Volume 1, Issue 1
Crystallizing Nanoscience
Paul Alivisatos has created nanocrystals of various shapes and sizes, including spheres, rods, and tetrapods. (courtesy LBL)
UC Berkeley chemist Paul Alivisatos, director of the Molecular Foundry under construction at Lawrence Berkeley National Laboratory (LBL), likens the facility to a kitchen. The comparison is surprisingly apt. When it's completed in 2006, the Department of Energy-funded, $85 million research center will provide scientists with the latest appliances, ingredients, and recipes to cook up state-of-the-art nanoscale materials, atom by atom. From quantum dots to biomolecular nanomotors, the kinds of novel structures that will emerge promise nothing short of a revolution in science and industry.
"Right now, scientists are inhibited in what they can do by the fact that they can't always get access to the materials they'd like to work with," Alivisatos says. "The Foundry will keep track of what nanofabrication techniques work well and make those available so all scientists can become experts. That will certainly accelerate the pace of innovation."
For a hint of what lies ahead for the Molecular Foundry, one only needs to look inside Alivisatos's own laboratory. Alivisatos's research focuses on nanocrystals, chemically-pure clusters of anywhere from 100 to 100,000 atoms. (A nanometer is one-billionth of a meter.) During the last decade, Alivisatos and his students pioneered the growth of high-quality nanocrystals by injecting semiconductors like cadmium selenide or cobal into pure, hot, soap-like films called surfactants. The beauty of the nanocrystals is that their physical and chemical properties can be tuned by controlling their size and surface.
An assortment of cobalt nanocrystals manufactured by the Alivisatos research group. (courtesy LBL)
In 1999, Alivisatos and LBL colleague Shimon Weiss reported a groundbreaking biomedical application for quantum dots, nanocrystals that emit different colors of light when a laser shines on them. The researchers discovered that the quantum dots' luminescent properties make them ideal "bar codes" to tag biological materials like DNA and proteins for detection. Now, in collaboration with Carolyn Larabell, a cell biologist and microscopist at LBL, Alivisatos is hoping to use similar nanocrystals to help visualize the interior of individual living cells. Inserted into a cell, the nanocrystals will act as contrast agents when bombarded with beams from the new X-Ray Microscope at LBL's Advanced Light Source.
"Ultimately, this could impact cancer research," Alivisatos says. 'There are a lot of things going on inside cells that we don't understand and cancer causes it all to go haywire."
Along with his life science efforts, Alivisatos is harnessing the unique properties of nanocrystals for renewable energy applications. Two years ago, he and his colleagues fashioned flexible solar cells from rod-shaped nanocrystals. More recently though, Alivisatos and fellow UC Berkeley chemistry professor Gabor Somorjai have shown that a nanocrystal they developed has promise as a nanoscale reactor for future fuel cells. The researchers' microporous nanocrystal features a hollow interior loaded with catalyst particles. Fuel cells, Alivisatos explains, depend on such catalytic systems to facilitate the chemical reaction that produces electrical power.
The Alivisatos research group fabricated this panel of eight plastic solar cells from inorganic nanorods and semiconducting polymers. (courtesy the researchers)
To synthesize the hollow structure, the researchers took advantage of an unusual atomic mechanism similar to the Kirkendall Effect, in which the difference in diffusion rates between two metallic materials causes pores to form. Here, oxidation of a cobalt nanocrystal resulted in the metal diffusing outward, leaving a hollow chamber inside. Encapsulating catalyst materials inside the self-contained but porous crystal results in an entirely different geometry for catalytic systems, Alivisatos says.
While Alivisatos continues to create new kinds of nanocrystals, he's also exploring ways to use the structures as building blocks for complex structures. To that end, he and LBL scientist Alex Liddle have developed a method to place nanoparticles in precise locations on a silicon chip to form transistors.
The technique is based on electron beam lithography, a method of fabricating nanoscale features on silicon substrates. The researchers' first pattern an array of wires on a silicon wafer with gaps where the nanocrystals will be placed. Then, they coat the wafer with a plastic layer that's subsequently riddled with holes, just 50 nanometers in size, above the gaps in the wires. Finally, a liquid solution containing 2 nm nanocrystals is flowed over the wafer. As it evaporates, the nanocrystals fall through the holes to land between the gaps in the wires where they complete the transistors. Future research is aimed at improving the reliability of the contacts between the nanocrystals and the metal leads.
"We'd really like to make devices where you use nanoparticles on a one-by-one basis," Alivisatos says. "We're far from there, but our research is certainly shifting in that direction."
And undoubtedly, those research results will become dog-eared pages in the Molecular Foundry's recipe book.
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Hunting the Achilles' Heel of Hepatitis
Jennifer A. Doudna is a Howard Hughes Investigator and Professor of Biochemistry and Molecular Biology, and is affiliated with the California Institute for Quantitative Biomedical Research (QB3).
One way to disrupt a mechanical process is to throw a wrench into the works. This also holds true for viruses, biological parasites that hijack a cell's reproductive mechanisms to replicate themselves. The key though to successful sabotage is knowing precisely where to toss the wrench.
Jennifer A. Doudna, a UC Berkeley professor of Biochemistry and Molecular Biology, is aiding the hunt for this kind of Achilles' Heel in the Hepatitis virus. According to the Center for Disease Control, nearly 4 million Americans and 170 million people worldwide have been infected with Hepatitis C, one of the strains Doudna studies. The failure of available therapies results in 10,000 deaths every year just in this country.
"It's a very serious pathogen and we don't have any good drugs to treat it," says Doudna, whose insights into the virus's structure and reproductive mechanisms could lead to the development of new treatments for the disease.
Doudna's research is focused on ribonucleic acid (RNA), the molecule that carries the genetic blueprint copied from DNA. Inside the cell, ribosomes use the RNA code to assemble proteins, the building blocks of life. Normally, the RNA recruits the ribosomes by using molecular beacons that help bring the two together.
The problem, Doudna explains, is that "viruses have figured out a way to fly under that radar and recruit the ribosome directly" without any molecular signaling. Doudna's efforts to understand the phenomenon began several years ago while she was a professor at Yale University. In 2001, she and collaborators Jeffrey Kieft, a postdoctoral fellow and UC Berkeley alum, and Joachim Frank, a researcher at the Howard Hughes Medical Institute, produced groundbreaking visualizations of the Hepatitis C RNA molecule that recruits ribosomes during a viral infection.
Through cryo-electron microscopy, a low-temperature variant of electron microscopy, the researchers took a close look at a complex structure on one end of the virus's RNA. The researchers determined that the structure, called an internal ribosomal entry site (IRES), physically forces the ribosome to change its shape so that the RNA's protein template is in the perfect location to spur protein synthesis.
"The viral RNA literally clamps around the ribosome," says Doudna, who also holds a faculty position in the College of Chemistry.
The cryo-electron microscopy experiments provided the researchers with "a ten mile view" of the biochemical interactions, Doudna says. Currently, she and her Berkeley colleagues are zooming in even further on the hijacking process. Their tool is x-ray crystallography, a technique made possible by the fact that x-rays are diffracted by crystals. The researchers crystallize the RNA molecule and then bombard it with x-rays generated by the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory. The resulting diffraction pattern is then used to reconstruct a three-dimensional image of the molecule.
"With that kind of high-resolution information, drug design becomes a very real possibility," says Doudna.
To that end, the laboratory participates in various scientific interactions with Isis Pharmaceuticals. Doudna hopes that the viral structural information uncovered in her laboratory could guide the design of new drugs to combat Hepatitis C.
In another research effort, Doudna and her colleagues are examining a rarer type of hepatitis virus, called Hepatitis Delta. Prevalent in southeast Asia, the virus only infects individuals who already have Hepatitis B.
Hepatitis Delta's genetic information is encoded in a circular piece of RNA. In this case, an RNA enzyme in an infected cell copies the RNA genome by a "rolling circle" replication mechanism, generating long strings of viral code. Then, in an amazingly efficient bit of biology, a catalytic RNA molecule called a ribozyme acts as a pair of "molecular scissors," chopping the just-duplicated viral genome into unit-length pieces for packaging.
This image, generated by cryo-electron microscopy, depicts the hepatitis C internal ribosome entry site (IRES) bound to a ribosomal subunit (yellow) of a rabbit cell. (visualization from Spahn, C.M.T, Kieft, J.S., Grassucci, R.A., Penczek, P., Zhou, K., Doudna, J.A., and Frank, J., 2001. Science 291:1959—1962)
"It's a neat way that the virus has figured out to use its genetic information to the max," Doudna says. "It has to have RNA to encode viral proteins, but it also uses the RNA itself to catalyze this essential cleavage reaction."
To visualize the nearly instantaneous cleaving process, the researchers are again turning to x-ray crystallography. First, Ailong Ke, a postdoctoral fellow in Doudna's lab, made subtle modifications in the RNA in order to halt the cleavage just before it occurs. Then, using the ALS's x-rays, the researchers grabbed a series of high-resolution snapshots of the molecule mid-cycle. What they observed is that the ribozyme undergoes a change in its molecular shape during the cleaving.
"From a basic science standpoint, we're interested in how enzymes have evolved in biology," Doudna says. "And now what we think is that this virus has evolved this particular ribozyme activity to place a very tight control over when the RNA is cleaved during the viral replication cycle."
As with Hepatitis C, understanding the structure of Hepatitis D's viral ribozyme and its machinations could reveal "a nice target for therapeutic intervention," Doudna says.
"In biology, a picture is worth more than a thousand words."
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The Mysterious Matter of Dark Matter
Chung-Pei Ma recently formed a string quartet (musical strings, that is) with two Berkeley computer scientists and a psychologist. (Wendy Edelstein photo)
Every day, UC Berkeley astronomy professor Chung-Pei Ma is reminded how little we understand about our universe. Familiar particles like protons and neutrons make up just a tiny fraction of the total mass and energy of the universe, perhaps just one percent. The rest--appropriately dubbed dark matter and dark energy--is literally invisible to us. Ma's research aim is to shine light on this ghostly universe surrounding us. Her efforts could aid scientists in understanding the evolution and destiny of the cosmos.
Dark matter was first proposed in the 1930s when astronomers noticed that the motion of galaxies and clusters of galaxies they observed did not jibe with the visible mass. Since then, dark matter and dark energy have theoretically been implicated in the expansion of the universe.
"The problem is that we don't know what dark matter and dark energy are," Ma says. "And we need more information to theorize about it."
Ma's latest results revolve around dark matter. Currently, she says, there are two primary candidates that may make up the stuff. The first are dead planets or stars that emit no detectable light but do interact with ordinary matter through gravitation.
"Our galaxy might be littered with the dead planets or stars, but the numbers still don't add up," Ma says. "Those big things that you can touch are probably just a small portion of dark matter."
Computer simulation of the initial Hubble expansion and subsequent formation of a galaxy-size halo of dark matter over the last 13.5 billion years--99 percent of the lifetime of the universe. The simulation shows an intricate pattern of swarming dark matter clumps, some of which may not host luminous matter such as stars and gas.
(courtesy Chung-Pei Ma and Ed Bertschinger)
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The second and more popular theory is that most dark matter consists of elementary particles like neutralinos or other theoretical supersymmetric particles. Indeed, researchers at Berkeley are attempting to detect these elementary particles in particle accelerators. According to Ma, using computer simulation to "profile the missing matter," analogous to the way criminal investigators determine the characteristics of an unknown perpetrator, will aid in the design of better detectors.
"Fortunately, we understand the forces behind dark matter, such as gravity," she says. "So we can postulate a number of things and then do large supercomputer simulations of a patch of the universe, maybe just hundreds of millions of light years across."
Already, Ma's simulations have shown that dark matter is not distributed smoothly, like a fog enveloping galaxies and clusters of galaxies. Rather, it clumps together into satellite galaxies, not unlike the luminous formations in the visible universe. This should mean that the dark matter universe somewhat mirrors the visible universe. The rub is that it doesn't, she says. Computer simulations predict that that the clumps of dark matter are far more abundant in a particular region than luminous matter.
To help resolve this conflict and others, Ma and Edmund Bertschinger of the Massachusetts Institute of Technology recently proved that Brownian motion--a phenomenon first explained by Einstein nearly one hundred years ago--can also be employed to model the dynamics of dark matter. Originally used to describe the way a grain of pollen travels through water, Brownian motion refers to the chaotic motion of particles as they're impacted by smaller particles. UC Berkeley professor emeritus of astronomy Ivan King previously applied the theory of Brownian motion to model the movement of stars within clusters, but this latest work, Ma says, "is the first time it has been applied rigorously to large cosmological scales."
To predict Brownian motion and other random phenomena, scientists refer to a standard mathematical formula called the Fokker-Planck equation. Ma and her colleagues are currently attempting to solve the equation for dark matter so that more advanced computer simulations can be created to better understand how the clumps move.
"Through more accurate computer modeling, we can begin to compare theoretical predictions about dark matter with our observations of the universe." Ma says.
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Berkeley's Scientific Legacy
1955: Emilio Segrè, Owen Chamberlain, and the matter of antimatter
During the fall of 1955, a blackboard at Lawrence Berkeley National Laboratory helped physicists Emilio Segrè and Owen Chamberlain keep track of two very important, but very different, tallies. One side of the board held the scores from that year's World Series, in which the Brooklyn Dodgers ultimately beat the Yankees. The blackboard was also where Segrè and Chamberlain kept a running tally of how many elusive antiprotons they observed after discovering the very first one.
Left to right are Dr. Emilio Segrè, Dr. Clyde Wiegand, Dr. Edward Lofgren, Dr. Owen Chamberlain and Tom Ypsilantis, then a graduate student. The photograph was taken at Lawrence Berkeley Laboratory in October, 1955 at the time of the discovery of the antiproton. (Courtesy LBL)
The hunt for antimatter began in earnest in 1932, with the discovery of the antielectron, or positron. Creating an antiproton though was far more difficult, requiring nearly 2,000 times the energy. In 1955 though, the Berkeley Bevatron--then the most powerful "atom smasher" in the world--went online, providing the scientists with the energy they needed to make antiprotons.
The next challenge was determining whether they succeeded. After all, almost instantly after an antiproton appears, contact with a proton annihilates them both. To detect the particles, Segrè and Chamberlain devised a maze of magnets and electronic counters through which only antiprotons could pass.
"We had to sort them out and weigh them within much less than one-millionth of a second," Segrè recalled later. "If we had wanted to have them for a longer time, we would have to dig a tunnel in the Berkeley hills to run after them."
After several hours of bombarding copper with protons accelerated to 6.2 billion electron volts of energy, the scientists counted a total of 60 antiprotons. Most likely, the discovery of one would have been sufficient to have earned them the 1959 Nobel Prize in Physics.
Professor Emilio Segrè in 1954 (Courtesy LBL)
Professor Owen Chamberlain in 1955 (Courtesy LBL)