SUNDAY STORY
Pushing the envelope
Doug Wallace and his Center for Molecular and Mitochondrial Medicine and Genetics at UCI are looking into what makes humans age
By Deirdre Newman
Daily Pilot
December 15 2002
Why do we die?
This question has intrigued mankind for centuries, leading to inquiries ranging from the quixotic to the scientific.
In 1513, Juan Ponce De Leon searched for the Fountain of Youth to no avail in what is now Florida.
In 1932, Aldous Huxley wrote "Brave New World," which explored a society where chemicals delay aging and prevent disease.
In 1992, geneticist Doug Wallace published his mitochondrial theory of aging, which suggests that mitochondria -- small cellular structures that create energy -- control the aging clock.
This fall, UC Irvine lured Wallace and his Center for Molecular and Mitochondrial Medicine and Genetics away from Emory University, giving him the prestigious title of Donald Bren Professor of Biological Sciences and Molecular Medicine.
The move will allow Wallace, a member of the National Academy of Science, to work on drugs that intervene in the aging process and potentially increase the human lifespan by 50% to 100%. Landing Wallace was a major coup because it enhances the university's reputation across the country and benefits faculty and students, said Thomas Cesario, dean of the college of medicine.
"First of all, his coming to the university brings us a first-class mind that can interact with the rest of the faculty, and it's a good stimulation for all of us and brings out the best in everybody to have people of that caliber," Cesario said. "It's good for our students because we're a teaching institution and he's a very charismatic teacher, so I think he'll have a great impact in the classroom as wells as in the research lab."
THE SCIENTIFIC MIND INSULT
At various times in his scientific career, Wallace has been called "crazy," "insane" and "radical." He can laugh at these monikers now that most of his revolutionary theories have been proven. Wallace's eyes sparkle with electricity when he talks, his mind spinning so fast that it seems like his speech is just trying to keep up.
Like Aristotle and Darwin, Wallace was intrigued by questions surrounding the human condition at an early age.
"Ever since I can remember, I always wanted to know, 'Who am I? Where did we all come from? Why do we always feel so bad?'" Wallace said. "I never stopped wondering about them and sought many paths to get reasonable answers."
Wallace explored psychology and theology to address these questions, but his insatiable intellectual appetite was satisfied most by biology.
He graduated from Cornell University in 1968 with a major in microbiology and a minor in chemistry. After working in public health for two years with the army in Washington, Wallace went to Yale to get a Ph.D. in microbiology. He was attracted to Yale because it was one of the first universities to apply techniques of microbiology to human genetics.
THE SCIENCE OF DNA
The double helix structure of DNA, which exists in the nucleus of cells and contains genetic information, was discovered in 1953. But scientists could not manipulate DNA as they can today because the tools were not available. It wasn't until the late 1960s that scientists developed a process to grow human cells in a culture, allowing them to apply the same genetic tools to human cells as they had to bacteria.
In 1968, scientists discovered a different type of DNA outside the nucleus -- mitochondrial DNA (mtDNA).
As a microbiologist, Wallace was attracted to this new form of DNA because it appeared that the mitochondria were a form of bacteria that formed a symbiotic relationship with the cells they inhabited.
Since the mitochondria were found to produce energy for the cells, Wallace postulated that they must play a significant role in the human body.
Wallace was one of the first to argue that their DNA can cause mutations and therefore had the capability of causing disease. He and his colleagues at Yale led the vanguard of mitochondrial DNA research, which evolved into the field of mitochondrial genetics in the early '70s.
"It was an exciting time because you're always trying something new, but that's science in general. You're always pushing the envelope," Wallace said. "It was also scary because I based my whole life on these three theories. But what if I was wrong?"
THE NEXT STEP
To prove these theories required defining the characteristics of the mtDNA bacterium, which took about 18 years, Wallace said.
The first challenge was showing that mtDNA had a function. Wallace did this with experiments that demonstrated genetic changes in one cell could be transferred through the mtDNA to another cell.
For proving mtDNA had a function, they let him out of Yale, Wallace joked.
But the question still lingered whether mtDNA could cause disease. Wallace continued to claim it could. People thought he was crazy for clinging to this belief.
After Yale, Wallace headed to Stanford to continue working on his theories. In doing so, he changed how scientists had viewed genetics for 125 years.
Up until the late '70s, scientists relied on the Mendelian concept of genetics, which states that genes are transferred to offspring by the mother and the father. But mtDNA is only transferred by the mother, Wallace found, because a female egg contains about 200,000 mtDNA and the egg sees the mtDNA in the male sperm as foreign and destroys it.
Through extensive worldwide research, this premise led Wallace to formulate the "Mitochondrial Eve" theory, which says that all mtDNA is related by mutations that can be traced back to one woman who existed about 200,000 years ago, around the time human life is thought to have started.
Wallace discovered another important difference between nuclear DNA and mtDNA as well. In nuclear DNA, there are only four ways the chromosomes in each cell can turn out -- two normal, two mutants or one of each. But with mtDNA, the spectrum is much wider, Wallace said.
THE POWER OF mtDNA
As a result of his research, Wallace discovered that mtDNA played a crucial role in each cell and explained this in a way anyone could understand. He likened the mtDNA to power plants that provide energy to the city (the cell), with the nucleus as the City Council.
"Each of the mtDNA is a capacitor," Wallace said. "You charge them by eating and breathing."
In each mtDNA are a set of blueprints for the power plants, and a mutation produces the same results as if the blueprints are stolen. Stages of certain diseases are based on how many mutations have occurred in the mtDNA, Wallace discovered.
"So this idea that you could have a continuous disease progress from nonexisting to mild to severe based on the number of something was radical!" Wallace said. "So here comes Doug Wallace, who no one's ever hear of, and proves this."
To prove it, Wallace headed back across the country to Emory University in Atlanta because he wanted to find a region of the country where ethnically diverse families had lived for generations. The goal was to monitor a disease that had been passed down through the generations, identify that it was passed by the mother and then find the mutation that caused the disease.
Five years later, Wallace found that a type of sudden-onset blindness was one of these diseases passed on by the mother. Other more complicated diseases were soon identified, enabling Wallace to prove definitively that severity of certain diseases was related to the percentage of mutated mtDNA.
"Now, a large number of complex disease processes have been re-examined, and at least part or all of them have been related to mtDNA," Wallace said.
MORE THAN JUST GENETICS
Wallace wasn't finished. More questions were percolating in his mind, so he turned his attention to the aging process.
Wallace discovered that mtDNA were not just susceptible to genetic mutations. They are also vulnerable to damage by free radicals that can pilfer the mtDNA blueprints and thereby deplete cells of energy. Organ failure is essentially a result of power outages in the mtDNA, Wallace found. In 1992, Wallace published his mitochondrial theory of aging.
"That's why suddenly what used to be a very arcane, obscure field of science has been thrust into the limelight," Wallace said. "Suddenly what people dismissed as unimportant may in fact be the most important part of science."
Now he and his colleagues at UCI are working on developing drugs to reduce free-radical damage.
But there is still even more to the mitochondria's awesome power, Wallace believes. Last year, he announced yet another "insane" theory: It's the mitochondria that convert energy derived from food into chemical energy for work and heat energy for body temperature.
This theory is based on analysis of mtDNA in various populations. It was the analysis Wallace had made to prove that mtDNA are passed on by the mother.
Wallace found regional-specific changes in mtDNA and extrapolated to show that where people live could have a negative affect on their health if it requires an adjustment in their heat/work ratio.
For example, someone who lives in an arctic environment will eat more fat and carbohydrates and then burn those calories to produce energy to work.
If you take a person who's used to living at the equator and put them in an arctic climate, they will naturally change their eating habits and eat more fat and carbohydrates. But they won't be able to burn the excess calories like those who grew up in an arctic-type climate, so the fat is stored instead, thereby creating an incompatibility between their diet and their genes that can result in obesity, diabetes and cardiovascular disease, Wallace said.
That means that it is essential for a doctor to look to a patient's genetic past to understand the disease that is plaguing them in the present -- a far cry from how diseases are diagnosed now, Wallace said.
"Biomedical science looks at people today and asks, 'Are you sick or not sick?' and the paradigm is to look at the recent past. But if you're living one lifestyle instead of another, that may be the problem," Wallace said.
WHY UCI?
Wallace started his Center for Molecular and Mitochondrial Medicine and Genetics at Emory because the theories he proved led to knowledge of how to directly intervene to treat certain diseases and delay the aging process. But most scientists know how difficult it is to take this knowledge and transform it into a viable product.
UCI, however, understood that Wallace needed to fully tap the potency of the mtDNA. Whereas at Emory, Wallace only had a lab and a clinic, UCI also provided space and support for a company, called Medergy, and for Mitomap, a central data processing center that links the four components of Wallace's programs in evolutionary medicine.
If Wallace and his team are successful in developing drugs to delay aging and treat certain diseases, UCI is poised to reap increased visibility and significant financial benefits, said Cesario, the College of Medicine dean.
"When inventions are developed by our own faculty, the university does have the possibility of licensing the technology, and that has the potential of creating a royalty stream," Cesario said.
INSIDE THE LAB
In the lab, researchers, including 12 who made the cross-country trek from Atlanta with him, are diligently trying to identify new disease mutations, develop better ways of diagnosing mtDNA-caused diseases, prove that many of the common degenerative diseases are driven by mtDNA mutations and find more evidence that mitochondrial decline is a significant cause of aging, Wallace said.
The researchers hope to develop genetic and chemical treatments for these diseases.
The lab is not fully functional yet. Eventually, there will be a warm room for growing bacteria cells and a tissue culture room to experiment with human and mouse cells.
About six weeks ago, researchers started using the fruit fly room, which contains approximately 30,000 of the tiny insects with various mutations. The scientists use the fruit flies to develop mutations that can't be achieved in mice because the mutations will kill them, said Nadja Dvorkin, a biology grad student and the lab coordinator.
Next year, the lab will be moving to the Hewitt building, enabling Wallace to recruit more faculty and triple the workspace. At the moment, he has seven post-doctoral candidates and five graduate students.
Pinar Coskin, a graduate student in biological chemistry, is working on two projects. One deals with Alzheimer's disease and aging in humans. The other has to do with aging and oxidative stress in mice.
Above her workspace are a recipe for genotyping -- the process by which she tracks the mutations, and a Domino's Pizza sticker -- a testament to the late hours she sometimes keeps.
Coskin wouldn't have it any other way. Her interest in why people get old led her to Wallace's lab.
"He's great," Coskin said. "He's really helpful and knowledgeable. When you ask him stuff, he doesn't give you just one answer. His knowledge is so broad."
With more than 30 years of research under his belt, Wallace hopes his work at UC Irvine will yield breakthroughs in drugs to treat degenerative diseases, cancer and aging.
"If our ideas are as radical as we think, it will have a major effect on health care in the region," Wallace said.
* DEIRDRE NEWMAN covers education. She may be reached at (949) 574-4221 or by e-mail at deirdre.newman@latimes.com.
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