Quest for a Gene Opens New Door in Personalized Medicine

Dr. Richard Gibbs (left) and Dr. James Lupski teamed up the resources of their facilities to identify the particular gene mutations responsible for the form of CharcotMarie Tooth syndrome that affects Lupski and members of his family.

In 2009, Baylor College of Medicine physician-scientist Dr. James Lupski completed a personal quest and, in collaboration with Dr. Richard Gibbs, opened the door to a new realm in medicine—the use of personal genome sequencing in the diagnosis and treatment of disease. Still a work in progress, whole genome sequencing could provide powerful answers to issues of personal health.

This new vista could enable physicians to tailor treatment directly to a patient, basing decisions on the information in the genome. However, for Lupski, it all began with the search for a gene.

Lupski, now vice chair of molecular and human genetics, came to Baylor College of Medicine in 1986 with newly minted M.D. and Ph.D. degrees in hand and a mission. He was going to find the gene that causes CharcotMarieTooth disease, a nerve disease that affects the ability of the nerves in legs, arms, hands and feet to function. He and three of his eight siblings have CharcotMarieTooth, and he knew that the fledgling field of human genetics would provide an answer.

His search took him to the answers to questions that had not yet been posed in the mid 1980s. He found the first gene for "his" disease, only to discover it was not "his" gene. That first finding, however, helped spark a new field that he pioneered—copy number variation. That first gene—PMP22—caused CharcotMarieTooth because it had too much genetic material—a duplication of the genome that gave patients with the duplication essentially three copies of the gene and too much protein. Later, he would find that genomic duplications and deletions also caused other diseases now referred to as genomic disorders.

Lupski, currently vice chair of the molecular and human genetics department at BCM, forged forward, finding genes and genomic causes for a variety of disorders, including PotockiLupski Syndrome. Those discoveries were satisfying, but the quest for the cause of his own disease continued. The numbers of genes associated with CharcotMarieTooth climbed to near 40, but the gene that affected Lupski and his family remained to be elucidated.

Better tools

In the meantime, however, the armamentarium he could bring to bear on the problem increased. His laboratory attracted the brightest of graduate students and postdoctoral fellows whose laboratory skills were matched only by their intellect. Molecular biology came into its own as a major force in the biomedical studies. Highthroughput genome sequencing, finetuned in the Baylor Human Genome Sequencing Center led by Gibbs, became a potent force. The rise of molecular biology, new understanding of cells and genes and, most important, Lupski's fierce intellect that doggedly refused to let go of the problem gave him the most powerful weapons.

Lupski's was one of the first 10 human genomes sequenced in the world, but his was an important first. His genome was sequenced to help find a gene that was causing disease.

Gibbs suggested the solution—sequencing Lupski's entire genome to look for that elusive gene. It came in the wake of the sequencing of Nobel Laureate James Watson's genome in 2007. Gibbs, Lupski and representatives of 454 Life Sciences presented Watson with a computer hard drive containing his full genome sequence on May 31, 2007 in ceremonies in Houston. (Watson received his Nobel Prize for work describing the helical structure of the DNA molecule.)

Gibbs once described the Human Genome Project, in which his Center played a lead role, as the development of an incredibly powerful tool. Now he wanted to see how potent it could be in a search for the cause of a disease.

Difficult task

Lupski knew it would not be easy. He had helped analyze the Watson data, and he knew how much information there was. He also knew that scientists do not know what the vast majority of genes actually do and how hard it was to identify those pieces that had significance in terms of individual health.

Determining the sequence itself took skill and strategy. Gibbs and his team broke Lupski's genome into different small fragments and used cutting edge technology to determine the sequence of his whole genome—his DNA blueprint. They then used powerful computer programs to reassemble the genome into its proper form. They closed in on the gene by identifying all the functional variants in genes that were likely to be related to CharcotMarieTooth.

"This is the first time we have tried to identify a disease gene through whole genome sequencing," said Lupski. "It shows that the technology is robust enough to find disease genes by virtue of doing the whole genome sequence. We can use it in a way to interpret clinical information in the context of the sequence—in the context of the hand of cards you have been dealt. In a way, isn't that the dream of personalized genomic medicine? Can we use your genome, to figure out a better treatment for you?"

Finding the gene

Lupski's sequenced gene

In the report, which appeared in the New England Journal of Medicine, Lupski, Gibbs and colleagues describe the study that led to finding two different mutations in one gene SH3TC2. Lupski and his siblings with CharcotMarie Tooth disease inherited mutated copies of the genes—one from each parent.

"I have the disease, and I have two mutant genes," said Lupski. "I know I have a genetically recessive disease, and I've known that for 40 years."

What became clear from his study, however, is that having only one of the mutations in a gene can have consequences. In his study, people with one gene that has the missense mutation (in which one letter in the genetic code (ATCG) is different from the normal gene, changing an amino acid and resulting in a protein that cannot carry out its appointed duties) suffer from axonal neuropathy, in which specific nerves malfunction. Those with one gene that has the nonsense mutation (in which the genetic message is prematurely stopped) are more prone to carpal tunnel syndrome.

"I wonder how often this occurs," Lupski said. "People who carry one gene for a recessive disease may have susceptibility for complex traits. Will we be able to look at some alleles (gene copies) like this to see what you might be susceptible to?"

Making medicine personal

Lupski's was one of the first 10 human genomes sequenced in the world, but his was an important first. His genome was sequenced to help find a gene that was causing disease. That search proved fruitful and it opened a new door for medicine. While scientists do not know what the vast majority of genes do, they do know the significance of mutations or copy number changes in many. Those differences could provide important treatment information—now and in the future.

"We will use that information we obtain on your genome in your clinical care," said Lupski. Sequencing his genome had clinical significance, and for that reason, editors at The New England Journal of Medicine insisted that he and Gibbs devise a glossary of genetics/genomics terms for the practicing physician.

"The practicing physician who thinks this won't happen in his/her lifetime needs this information," said Lupski.

The human condition

While sequencing his genome was not an intellectual exercise, Lupski is still an intellectual. The implications of everything in his genome gave him pause.

"The amount of rare variation is tremendous. My genome has 3.5 million differences from the reference genome (the sequenced human genome) and so does that of most people. I still don't think we have a good feel for the rate of new mutations," he said.

Lupski holds The Cullen Foundation Endowed Chair in Molecular and Human Genetics and Gibbs holds The Wofford Cain Chair in Molecular and Human Genetics.

Better tools

Difficult task

Finding the gene

Making medicine personal

The human condition

Features

News

Spotlight

Briefs

Development/Alumni

Development Briefs

Volume 6, Issue 1, Summer 2010


	Quest for a Gene Opens New Door in Personalized Medicine by Ruth SoRelle, M.P.H. Dr. Richard Gibbs (left) and Dr. James Lupski teamed up the resources of their facilities to identify the particular gene mutations responsible for the form of CharcotMarie Tooth syndrome that affects Lupski and members of his family. In 2009, Baylor College of Medicine physician-scientist Dr. James Lupski completed a personal quest and, in collaboration with Dr. Richard Gibbs, opened the door to a new realm in medicine—the use of personal genome sequencing in the diagnosis and treatment of disease. Still a work in progress, whole genome sequencing could provide powerful answers to issues of personal health. This new vista could enable physicians to tailor treatment directly to a patient, basing decisions on the information in the genome. However, for Lupski, it all began with the search for a gene. Lupski, now vice chair of molecular and human genetics, came to Baylor College of Medicine in 1986 with newly minted M.D. and Ph.D. degrees in hand and a mission. He was going to find the gene that causes CharcotMarieTooth disease, a nerve disease that affects the ability of the nerves in legs, arms, hands and feet to function. He and three of his eight siblings have CharcotMarieTooth, and he knew that the fledgling field of human genetics would provide an answer. His search took him to the answers to questions that had not yet been posed in the mid 1980s. He found the first gene for "his" disease, only to discover it was not "his" gene. That first finding, however, helped spark a new field that he pioneered—copy number variation. That first gene—PMP22—caused CharcotMarieTooth because it had too much genetic material—a duplication of the genome that gave patients with the duplication essentially three copies of the gene and too much protein. Later, he would find that genomic duplications and deletions also caused other diseases now referred to as genomic disorders. Lupski, currently vice chair of the molecular and human genetics department at BCM, forged forward, finding genes and genomic causes for a variety of disorders, including PotockiLupski Syndrome. Those discoveries were satisfying, but the quest for the cause of his own disease continued. The numbers of genes associated with CharcotMarieTooth climbed to near 40, but the gene that affected Lupski and his family remained to be elucidated. Better tools In the meantime, however, the armamentarium he could bring to bear on the problem increased. His laboratory attracted the brightest of graduate students and postdoctoral fellows whose laboratory skills were matched only by their intellect. Molecular biology came into its own as a major force in the biomedical studies. Highthroughput genome sequencing, finetuned in the Baylor Human Genome Sequencing Center led by Gibbs, became a potent force. The rise of molecular biology, new understanding of cells and genes and, most important, Lupski's fierce intellect that doggedly refused to let go of the problem gave him the most powerful weapons. Lupski's was one of the first 10 human genomes sequenced in the world, but his was an important first. His genome was sequenced to help find a gene that was causing disease. Gibbs suggested the solution—sequencing Lupski's entire genome to look for that elusive gene. It came in the wake of the sequencing of Nobel Laureate James Watson's genome in 2007. Gibbs, Lupski and representatives of 454 Life Sciences presented Watson with a computer hard drive containing his full genome sequence on May 31, 2007 in ceremonies in Houston. (Watson received his Nobel Prize for work describing the helical structure of the DNA molecule.) Gibbs once described the Human Genome Project, in which his Center played a lead role, as the development of an incredibly powerful tool. Now he wanted to see how potent it could be in a search for the cause of a disease. Difficult task Lupski knew it would not be easy. He had helped analyze the Watson data, and he knew how much information there was. He also knew that scientists do not know what the vast majority of genes actually do and how hard it was to identify those pieces that had significance in terms of individual health. Determining the sequence itself took skill and strategy. Gibbs and his team broke Lupski's genome into different small fragments and used cutting edge technology to determine the sequence of his whole genome—his DNA blueprint. They then used powerful computer programs to reassemble the genome into its proper form. They closed in on the gene by identifying all the functional variants in genes that were likely to be related to CharcotMarieTooth. "This is the first time we have tried to identify a disease gene through whole genome sequencing," said Lupski. "It shows that the technology is robust enough to find disease genes by virtue of doing the whole genome sequence. We can use it in a way to interpret clinical information in the context of the sequence—in the context of the hand of cards you have been dealt. In a way, isn't that the dream of personalized genomic medicine? Can we use your genome, to figure out a better treatment for you?" Finding the gene Lupski's sequenced gene In the report, which appeared in the New England Journal of Medicine, Lupski, Gibbs and colleagues describe the study that led to finding two different mutations in one gene SH3TC2. Lupski and his siblings with CharcotMarie Tooth disease inherited mutated copies of the genes—one from each parent. "I have the disease, and I have two mutant genes," said Lupski. "I know I have a genetically recessive disease, and I've known that for 40 years." What became clear from his study, however, is that having only one of the mutations in a gene can have consequences. In his study, people with one gene that has the missense mutation (in which one letter in the genetic code (ATCG) is different from the normal gene, changing an amino acid and resulting in a protein that cannot carry out its appointed duties) suffer from axonal neuropathy, in which specific nerves malfunction. Those with one gene that has the nonsense mutation (in which the genetic message is prematurely stopped) are more prone to carpal tunnel syndrome. "I wonder how often this occurs," Lupski said. "People who carry one gene for a recessive disease may have susceptibility for complex traits. Will we be able to look at some alleles (gene copies) like this to see what you might be susceptible to?" Making medicine personal Lupski's was one of the first 10 human genomes sequenced in the world, but his was an important first. His genome was sequenced to help find a gene that was causing disease. That search proved fruitful and it opened a new door for medicine. While scientists do not know what the vast majority of genes do, they do know the significance of mutations or copy number changes in many. Those differences could provide important treatment information—now and in the future. "This is an immense step forward for personalized medicine," said Gibbs. "We will use that information we obtain on your genome in your clinical care," said Lupski. Sequencing his genome had clinical significance, and for that reason, editors at The New England Journal of Medicine insisted that he and Gibbs devise a glossary of genetics/genomics terms for the practicing physician. "The practicing physician who thinks this won't happen in his/her lifetime needs this information," said Lupski. The human condition While sequencing his genome was not an intellectual exercise, Lupski is still an intellectual. The implications of everything in his genome gave him pause. "The amount of rare variation is tremendous. My genome has 3.5 million differences from the reference genome (the sequenced human genome) and so does that of most people. I still don't think we have a good feel for the rate of new mutations," he said. However, the differences are important. "Every person is truly unique," said Lupski. Lupski holds The Cullen Foundation Endowed Chair in Molecular and Human Genetics and Gibbs holds The Wofford Cain Chair in Molecular and Human Genetics.		Search all issues: Features The Future of Health Care Starts at Med High Emergency Medicine: The Art of Juggling A Quarter Century of Invention at Baylor College of Medicine "Passport" Gives Childhood Cancer Survivors Entry into Adult Healthcare Dan L. Duncan Cancer Center Educates Through Entertainment Getting to the Roots of Cancer News Dr. Paul Klotman: BCM's New Top Man Dan Duncan Leaves Solid Foundation for BCM's Research Future DeBakey Library & Museum Showcases Innovations of Pioneering Heart Surgeon Spotlight 1,000 Chances for New Life BIPAI Doctor Seeks to Serve in Africa Space Medicine Takes Medical Education Across New Frontiers Quest for a Gene Opens New Door in Personalized Medicine Briefs Out of This World Science Experiment Generates International Interest Out of Africa Predicting the Progression of Alzheimer's Disease Pool to Receive Academic Clinical Professionalism Award The Pea Aphid and the Wasp Genome Development/Alumni Dr. Wheeler Donates Royalties Believe in BCM Campaign Engages Campus Development Briefs National Osteoporosis Foundation Honors Lawrences DeBakey Heart Center of BCM Benefits from Partnership Event Pink Ribbon House Project Celebrates Success Awards and Honor Wall Highlight Alumni Reunion 2010 The Road Ahead Promises Continued Success

	Volume 6, Issue 1, Summer 2010



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