December 2016/January 2017

Transformational Science: Q&A with Douglas Wallace, PhD, Winner of Franklin Medal

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Douglas Wallace, PhD, does not shy away from controversial ideas in science. But unlike your kooky uncle who proselytizes about grand theories of the universe, Dr. Wallace has pushed forward several ideas that have turned out to be correct, overturning longstanding assumptions about biology, medicine, and even human history along the way. Dr. Wallace, founding director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia, is a world-renowned expert in the genetic study of mitochondria, the organelles inside cells that produce most of the body’s energy and that have several of their own genes distinct from the genes in a cell’s nucleus. Through the study of these mitochondrial DNA genes, Dr. Wallace founded the field of mitochondrial genetic medicine.

In recognition of his achievements, Dr. Wallace was recently named the 2017 recipient of the Franklin Medal in Life Sciences from the Franklin Institute. The Franklin Medal, a highly esteemed international award established in 1824, has been awarded to scientific superstars including Albert Einstein, Thomas Edison, Stephen Hawking, Marie Curie, Nikola Tesla, Niels Bohr, Bill Gates, and Max Planck. More than 100 Franklin Medal laureates also have received Nobel Prizes.

On the occasion of this honor, we sat down with Dr. Wallace to reflect on his career, his noteworthy discoveries, his unflagging support of patients with mitochondrial diseases, and the audacious ideas that he believes could result in a major medical transformation. The edited conversation follows below.

You’ve made so many noteworthy discoveries over the course of your career, it will be hard to cover them all. So let’s narrow down. Can you describe what you think of as the top four?

Sure. Number one, in the early 1970s, we showed in cultured cells that the mitochondrial DNA (mtDNA) had heritable traits. We did this by inventing the “cybrid transfer technique.” In cybrid analysis, we start with a cell that has a particular trait; we first used cells resistant to the drug chloramphenicol which inhibits mitochondrial protein synthesis. We physically remove the nucleus for the mutant cell so we just have the cytoplasm with the mitochondria and mtDNA. We then fuse this “cytoplast” to a cell that doesn’t have that genetic trait. The resulting cybrid cell will then have the non-mutant cell nucleus, but the mutant cell mtDNA. If the mutant trait is transferred with the mitochondrion, it must be coded in the mtDNA. By this approach, we showed that chloramphenicol resistance is coded in the mtDNA, providing the first proof that the mtDNA could code for heritable traits. These studies were done in the early 1970s. Yet our cybrid technique is still the standard method for determining if a genetic trait is mtDNA encoded.

Number two, in the late ‘70s, we found that the human mtDNA had a high degree of sequence variation. We then used these sequence polymorphisms as genetic markers to follow the inheritance of the mtDNA in families: mother, father, and children. This showed that in every case the mtDNA came only from the mother, not from the father. Hence, the human mtDNA is exclusively maternally inherited.

Number three, we decided to survey the mtDNA variation between different aboriginal populations around the world. This revealed that every regional population had its own unique mtDNA polymorphisms. Since the mtDNA is exclusively maternally inherited, then the only way that the mtDNA sequence can change is by the sequential accumulation of mutations along radiating maternal lineages. Therefore, the number of mtDNA variants between any two individuals is proportional to that time that they shared a common mother. By comparing the number of mutations between aboriginal populations, we could reconstruct the genetic relationship between them and even calculate the time since they separated. By correlating this with their geographic locations, we were able to reconstruct the history of women.

Number four, since we found that mtDNA variation was much higher than nuclear DNA variation, then mtDNA mutations must be very common, and some of these mutations must damage critical mtDNA energy genes and cause disease. Our search for these mtDNA diseases culminated in 1988 in our reporting two maternally inherited diseases, Leber Hereditary Optic Neuropathy, and Myoclonic Epilepsy and Ragged Red Fiber Disease, thus creating the field of mitochondrial medical genetics.

All of those achievements are transformative ideas in biology. You’re now a proponent of a newer controversial idea about mitochondria, that medical models of disease based on the anatomy of organs should give way to a disease model based on bioenergetics. Do you encounter a fair amount of skepticism about that?

That’s putting it mildly. Any new idea is going to be challenged. That’s how science works. Those ideas that lead to a new way of looking at the disease process and ultimately benefit patients and society will survive. Since our demonstration that mtDNA mutations can cause diseases, defects in the mtDNA bioenergetic genes have been associated with forms of blindness, deafness, epilepsy, dementia, heart disease, renal problems, chronic fatigue, diabetes, various cancers, and aging. Since the mtDNA only codes for bioenergetic genes, it follows that these clinical manifestations can be caused by chronic systemic energy deficiency. The organs with the highest energy demand are the brain, heart, muscle, renal, and endocrine system, so it follows that partial systemic energy deficiency could be responsible for the symptoms commonly observed in these organs.

Therefore, the common “complex” diseases, such as diabetes, neuropsychiatric disorders, cardiac and renal problems might all be the result of mitochondrial energy defects. If so, then by classifying diseases by the organ of the primary symptom, we may have completely missed the underlying bioenergetic etiology of these diseases.

If correct, this would be transformative. We would need to stop focusing on treating organ specific symptoms and start treating the underlying systemic mitochondrial energy deficiency.

But that would require changing the way medicine is organized, because for the past half a millennium Western medicine has been organized around anatomy from divisions, to departments, to NIH Institutes.

While the bioenergetic basis of common disease is a hypothesis, every experiment that we have done to date has validated it. Still, the idea that systemic energy defects could cause organ-specific symptoms is very different from the way medicine has been taught. That this idea would be recognized by the Franklin Institute is quite exciting since it indicates that the bioenergetics hypothesis of diseases is finally getting traction.

For trainees starting out now, what do you think mitochondrial science and medicine might look like in the next 40 or 45 years?

Keep in mind you’re talking to the world’s most extreme “mitochondriac.” Still, I believe that bioenergetic deficiency is a major factor in the etiology of the common complex diseases. If so, there will come a time when medicine will emphasize bioenergetics in the etiology of disease, and this will not just be a subspecialty, but a main trust of medicine. If so, this may permit us to understand and treat many clinical problems that are currently difficult to manage.

A new approach is badly needed, since the number of patients who cannot be successfully cured is legion. Unfortunately, these patients are frequently left outside “modern” medicine because they don’t fit into the current diagnostic paradigms. As an example, I saw a woman in the clinic at Emory 30 years ago. She was 23 or 24 at the time, was obviously very weak, had myoclonus, progressive memory loss, and a large cervical fat pad (cervical lipoma) on her back. But for much of her life, she had been referred to psychiatrists. You only needed to examine her back to know this was not a psychiatric problem. We ultimately showed that she harbored a mtDNA mutation. Referral to the psychiatrist had often been the fate of such patients.

How did you become a leading authority on mitochondria, when it wasn’t something people thought about as significant to medicine when you started out?

I’ve always been interested in science. There are three things that I’ve always wanted to know: Who am I? Where did I come from? And why do I feel bad? Those have really been, ever since I could think, what I wanted to know about. After a lot of searching, I realized that science had the most meaningful answers for me.

I was very fortunate be able go to Cornell University quite inexpensively because I was a resident of the state of New York. I will always be grateful to New York for their support. At Cornell, I had the opportunity of having a very open curriculum, so I took a lot of science because that is what I was interested in. I was particularly interested at that time in physics. This was, ’64 to ’68, and people were just working out the elementary particles of matter. Cornell was strong in that area, so I was fortunate to be exposed.

After two years in the public health service, I went to Yale. At Yale, I decided to study human mitochondrial genetics. I rationalized that since the mitochondria produce 90 percent of our energy, they could not be trivial, and since the mitochondria had its own DNA, that DNA must mutate and cause disease. Moreover, it had just been reported by Vinograd at Caltech that the mtDNA could be purified from human cells. Hence, for the first time, we could do molecular biology on a specific human DNA sequence.

Yale was perfect for me since one of the professors was Harold Morowitz, a physicist who was thinking about physical principles in biology. Also, Yale had just decided to form a human genetics department out of microbiology and parts of medicine. Thus, I spent one day a week with Harold Morowitz thinking about the physics of biology and six days a week studying mitochondrial bioenergetics and determining if the mtDNA was relevant to medical genetics.

By developing the cybrid system, we showed there was a mtDNA genetics, resulting in my PhD. The problem was, where should I go after graduation since no one else in the world was doing what I was. So I wrote to NIH and said, “There is no other laboratory that does what I do, so I want to stay where I am and continue this work.” NIH said OK, so I just stayed at Yale in my back corner lab and continued to do mitochondrial genetics work until I got an assistant professorship at Stanford.

Even up until the late 1980s, it was very difficult to get funded to study the clinical biology of the mitochondria. Mitochondrial disease had not been discovered yet. I was told, “Mitochondria has nothing to do with medicine,” or, “There is no such thing as a mitochondrial disease.” How could I say that I was going to study mitochondrial disease if it didn’t exist?

So finding resistance to your controversial ideas is familiar territory.

Absolutely. However, it was clear to me that humans were the most animated objects in my environment, and Newton had shown that mass does not move unless acted on by energy. Therefore, energy must be critical to being human. The cadaver has excellent anatomy. It is just dead. What it lacks is energy. This seems so compelling to me that it doesn’t matter how many times I’m told, “No.” I remain determined to pursue the bioenergetic perspective of health and disease.

After my discoveries at Stanford of the maternal inheritance of human mtDNA and the high mtDNA sequence variability, I was approached by the Division of Medical Genetics at Emory Medical School. Emory appreciated the potential clinical implications of our discoveries. Accordingly, Emory offered me a professorship, so I moved to Emory advancing from assistant professor to full professor, bypassing associate professor.

Tell us about some of the other milestones in mitochondrial medicine that you went on to achieve.

At Emory, we continued to define the principles of mtDNA genetics, were among the first to clone nuclear DNA-coded mitochondrial genes, used mtDNA variation to reconstruct the origins and ancient migrations of women, identified the first maternally inherited diseases, showed that mtDNA mutations accumulate with age creating the aging clock, identified the first mtDNA variants that predispose to Alzheimer’s and Parkinson’s disease, and created the first mouse models of mitochondrial disease. Based on this work, we set up a combined mitochondrial medicine clinical-diagnostic-research program at the beginning of the 1990s, which provided truly integrated care for mitochondrial disease patients. As a result, we had referrals from all over the world.

Even today, I’m still working on some of the Emory cases. My pact with my patients and their families is that I will not give up until I either find the answer to their problem or die. Unfortunately, many of the patients have died. However, we are still working on their problems because the answers may save the lives of others.

After being at Emory for 19 years, I was recruited to the University of California, Irvine (UCI) to build an integrated mitochondrial medicine program for the California university system. This we did, expanding our clinical research, maintaining a cutting-edge mitochondrial genetic diagnostics program, developing powerful new mouse models of mtDNA disease, and moving strongly into studies of the role of mitochondrial dysfunction on common diseases such as Alzheimer’s and Parkinson’s disease, diabetes, and cardiac disease.

In 2009, I was invited by Dr. Marni Falk to present a lecture at CHOP on our mitochondrial medicine work. Over dinner that evening, Drs. Falk and Marc Yudkoff indicated that CHOP wished to expand its mitochondrial medicine program and was looking to recruit a leader in that field. CHOP already had outstanding clinical investigators such as Drs. Falk and Yudkoff plus a 50- year tradition of research in bioenergetics under the leadership of Dr. Britten Chance. I saw this as an outstanding opportunity to advance patient care in mitochondrial medicine. So I signed up to form the Center for Mitochondrial and Epigenomic Medicine, where we are applying our novel concepts to find powerful new approaches to understand and treat both rare and common diseases.

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