March 26-April 8, 2004
Vol. 34, Issue 6
Back Issues
Someone else’s shoes
Fraser answers call
Research week showcases students’ work
Headlines @ U.Va.
Conference to examine where the arts belong
Ayers wins Bancroft Prize
Davis Parker’s Magnum Opus
Move over, Sigmund
Emily Couric’s political papers now part of U.Va. library collection
‘Telling Moments’ project aids high school Spanish teachers
Expert to discuss new findings on equity in higher education
Students, employees give back to community
Dr. W. Davis Parker Jr. studies the relationship between mitochondria and disease.
Photo by Jim Carpenter
Dr. W. Davis Parker Jr. studies the relationship between mitochondria and disease.
Davis Parker’s Magnum Opus

By Kathleen D. Valenzi

[Excerpted from U.Va. Medical AlumNews, Fall ’03]

Dr. W. Davis Parker Jr., the Eugene P. Meyer Professor of the Neurosciences, remembers the events that led to his pursuit of scientific truth: the place where the magnum opus he is still composing all began.
While a student at the University of South Florida College of Medicine, Parker developed an interest in metabolic diseases, which interfere with the biochemical process of turning nutrients into energy at the cellular level. As part of his clinical training, he took care of children with Reye’s Syndrome, a deadly but relatively rare metabolic disease affecting the liver and brain.

One day in 1974, late in his senior year, Parker came across a journal article. It described a newly discovered metabolic problem called Carnitine Deficiency, which sounded suspiciously like Reye’s Syndrome.

A few weeks into Parker’s internship in medicine and pediatrics at University of South Florida Affiliated Hospitals, another child with Reye’s Syndrome was admitted. Parker examined the child and ran some tests. Sure enough, the child’s concentrations of carnitine, an essential amino acid, were well below normal.

The child “made the third case of Carnitine Deficiency ever described,” Parker said, and the discovery, reported in Pediatric Research in 1976, ave Parker his first journal byline.

It was a pivotal moment in Parker’s career. A metabolic problem — a biochemical defect — had been shown to underlie Reye’s Syndrome. “And it was totally mitochondrial,” Parker said.

Which, according to established views, was also totally impossible. Mitochondria are the energy-producing structures within cells, and they are essential for life. Therefore, scientists believed that defective mitochondria could only lead to death, not disease. Parker now believed otherwise.

After conducting residencies in pediatrics at the University of South Florida and then pediatric neurology at the University of Virginia, Parker headed to the University of Colorado School of Medicine. There, he had the freedom to contemplate mitochondrial DNA in earnest.

Parker developed three important theories: One, he could study brain disease at the metabolic level by using fresh, intact mitochondria drawn from blood platelets. Two, mitochondrial DNA, which is inherited only from the mother, might be the cause of neurodegenerative diseases that appear to occur sporadically, or randomly, instead of in a predictable pattern, as do diseases involving chromosomal DNA inherited from both parents. Three, the lifelong replication of mitochondrial genes could explain why some sporadic diseases, like Parkinson’s, are typically late-onset. If abnormal mitochondrial genes replicated at a faster rate than healthy ones, then late-onset diseases might be catalyzed by the abnormal genes having reached a particular level of abundance.

“ He was thinking about all of this way before anything of this sort was being written about or talked about,” said Janice K. Parks, his lab partner.

Using his platelet technique, Parker began to study the mitochondria of patients with Leber’s Hereditary Optic Neuropathy, which is inherited through the mother and causes blindness.

These studies allowed Parker to “conclude that mitochondrial diseases, for whatever reason, can be both systemic and extremely focal,” he said.

And if one mitochondrial disease could knock off the optic nerve and produce Leber’s, “why couldn’t there be another mitochondrial disease that knocks off the substantia nigra, in which case you’ve got Parkinson’s?” Parker speculated.

Unfortunately, “this type of mutation was thought not to exist,” Parker said.

Back in the late 1980s, scientists investigating sporadic neurodegenerative diseases believed the diseases were caused by toxins or traumas, maybe even nutritional imbalances, but not by genetic error. Additionally, disease investigators rarely talked across pathological boundaries. Not everyone appreciated Parker’s describing biochemical problems suggesting that individual diseases were, in fact, “absolute kissing cousins,” he said.

Parker was entering “dangerous territory,” Parks said.

The professional hazards didn’t deter Parker, although they were “kind of nerve-wracking,” he admitted. Yet, he pressed forward.

“I was used to criticism,” he said. “Besides, for the life of me, I couldn’t see what the big deal was. If I was wrong, I was wrong. An awful lot of research is ultimately either wrong, or it becomes a subset of somebody else’s research. One of the things I love about science is that the truth is what the truth is. Nothing can change that.”

Over time, Parker’s platelet studies show very specific, albeit closely related, mitochondrial defects underlying Parkinson’s, Alzheimer’s and Lou Gehrig’s disease.

Parker then developed an innovative laboratory technique which proved that the defects were genetically based, and not the result of exposure to toxins, as many scientists still conjectured.

Despite the big media splash this discovery made, Parker’s victory in the “gene-versus-toxin” debate was qualified. The medical research community now demanded that he show them the abnormalities.

“That sounds like about two weeks of work, but it ain’t,” Parker said. “If you’re looking at a chromosomal gene to see whether it causes, say, sickle cell anemia, you’ve only got three choices: either both genes work, or only one works, or neither of them work,” Parker said. “It’s pretty easy to figure that out by sequencing the chromosomal DNA.”

But what about an adult brain cell that, by midlife, may contain 50,000 copies of every mitochondrial gene? How many of them have to be defective, or in what combinations, before a genetic disease occurs?
After a couple of years of daunting technical endeavor, Parker is now showing through DNA sequencing that mitochondrial genes are replete with mutations. “In fact, there are so many errors in the mitochondrial genes we’ve sequenced that we’re having trouble figuring out what is relevant and what isn’t,” he said.

Even so, despite a mounting pile of evidence published in journals and replicated by other scientists, Parker still runs into the scientific stalwart who wants to dismiss his hypothesis out of hand. This doesn’t bother him too much.

“You can lead people to water, but you can’t make them think,” Parker jested. “There is nothing you can do except groan and move on.”

Undoubtedly, the patients who stand most to gain from Parker’s magnum opus are happy about that, too. His research has enormous potential for the diagnosis, treatment and cure of diseases caused by errors in mitochondrial DNA like Alzheimer’s, Parkinson’s, ALS, schizophrenia and autism.

“The ultimate goal is that we can learn to make sick mitochondria better,” Parker said. “And if we can’t do that, at least to freeze the progression of a disease caused by sick mitochondria before you even know you’ve got it.”


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