The body's basic building block takes quite a daily beating. The familiar double helix that graces science magazine covers and defines who we are is under constant assault from the likes of cosmic rays, radon in the soil and water, even certain rare forms of potassium and carbon in our own bodies. In addition, immune system cells deliberately introduce breaks into their own DNA as part of the process that forms unique receptors capable of recognizing a previously unseen bacterium or virus and mounting an attack.
When both DNA strands break for whatever reason, some 20 different protein components previously scattered about the cell nucleus assemble, fix the break, then disperse.
Most of the time, all goes well.
Sometimes, when it doesn’t, the cell dies.
Other times, you get cancer.
This basic body machinery that mostly works like a charm is providing scientists a sort of biological template for building their own machinery to fix genetic defects and disease.
The new Nanomedicine Center for Nucleoprotein Machines, one of eight Nanomedicine Development Centers funded by the National Institutes of Health in the last two years, is starting with the machinery that joins broken ends of DNA, one of the most lethal kinds of damage.
“Pieces of broken DNA that float around in the cell are very, very bad for the cell,” said Dr. William S. Dynan, chief of the MCG Cancer Biology & Gene Regulation Program, Georgia Alliance Eminent Scholar in Biochemistry and associate director of the new center. “They have a tendency to get glued onto another piece of DNA where they don’t belong in an effort to heal themselves. That is how a lot of leukemia gets started.”
The center, based at the Georgia Institute of Technology, is directed by Dr. Gang Bao, biomedical engineer, who also directs the National Heart, Lung and Blood Institute Program of Excellence in Nanotechnology at Georgia Tech and Emory University.
“This is the third nanomedicine/nanotechnology center that NIH has awarded to Georgia Tech and Emory University, and we are pleased to have the Medical College of Georgia join us as a partner in this one,” Georgia Tech President G. Wayne Clough said in announcing the new center in October. “Together, we are helping Georgia emerge as a top region for nanomedicine.”
Nanomedicine seeks to understand and manipulate fundamental biological processes at a minute scale.
“We begin by studying how the body carries out certain tasks through these naturally occurring machines within cells, and understanding them in terms an engineer would understand: the materials they are made of and the forces they generate,” Dr. Dynan said.
“If we understand the mechanisms, we [can potentially] alter or redirect the machinery so it does what we want,” said Dr. Bao. “The goal is to generate something like vaccines to alter the genome. That is where a lot of science is headed.”
This new direction will change, in a sense, the whole practice of medicine.
“Instead of waiting for the disease to develop, we cure the disease at the very beginning by altering the genetics or fixing the genetic defects,” said Dr. Bao.
Interestingly, the scientists can’t yet see what they seek to understand and replicate.
A nanometer is one-billionth of a meter, too small to see with even the best microscopes. Electron microscopy offers finer resolution, but only in fixed cells, so it cannot provide working images of endogenous DNA-repair machines. First-generation nanoscopes, which should become available late this year, allow scientists to watch activity in a living cell that is about five times smaller in each dimension than what can be seen through standard microscopes, but that’s still not good enough.
“You can see the DNA, but not the fine details of what it’s doing; we want to be able to do that,” said Dr. Dynan. “It would be like the difference between looking at little points of light in the night sky with the naked eye and looking with a telescope and really knowing what they are.”
“We want to see how these nanomachines assemble in a living cell; therefore, we have to work with a living cell,” echoed Dr. Bao. “One thing the center will try to do is develop technologies so we can visualize the components of the protein machine.”
Helping to focus these points of light is the center’s “dream team.”
Dr. Grant Jensen, cryo-electron microscopist at the California Institute of Technology in Pasadena, Calif., is an expert in visualizing molecules based on their ability to scatter electrons. Dr. David L. Spector of Cold Spring Harbor Laboratory in New York City, a pioneer in looking at events in the nucleus of a living cell, envisions a new microscope that can follow single molecule events. Dr. Shuming Nie, a chemist and biological engineer at Emory University, is an expert in quantum dots—bright, stable nano-scale crystals that emit light and can attach to proteins to help monitor their activity.
Dr. David Roth, chair of pathology at New York University, is an expert in DNA end-joining who, like Dr. Dynan, brings a clinical perspective as a physician. Dr. Alice Ting of the Massachusetts Institute of Technology, widely regarded as one of the best young chemists in the country, is another expert at making proteins glow by tagging them specifically. Dr. Roland Eils, head of theoretical bioinformatics at the German Cancer Research Center, is an expert on theory and modeling. Dr. Stefan W. Hell, adjunct professor of physics at the University of Heidelberg and inventor of the nanoscope, is a center consultant and will help modify the nanoscope the Georgia Research Alliance will help purchase for the center.
Closer to home, Dr. Hernan Flores-Rozas, MCG molecular biologist, Georgia
Cancer Coalition Distinguished Cancer Scholar and an expert in yeast genetics
and biochemistry, will lead studies in yeast cells, which are quicker and easier
to work with than human cells. “I expect some of the first results will come
through his work,” said Dr. Dynan, as yeast cells are more amenable to
replacement of natural proteins with re-engineered ones.
Dr. Yoshihiko Takeda, MCG molecular biologist and rheumatologist, already is taking seven proteins known to be part of the double-strand DNA break repair process, putting them in a test tube with broken DNA, and watching them work, even in such austere confines. “They don’t seem to do it in an organized way,” said Dr. Dynan, but it’s a start. “There are important aspects of the design of the machine that we don’t understand just because we have the pieces in a box. We need to understand how these work in their natural environment in the cell.”
The team’s diverse expertise was no doubt part of what NIH reviewers liked, said Dr. Bao. “By having a center, we have some of the best people in different fields working together. By working together, we can address important issues that none of us could address alone.”
He projects a three- to five-year timeline to understand the assembly/disassembly process and 10-plus years to successfully alter it. “Even if it takes a whole generation, you do not give up,” he said.
The finding, when it comes, likely will be one any engineer would love: a complex, quantitative mathematical description of the internal machinery that is a model for the therapeutic one.
- Toni Baker