ozone layer, located in the stratosphere six to 30 miles above the Earth, protects our planet from ultraviolet rays. Scientists now agree that ozone depletion is due in large part to the release of chlorofluorocarbons (CFCs) and other industrial chemicals. Boering hopes to put more concrete numbers on the human impact on the ozone layer and climate.
"Even though it's no longer a mystery of how the ozone layer was destroyed over Antarctica, we still need to know how the hole will recover over the next sixty years or so," Boering says. "That depends on the details we're trying to quantify."
The devil may indeed lie in the details. For example, Boering and her students are working to characterize the relationship between the ozone layer and global climate change, spurred by both nature and human forces. Feedback may occur in both directions, she says, but traditional computer models of the atmosphere aren't accurate enough yet to forecast such phenomena.
"Our models are good enough to understand what happened so far and probably enough to prevent a big disaster, but what if we tweak the system in the physical world from where our computer simulations happen to be working?" Boering says.
Two NASA ER-2 high altitude research aircraft used to obtain arm samples from the stratosphere for analysis. The ER-2 is a civilian version of the Air Force's U-2 reconnaissance plane. (courtesy NASA)
To improve the global models, Boering conducts physical chemistry experiments on the air samples retrieved by both the ER-2 plane and arena-sized stratospheric balloons. By measuring the composition of greenhouse gases such as methane, carbon dioxide, and nitrous oxide in samples taken in various parts of the atmosphere on a number of timescales, Boering and her colleagues can help identify where the chemicals come from, where they go, and perhaps most importantly, how they get there.
The new measurements are possible due to analytical techniques that Boering helped pioneer. Previously, measuring greenhouse gases collected in the stratosphere required a sample of thousands of liters of air. Now, the same measurements can be conducted on less than 100 milliliters of air.
Last year, Boering and collaborators from the California Institute of Technology, National Center for Atmospheric Research and UC Irvine published a study in the journal Nature identifying a major sink of hydrogen gas in the environment that had previously been a mystery. The results are essential in assessing the likely impact of additional hydrogen in the atmosphere resulting from an increase in vehicles that run on hydrogen rather than fossil fuel. Boering is currently working to analyze their data to quantitatively predict whether the hydrogen economy will have any unforeseen impact as its main byproduct flows into the skies above.
"We decouple the chemistry from the circulation and then put them back together again in the computer models," she says. "Like a good chemical engineer working in an industrial plant, you need to know both the chemistry and how things move through the pipes."
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Quantum Computing's Magnetic Attraction
Tomorrow's nanocomputers may be incredibly powerful, but they'll also be mind-bogglingly strange. Instead of binary numbers, these machines will speak a language of "quantum bits" that can exist as zeros, ones, or both at the same time. By harnessing the unusual properties of quantum physics, quantum computers will perform calculations up to a billion times faster than today's silicon-based processors and store data in the spin of individual magnetic atoms.
Michael Crommie beside his customized Scanning Tunneling Microscope (STM).
UC Berkeley physicist Michael Crommie is bringing us closer to the next computer revolution by understanding and manipulating magnetism at the atomic level.
"The magnets that most of us know are simple things with a north and south pole," says Crommie, also a faculty scientist at Lawrence Berkeley National Laboratory (LBNL). "But when you shrink a magnet down to the size of a single atom or molecule, the properties change considerably. There's a whole world down there with a wealth of different phenomena that depend on very subtle interactions."
At the atomic scale, magnetism is known as "spin." An electron's spin is similar, at least conceptually, to the direction of a rotating top. It can either be "spin-up" or "spin-down" or, Crommie says "kind of up and kind of down." This spin state, called a "superposition" state, can be altered by a magnetic field.
In a futuristic quantum computer, Crommie explains, the direction of an electron's spin could be used as a quantum bit, or "qubit." The power of quantum computers lies in the qubit's ability to exist in a superposition state, representing multiple values at one time. This quantum weirdness is what enables quantum computers to process so much data at once. As more qubits are strung together, the power of the quantum processor grows exponentially.
"The big questions though are can we precisely control the quantum state of these microscopic structures, measure them, and connect them to create an extended circuit of quantum mechanically-interacting bits?" Crommie says.
To tackle these challenges, Crommie is collaborating with colleagues from the Physics Department, College of Chemistry, and College of Engineering on a $4.5 million grant funded by the National Science Foundation. The aim is to evaluate whether different schemes for the seemingly far-fetched technology will actually work.
In 1993, Crommie was part of a team that discovered a new method for confining electrons inside a "quantum corral" of iron atoms. (courtesy the researchers)
Crommie and collaborators Yossi Yayon, Xinghua Lu, and Andre Wachowiak are exploring ways to reliably control spin states of single atoms and molecules in the laboratory. The tool of the trade is the scanning electronic microscope (STM). Unlike the lens of an optical microscope, an STM has an extremely sharp tip as its probe. As the stylus scans across a sample, the amount of electrical current flowing between the tip and surface is measured. This enables a profile of the sample to be generated and visualized with atomic-scale resolution. STMs can also be used to push atoms around into desired structures. Last spring, Crommie and his collaborators used their STM to change the electrical properties of a single buckminsterfullerene molecule ("buckyball") by moving it on a surface where it picked up potassium atoms one at a time.
As a buckyball acquires potassium atoms, its energy state changes, causing it to "light up" in this STM image. (courtesy the researchers)
In their spin experiments, the researchers sandblast a crystal surface in a vacuum chamber until it's perfectly flat and clean. They then heat up a chunk of iron until the atoms jump off onto the crystal surface where the STM can be wielded to drag them into desired geometries. The researchers customized their STM with a magnetic tip that allows them to measure the spin of the atoms.
"Typically, the electrons jumping off an STM tip to measure the properties of atoms have spins that are arranged randomly," Crommie says. "But if the electrons coming off the tip can be made to have a net spin orientation, then you can detect the spin orientation of what's on the surface."
Most recently, the researchers used the STM to study clusters of magnetic molecules. The molecules consist of one or more magnetic atoms surrounded by organic molecular structures such as benzene rings or alkane chains. These outside structures can link one molecule's magnetic state with other neighboring molecules. Potentially, coupling the molecules could lead to a technique for controlling the spin states within the clusters.
For example, Crommie says, it may be possible to attach a magnetic molecule to tiny carbon nanowires so that the flow of electrons through a circuit is controlled magnetically rather than electrostatically, the basis of traditional electrical engineering. Spintronics, as the new paradigm is known, has already been used in a coarser way in computer hard disk drive heads to increase storage density. Nanocomputers, however, remain a quantum leap away.
"We're not building the world's smallest disk drives or the next quantum computer," Crommie says. "But we're figuring out what may be possible and the knowledge we collect might have applications for those future technologies."
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Berkeley's Scientific Legacy
1959: Horace Albert Barker and the power of Vitamin B-12
If Horace Albert Barker were to tell you to take your vitamins, you knew he spoke with authority. One of the leading biochemists of the last century, the late UC Berkeley professor discovered the active form of vitamin B-12, an ingredient that's essential to the complex chemistry of life. Indeed, Barker's career-spanning studies in vitamin chemistry, amino acids, carbohydrates, and metabolism led directly to our current understanding of how chemical changes in our bodies make us sick or well.
A lifelong outdoorsman, Barker hiked and fished at his Mount Lassen cabin into his 90s.
Before his B-12 breakthrough, Barker was part of a team in 1944 that discovered how living cells synthesize sucrose. The success of that research was based in no small part on Barker's pioneering use of radioactive carbon-14 tracers to illuminate the biochemical reactions taking place in the cell.
In 1959, Barker was studying common soil bacterium found in the mud from nearby San Francisco Bay. He and his colleagues were examining the bacteria's anaerobic fermentation of amino acids. Once they found that the reaction was dependent on vitamin B-12, the researchers isolated and partially characterized the vitamin in its coenzyme form. Barker's continued studies of the coenzyme eventually helped physicians understand and treat diseases related to B-12 deficiencies, such as pernicious anemia.
Born in Oakland in 1907 and educated at Stanford University, Barker joined the UC Berkeley faculty in 1936 to teach soil microbiology. During his tenure at the university, he chaired the Department of Plant Nutrition, the Department of Plant Biochemistry, and from 1962-1964, the newly-formed Department of Biochemistry in the College of Letters and Science. A building on campus was named in his honor in 1988. A professor emeritus of biochemistry and recipient of the prestigious National Medal of Science, Barker died in 2001 after a brief illness at the age of 93.