Deirdre Newman Why do we die? This...

Deirdre Newman

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 [email protected].