Discovery Adds New Twist to Certain Genetic Diseases

James R. Lupski, M.D., Ph.D., is excited about potential treatments for diseases that result from copy number variation, such as Charcot-Marie-Tooth, a genetic disease he has battled since childhood.

James R. Lupski, M.D., Ph.D., is prone to bursts of excitement when he talks about an important discovery he and colleagues made in human genetics called copy number variation (CNV)—structural changes in the genome that result in duplicated or deleted genes. This newly found source of human genome variation can cause disease and other human traits and is gaining momentum in an increasingly enthusiastic research community.
"CNV is hot right now, so hot," Lupski said with a chuckle that reveals his understanding of the ways of science.

"Here's the deal with science," said Lupski, Vice Chair and Professor of Molecular and Human Genetics and Professor of Pediatrics at Baylor College of Medicine. "Only time will tell if your research findings are going to ferment like a fine wine and get better and better."

Lupski's interest in that "fine wine" of science began on a very personal note. He has a genetic disease called Charcot-Marie-Tooth (CMT). When his career path led him to biomedical science, it made sense to pursue the genetic disease with which he had the most experience.

The discovery of copy number variation in genetic disease arose from that pursuit in 1991, when he discovered that people with CMT disease had an extra copy of the gene associated with the disease.

Initially, it was thought that this was an odd genetic mechanism only seen in Charcot-Marie-Tooth disease. It differed from the standard view that single base pair mutations in genes cause inherited diseases.

"What is being appreciated now by many more scientists and researchers," Lupski said, "is that this kind of structural variation in the human genome is going to be significant with respect to investigating human disease traits and trying to find the basis of those and other traits."

As Lupski has seen the tide turn with respect to his seminal research, he has also witnessed changes to the field of genetics. When he first became interested in a research career, there was limited understanding of medical or human genetics. By 2003, the entire human genome had been sequenced.

"It has come a long way, but there is still a long way to go. I think a lot of people felt like sequencing the human genome was going to be the magic bullet, but we haven't yet found the cure for any diseases based on genome sequence," Lupski said. "But what we do know is that we're all starting with a different hand of cards. And maybe by knowing exactly what you've been dealt, you can better maximize your potential for a long-lived life through lifestyle choices and other things. Perhaps this is what personalized medicine is all about."

"...against all the odds and many people nationally and internationally telling him (Lupski) he couldn't be right—he actually founded a whole new field of genomic medicine."
– Ralph D. Feigin, M.D.
Chair, Department of Pediatrics

Lupski is optimistic about the therapeutic advances possible through medical genetics. He's especially encouraged about potential treatment for diseases that result from copy number variation versus a mutated gene that produces an abnormal protein.

Copy number variation is a more tractable problem, he explained. "It's extremely difficult to fix an abnormal protein. But if you've got a genetic disease that's related to copy number variation and you're making a little too much of this protein, or a little too little of that protein, and you just have to alter those protein levels... well, that's a very different therapeutic approach to the problem."

"One of the things that really interested me," Lupski said, "was that there was a tremendous lack of knowledge about the disease process, including my disease. When I started thinking about my research, it made sense that I turn my attention to CMT."

Charcot-Marie-Tooth disease is a neurological disorder that affects about 150,000 people in the Unites States. Its symptoms are variable, but in general, patients slowly lose normal use of their extremities as nerves degenerate and the muscles become weakened. Many also experience partial loss of sensory nerve function.

As a child growing up in Hicksville, New York, he underwent a series of surgeries that helped him walk better. Lupski earned his medical and doctoral degrees from New York University and planned to join the faculty there. But Baylor offered him an opportunity no other place could—the chance to complete his residency in pediatrics while also doing a fellowship in medical genetics and beginning his independent research career.

"That was a major attraction to coming here, and by the end of my residency I started setting up my own lab," Lupski recalled. "Baylor was very supportive, and it took visionaries because at that time medical genetics was a fledgling field."

He credits the foresight of C. Thomas Caskey, M.D., then head of genetics (which was not yet a BCM department), and Ralph Feigin, M.D., who was chair of BCM's Department of Pediatrics when Lupski came to the College for his residency. Feigin served as the institution's President from 1996 to 2003 and continues as Chair of Pediatrics.

Lupski had already established himself as a researcher when he came to BCM for his residency, noted Feigin, who is also Physician-in-Chief at Texas Children's Hospital.

"He could have gone anywhere," Feigin said. "He's very modest and would never toot his own horn, but—against all the odds and many people nationally and internationally telling him he couldn't be right—he actually founded a whole new field of genomic medicine."

Lupski would not allow colleagues who doubted his research findings to deter him. That's just part of the process, he said. Good scientists, he added, are almost as excited when a hypothesis is proven wrong because the main goal is to find the truth.

"Right from the beginning, we thought copy number variation was an interesting idea, an interesting mechanism of disease. And we thought we had proven it many different ways," he said. "But anytime something is novel or new, outside the frame of reference, it's harder to get it accepted."

The excitement in the scientific community about CNV has grown since the human genome project, which spurred the development of technology that allows scientists to assay all the pieces of the genome.

Now researchers are beginning to look beyond the role of copy number variation in human disease and are studying how it is tied to the emergence of other human traits. Lupski is writing a synopsis for a paper that measured the copy numbers of the genes in several species of primates and links that variation to the emergence of distinctly human traits, such as larger brains that allowed for higher-order thinking and attributes needed for long-distance running.

"I have to admit, the implications of CNV are very exciting. It has turned out to have implications much broader than I ever anticipated it possibly could have. But I don't want there to be too much hype," he cautioned.

Nicholas Katsanis, Ph.D., a former postdoctoral associate in Lupski's lab and now an Associate Professor at Johns Hopkins University, recalled that Lupski always said, "Something that's hot today may not be hot tomorrow."

Katsanis said his career was guided in immeasurable ways by Lupski, just as Lupski benefited from the mentorship of others early in his career. When Katsanis completed his postdoctoral research, Lupski let him take a research project on Bardet-Biedel syndrome to his new lab at Johns Hopkins.

"I learned not just about science and research, but about politics and publishing and personal relationships—all of those things that are so very important to a successful career," Katsanis said.
Perhaps the most important lesson he learned was that scientists need to be able to reinvent themselves.

"The challenge for all of us—and Jim has done this extremely well—is to reinvent yourself every few years and move forward in the field," Katsanis said. "Something else will come along that's got more buzz than copy number variation or Bardet-Biedel syndrome, and some of us will be able to adapt."

For now though, Lupski is surfing the wave of copy number variation while it's still hot.

Best Minds Best Medicine

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Volume 4, Issue 1, Summer 2008


	Discovery Adds New Twist to Certain Genetic Diseases by Dana Benson James R. Lupski, M.D., Ph.D., is excited about potential treatments for diseases that result from copy number variation, such as Charcot-Marie-Tooth, a genetic disease he has battled since childhood. James R. Lupski, M.D., Ph.D., is prone to bursts of excitement when he talks about an important discovery he and colleagues made in human genetics called copy number variation (CNV)—structural changes in the genome that result in duplicated or deleted genes. This newly found source of human genome variation can cause disease and other human traits and is gaining momentum in an increasingly enthusiastic research community. "CNV is hot right now, so hot," Lupski said with a chuckle that reveals his understanding of the ways of science. "Here's the deal with science," said Lupski, Vice Chair and Professor of Molecular and Human Genetics and Professor of Pediatrics at Baylor College of Medicine. "Only time will tell if your research findings are going to ferment like a fine wine and get better and better." Lupski's interest in that "fine wine" of science began on a very personal note. He has a genetic disease called Charcot-Marie-Tooth (CMT). When his career path led him to biomedical science, it made sense to pursue the genetic disease with which he had the most experience. The discovery of copy number variation in genetic disease arose from that pursuit in 1991, when he discovered that people with CMT disease had an extra copy of the gene associated with the disease. Initially, it was thought that this was an odd genetic mechanism only seen in Charcot-Marie-Tooth disease. It differed from the standard view that single base pair mutations in genes cause inherited diseases. "What is being appreciated now by many more scientists and researchers," Lupski said, "is that this kind of structural variation in the human genome is going to be significant with respect to investigating human disease traits and trying to find the basis of those and other traits." As Lupski has seen the tide turn with respect to his seminal research, he has also witnessed changes to the field of genetics. When he first became interested in a research career, there was limited understanding of medical or human genetics. By 2003, the entire human genome had been sequenced. "It has come a long way, but there is still a long way to go. I think a lot of people felt like sequencing the human genome was going to be the magic bullet, but we haven't yet found the cure for any diseases based on genome sequence," Lupski said. "But what we do know is that we're all starting with a different hand of cards. And maybe by knowing exactly what you've been dealt, you can better maximize your potential for a long-lived life through lifestyle choices and other things. Perhaps this is what personalized medicine is all about." "...against all the odds and many people nationally and internationally telling him (Lupski) he couldn't be right—he actually founded a whole new field of genomic medicine." – Ralph D. Feigin, M.D. Chair, Department of Pediatrics Lupski is optimistic about the therapeutic advances possible through medical genetics. He's especially encouraged about potential treatment for diseases that result from copy number variation versus a mutated gene that produces an abnormal protein. Copy number variation is a more tractable problem, he explained. "It's extremely difficult to fix an abnormal protein. But if you've got a genetic disease that's related to copy number variation and you're making a little too much of this protein, or a little too little of that protein, and you just have to alter those protein levels... well, that's a very different therapeutic approach to the problem." "One of the things that really interested me," Lupski said, "was that there was a tremendous lack of knowledge about the disease process, including my disease. When I started thinking about my research, it made sense that I turn my attention to CMT." Charcot-Marie-Tooth disease is a neurological disorder that affects about 150,000 people in the Unites States. Its symptoms are variable, but in general, patients slowly lose normal use of their extremities as nerves degenerate and the muscles become weakened. Many also experience partial loss of sensory nerve function. As a child growing up in Hicksville, New York, he underwent a series of surgeries that helped him walk better. Lupski earned his medical and doctoral degrees from New York University and planned to join the faculty there. But Baylor offered him an opportunity no other place could—the chance to complete his residency in pediatrics while also doing a fellowship in medical genetics and beginning his independent research career. "That was a major attraction to coming here, and by the end of my residency I started setting up my own lab," Lupski recalled. "Baylor was very supportive, and it took visionaries because at that time medical genetics was a fledgling field." He credits the foresight of C. Thomas Caskey, M.D., then head of genetics (which was not yet a BCM department), and Ralph Feigin, M.D., who was chair of BCM's Department of Pediatrics when Lupski came to the College for his residency. Feigin served as the institution's President from 1996 to 2003 and continues as Chair of Pediatrics. Lupski had already established himself as a researcher when he came to BCM for his residency, noted Feigin, who is also Physician-in-Chief at Texas Children's Hospital. "He could have gone anywhere," Feigin said. "He's very modest and would never toot his own horn, but—against all the odds and many people nationally and internationally telling him he couldn't be right—he actually founded a whole new field of genomic medicine." Lupski would not allow colleagues who doubted his research findings to deter him. That's just part of the process, he said. Good scientists, he added, are almost as excited when a hypothesis is proven wrong because the main goal is to find the truth. "Right from the beginning, we thought copy number variation was an interesting idea, an interesting mechanism of disease. And we thought we had proven it many different ways," he said. "But anytime something is novel or new, outside the frame of reference, it's harder to get it accepted." The excitement in the scientific community about CNV has grown since the human genome project, which spurred the development of technology that allows scientists to assay all the pieces of the genome. Now researchers are beginning to look beyond the role of copy number variation in human disease and are studying how it is tied to the emergence of other human traits. Lupski is writing a synopsis for a paper that measured the copy numbers of the genes in several species of primates and links that variation to the emergence of distinctly human traits, such as larger brains that allowed for higher-order thinking and attributes needed for long-distance running. "I have to admit, the implications of CNV are very exciting. It has turned out to have implications much broader than I ever anticipated it possibly could have. But I don't want there to be too much hype," he cautioned. Nicholas Katsanis, Ph.D., a former postdoctoral associate in Lupski's lab and now an Associate Professor at Johns Hopkins University, recalled that Lupski always said, "Something that's hot today may not be hot tomorrow." Katsanis said his career was guided in immeasurable ways by Lupski, just as Lupski benefited from the mentorship of others early in his career. When Katsanis completed his postdoctoral research, Lupski let him take a research project on Bardet-Biedel syndrome to his new lab at Johns Hopkins. "I learned not just about science and research, but about politics and publishing and personal relationships—all of those things that are so very important to a successful career," Katsanis said. Perhaps the most important lesson he learned was that scientists need to be able to reinvent themselves. "The challenge for all of us—and Jim has done this extremely well—is to reinvent yourself every few years and move forward in the field," Katsanis said. "Something else will come along that's got more buzz than copy number variation or Bardet-Biedel syndrome, and some of us will be able to adapt." For now though, Lupski is surfing the wave of copy number variation while it's still hot.		Search all issues: Best Minds Best Medicine BCM Campaign Seeks to Raise $1 Billion Attracting Stars: McNairs Give $100 Million To Recruit Top Scientists Lester and Sue Smith Gift Tackles Breast Cancer in the Clinic and Lab Two Alumni Share Commitment to Scholarship Support Features Taking Personalized Medicine to New Heights Creating Culture While Building Walls Changing Complexion of Medicine Spotlight Click for your Doctor: New eVisits Trade Exam Room for Inbox Kjersti Aagaard: 2007 Winner of NIH New Innovator Award Getting World-Class Breast Cancer Care...With or Without Insurance James Lupski's Tenacity Founds New Field of Genomic Medicine Briefs BCM Named National Diabetes Research Center DeBakey Takes the Gold The Trash is no Place for Expired Medication Removing Brain Tumors Through the Nose SPORE Spawns New Lymphoma Efforts The Coffee-Cholesterol Connection BCM Campaign puts Personalized Medicine on the Fast-Track

	Volume 4, Issue 1, Summer 2008



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