Volume 1, Issue 5
Supernovas Illuminate Dark Energy
Einstein called it his biggest blunder. His early equations for general relativity accounted for a strange cosmic antigravity precisely balancing the attractive force of gravity. But after Edwin Hubble discovered that the universe is expanding, Einstein yanked the mysterious force from his equations. Several years ago though, UC Berkeley astronomer Alex Filippenko helped prove that Einstein was right after all. In fact, the magnitude of the antigravity effect is greater than Einstein had even thought. The universe is not only expanding, but it's speeding up every day. Why? And how fast? Filippenko is now asking those questions, using exploding stars as his cosmic mile markers.
A recipient of UC Berkeley's two most coveted teaching awards, Alex Filippenko is also the co-author of the introductory astronomy textbook, "The Cosmos: Astronomy in the New Millennium." (photo by Jock McDonald)
Filippenko is a world-renowned hunter of supernovas, massive stars that die a violent death. Because of their power, supernovas are much more visible to observers compared to other objects in distant space. In September, Filippenko used the NASA Hubble Space Telescope to image the brightest and closest supernova of the decade, just 11 million light-years from Earth and glowing with the intensity of 200 million suns.
Classified by the process by which they die, Type Ia supernova are the most commonly observed, primarily because they are the most powerful of the dying stars. Filippenko and his colleagues have found several hundred of the objects. By measuring a supernova's brightness and determining its true power through various observational techniques, scientists can determine its distance from Earth.
"It's like looking at the label of a lightbulb to see how powerful it is," Filippenko says.
A star explodes (arrow) in a galaxy 11 million light years away. The heart of the galaxy, NGC 2403, is the glowing region at lower left. Sprinkled across the region are pink areas of star birth. The myriad of faint stars visible in the Hubble image belong to the galaxy, but the handful of very bright stars in the image belong to our own Milky Way and are only a few hundred to a few thousand light-years away. (Photo courtesy NASA, ESA, A.V. Filippenko [UC Berkeley], P. Challis [Harvard-Smithsonian Center for Astrophysics], et al.)
Once a supernova's distance is determined, it can also provide clues to the rate of cosmic expansion. As objects recede from the Earth, the wavelengths of the light they emit lengthen, shifting into the red part of the spectrum. Measuring a supernova's "redshift" indicates its speed.
Until 1998, astronomers believed that the universe's expansion as a result of the Big Bang was slowing down due to gravity and might eventually reverse itself. Imagine throwing a ball into the air. At some point, it will slow down and fall back to the ground. But what if you tossed it upwards and it kept going, gaining speed as it went? Observations of dozens of supernovas by Filippenko, physics professor and Lawrence Berkeley National Laboratory (LBNL) scientist Saul Perlmutter, and their colleagues showed that this is exactly what's happening with objects in the universe. The supernovas turned out to be farther away from Earth than the scientists predicted based on the redshifts.
"It appears there is some funny energy in the universe that makes it expand forever, but at an ever increasing rate," Filippenko said at the time.
The invisible force is now known as dark energy. While it may account for as much as two-thirds of the mass in the universe, scientists really have no idea what it is. One theory is that it's vacuum energy of empty space that exerts a negative pressure, as postulated by quantum physics. Others suggest that it's a low-energy field called quintessence, whose detailed properties are still unknown.
According to Filippenko, supernovas may contain clues to solve that puzzle, considered by many to be the hottest mystery in modern physics. Uncovering the secret of dark energy, he says, may dramatically increase our knowledge about what really happened about 14 billion years ago during the Big Bang, and inform scientific predictions about the ultimate fate of our universe.
"Unless the dark energy changes into an attractive force in the future, we think that the universe will expand forever, eventually becoming cold and dark," Filippenko says.
A before and after shot of a galaxy where the UC Berkeley team discovered a supernova (noted by the arrow) using their Katzman Automatic Imaging Telescope. (courtesy the researchers)
To gain insight into dark energy's traits--its pressure versus density, for example--Filippenko employs several state-of-the-art telescopes. Based on his track record, he's granted time on the world's most advanced systems, from the Keck Observatory in Hawaii to the Hubble Space Telescope orbiting the Earth. In January though, NASA announced that due to safety concerns it would no longer service the telescope. Already, components vital to Filippenko's research have failed.
"The announcement was a huge blow to all of us," he says.
Fortunately in October, NASA agreed to consider robotic servicing machines to keep the telescope operational for another five to seven years. Meanwhile, just east of San Jose, a robotic telescope built by Filippenko's group keeps a constant vigil for supernovas every clear night. Filippenko calls the 76-centimeter diameter Katzman Automatic Imaging Telescope (KAIT) a "supernova search engine." This year alone, the group has discovered more than sixty supernovae using KAIT's unblinking eye.
"Cosmology is spurring a revolution in physics and I'm excited to contribute to it in any way I can," Filippenko says.
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Neurobiology's Lighter Side
What happens when you touch a hot pan on the stove? You probably yell and yank your hand away. Between the sizzle and the scream though, an amazingly fast and complex cascade of cellular communication occurs inside your body. To study the electrical intricacies of the nervous system, neurobiologist Ehud Isacoff is developing new optical methods that enable scientists to watch the cellular symphony unfold at the nanoscale.
Ehud Isacoff is also Chair of the Graduate Group in Biophysics.
Understanding the dynamic structure of neuronal proteins could lead to new treatments for diseases like cystic fibrosis, epilepsy, and some forms of paralysis, Isacoff says. The first step though is to take a long, hard look at the dynamics of ion channels, the tiny electrical gates in a cell's membrane that govern cellular transport and signaling.
"An ion channel operates like a transistor with extreme speed, at an extremely small scale, and with tremendous reliability," says Isacoff, professor of Molecular and Cellular Biology. "The question is how it works mechanistically."
Ion channels are proteins that function as pores to selectively let ions like sodium and potassium pass in and out of a cell. As the ion channels rapidly open and close, the voltage of the cell changes and a voltage wave is produced. The ion channels themselves are triggered by a change in voltage as well, enabling electrical impulses to propagate from cell to cell through the nervous system.
To truly understand the molecular dynamics of an ion channel, you have to watch the protein move. The problem though is that traditional protein visualization techniques like x-ray crystallography can only produce high-resolution "still lifes" of a particular structural state. Furthermore, crystallography requires the protein to be removed from the cell and purified.
Isacoff and his colleagues have developed a method to study ion channel structure and protein motion within the cell in real time. He calls the technique "in situ optical biochemistry."
"It allows us to get a dynamic measure of the functioning protein within its natural physiological environment," says Isacoff, who is also a faculty scientist at Lawrence Berkeley National Laboratory.
First, the researchers attach fluorescent molecules to specific points in the ion channel's amino acid sequence. The fluorophore's brightness and wavelength change based on the local chemistry. As the protein structure changes, the fluorescent molecule moves as well. Even a very small motion affects the chemistry around the fluorophore, altering its color or brightness.
"The fluorescent lightbulbs in different locations illuminate who moves when and in what sequence," he says. "And that can be detected by a simple camera."
At the same time, a functional measurement of the ion channel is taken. That way, the visual "signature" of the transition as indicated by the fluorescence can be matched to particular function.
Once the technique is perfected, Isacoff hopes it can be used as the basis for a biochemical "device" that scientists could deliver to specific parts of an animal's nervous system. The strategically-placed fluorophores would illuminate the pathways of neural impulses, possibly even revealing how and where certain sensory inputs are processed in the brain.
"By using these kinds of optical systems, the hope is that you can follow voltage, which is one of the key signals in the nervous system," Isacoff says.
The fluorescent molecule rhodamine is attached to a fruit fly potassium channel. It becomes brighter when the channel protein changes its structure in response to a change in membrane voltage. Someday, Isacoff's research on ion channels could aid engineers in developing advanced biosensors, "artificial noses" that detect the most miniscule amount of pathogens or contaminants in the air.
The next step, he explains, is using optics as a tool not just to measure protein activity, but actually control it. For example, ion channels genetically engineered to be light sensitive could be switched on and off with a beam of a certain wavelength. That way, cells in neuronal circuits could be easily knocked in and out of service, helping scientists deduce their function.
"What you'd like to do is turn on or off a protein in a particular cell in a reversible manner without altering its ability to function otherwise," Isacoff says. "That would revolutionize biology. And an ideal way to do that would be with light.
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A Twist on Cancer DNA
Crammed inside every human cell are numerous strands of chromosomal DNA that, if laid end-to-end, would span a distance of about two meters. A special enzyme mechanically untangles the DNA, keeping our chromosomes from resembling a string of Christmas tree lights jammed into a box after the holiday. Someday, biochemist James Berger's efforts to understand the same enzyme in cancer cells could lead to new tumor-fighting drugs.
James Berger is also a faculty scientist in Lawrence Berkeley National Laboratory's Physical Biosciences Division and a faculty affiliate with the California Institute for Quantitative Biomedical Research (QB3).
"When an extension cord has tangles in it, you'd like to be able to cut it, specifically take out each knot, and put it back together again as opposed to threading the ends of cord through one another," says Berger, a professor of Molecular and Cell Biology. "Cells evolved an enzyme to do just that."
The enzyme is called a topoisomerase, so-named because it literally resolves topological dilemmas like knots and twists. Essential to the survival of many cells and viruses, topoisomerases have in recent years become prime targets for anticancer and antimicrobial drugs. Indeed, many traditional forms of chemotherapies are based on natural and synthetic compounds that inhibit the process. But Berger hopes his efforts to unveil the enzyme's subtle mechanics may inform the development of better drugs that throw a wrench in the cancer's topoisomerases while sparing healthy cells.
Think of a topoisomerase as a tiny multi-armed robot that clamps around a knot or twist in the DNA. One set of the arms grabs either side of the knot and pulls the strand apart while another uses a free segment of DNA to push through the break. After the strand is closed again, the DNA that was just transported through the break is expelled from the bottom of the enzyme.
"All of the components are coupled and coordinated so that the enzyme can remove two to three knots every second," Berger explains. "If it screws up though and doesn't paste the DNA back together correctly, the cell won't survive. That's the Achilles' Heel that many chemotherapeutics exploit."
"Classic" chemotherapeutics like Etoposide, Adriamycin and Mitoxantrone stop the enzyme in the middle of the reaction, preventing the gap from closing. Because tumor cells divide so rapidly, "jamming the enzymes just shreds the DNA," Berger says.
This model depicts the topoisomerase during one step of its unknotting reaction. The DNA (visible in green) has been cleaved and opened by the enzyme while the DNA being passed through the break is viewed end-on. (courtesy the researchers)
"Of course, these compounds hit the good cells as well as the bad cells, which is why the classic chemotherapy drugs from the last few decades make you sick," he adds. "On the other hand, the drugs achieve their goal remarkably well."
Most of those drugs, he explains, were discovered decades ago through trial-and-error methods. Since then, Berger and other researchers have produced detailed pictures of the topoisomerase reactions and deduced how certain drugs muck up the works. The biologists' technique, called X-ray crystallography, enables the position of every atom in a protein to be visualized, resulting in an "exploded view" of the molecule.
"It's like looking at a car engine that you've taken apart and put back together to get a much better idea of how it works," says Berger, who conducts his crystallography work at Lawrence Berkeley National Laboratory's Advanced Light Source.
Armed with the new physical information, Berger and his team are now studying a more recently-developed class of anti-cancer drugs called bisdioxopiperazines that inhibit the topoisomerase reaction in a different way than the classic compounds. Currently used to help alleviate the heart risk associated with chemotherapy, a bisdioxopiperazine may also be useful on its own, possibly with less impact on healthy cells.
It turns out that the drug works by acting similarly to a mortise-and-tenon joint in fine carpentry. It binds to one of the mechanical gates the enzyme uses to direct the transport of the DNA segments and locks it shut. Already, the Berkeley group's efforts have revealed how some cells develop mutations that increase their resistance to the drug.
"In the future, we'd like to tinker with it," Berger says. "Rational drug design is very difficult, but here we have something we already know is effective. So maybe it could be a good starting point to see if we can help make an even better drug."
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Berkeley's Scientific Legacy
1958: Daniel Koshland and shape-shifting proteins
Among Daniel Koshland's honors are the National Medal of Science, the Edgar Fahs Smith and Pauling Awards of the American Chemical Society, the Rosenstiel Award of Brandeis University, the Waterford Prize, and the Merck Award of the American Society of Biochemistry and Molecular Biology.
Inside our bodies, an intricate dance of mechanical motion is taking place. At the cellular level, the proteins that are the building blocks of life are shifting their shape as they interact, flexing as they bind in a biophysical ballet.
In the 1960s, UC Berkeley biochemist Daniel E. Koshland formulated new theories that changed science's fundamental understanding of this complex choreography. His discoveries helped lay the groundwork for decades of research on the relationship between protein structure and function and the correlation of protein chemistry to various diseases.
Koshland, who obtained his BS in chemistry from Berkeley in 1941, is best known for his "induced fit theory," an explanation he first proposed in 1958 of how enzymes catalyze the chemical reactions of life, converting one substance into another. At the time, scientists supported a theory first laid out in 1894 that enzymes are like locks with the compounds they affect acting as keys. When one fits into the other, catalysis occurs.
Koshland argued that the rigid key-lock theory didn't explain the specificity and regulation demonstrated by many reactions. In many cases, he believed, the enzyme is flexible and the compound binds to it like a hand inside a glove. If the hand (the substrate) is too big to fit or too little to fill the glove (the enzyme), the reaction won't occur.
It wasn't until the 1970s that the induced fit theory was verified using X-ray crystallography, a technique to visualize the location of atoms in a protein. Meanwhile, Koshland's further research led to insights into hormone interactions and the mechanisms by which biological processes are regulated.
In 1998, Koshland was awarded the prestigious Albert Lasker Award for Special Achievement in Medical Science. He has published more than 400 scientific papers and was the editor of Science magazine from 1985-1995. During more than three decades as a Berkeley researcher and professor, Koshland was instrumental in focusing and growing Berkeley's biological sciences.
Still a Professor of the Graduate School in the Department of Molecular and Cell Biology, Koshland, 85, continues his research on proteins. Currently, he's applying genetic engineering and protein chemistry to design therapies for Alzheimer's Disease and exploring how enzymes might be modified for use in environmental clean-up.