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An Expanded Timeline of Personalized Medicine

A sampling of the many initiatives that are helping to shape a clinical revolution

Photo courtesy of Justin Knight/Partners Healthcare Center for Personalized Genetic Medicine

 

Note: Bold entries are specific to Harvard.

1984

  • George Church, now an HMS professor of genetics, collaborates with Harvard professor and Nobelist Walter Gilbert to develop the first direct genome sequencing method. Both scientists go on to help initiate the Human Genome Project.

1990

  • The Human Genome Project officially launches, with the goals of identifying all human genes and sequencing the 3 billion bases of a composite human genome.

2000

  • U.S. President Bill Clinton and British Prime Minister Tony Blair jointly announce that scientists with the Human Genome Project have completed a rough draft of the human genome. “Without a doubt,” Clinton says, “this is the most important, most wondrous map ever produced by humankind.”

2001

  • Mark Daly, now an HMS associate professor of medicine at Massachusetts General Hospital, observes that DNA recombines in large blocks, or haplotypes. This discovery helps set the stage for the International HapMap Project, which David Altshuler ’90, an HMS professor of genetics at Massachusetts General Hospital, will go on to help lead.
     
  • The collaboration now known as the Partners HealthCare Center for Personalized Genetic Medicine begins. Within a year, under the scientific direction of Raju Kucherlapati, the center opens a genotyping service to provide precise genomic analyses, especially those of variations known as single-nucleotide polymorphisms, or SNPs, which can signal heightened risk for a given disease.

2002

  • The International HapMap Project officially launches with the aim of describing the common patterns of human genetic variation. If the Human Genome Project provides a phone book of all the genetic suspects, says Rudolph Tanzi, director of the genetics and aging unit at Massachusetts General Hospital, then the International HapMap Project narrows those listings by neighborhood.

2003

  • The Human Genome Project is completed two years ahead of schedule, at a total cost of nearly $3 billion. This milestone coincides with the 50th anniversary of James Watson and Francis Crick’s discovery of the double helical structure of DNA. Harvard’s George Church later likens access to data from the project to being able to glimpse the picture on the box of a giant jigsaw puzzle.

2004

  • Researchers from Massachusetts General Hospital and a team from the Dana–Farber Cancer Institute and Brigham and Women’s Hospital independently report that the drug gefitinib—sold as Iressa—produces dramatic benefits in about 10 percent of patients with non–small-cell lung cancer who carry an unusual mutation of a key protein. This discovery offers hope to tens of thousands of patients. Among the scientists involved from Mass General are Daniel Haber, now the Kurt J. Isselbacher/Peter D. Schwartz Professor of Medicine, and Thomas Lynch, then an HMS professor of medicine; members of the team from Dana–Farber and Brigham and Women’s include Matthew Meyerson ’89, now an HMS professor of pathology at Dana–Farber Cancer Institute; Bruce Johnson, an HMS professor of medicine; Pasi Jänne, an HMS associate professor of medicine; and former HMS associate professor of medicine William Sellers.
     
  • The Broad Institute of MIT and Harvard launches under the direction of Eric Lander, a driving force behind the Human Genome Project. The institute will go on to house one of the largest genome sequencing centers in the world.

2005

  • Researchers from institutions worldwide—including several HMS affiliates—join The Cancer Genome Atlas, a project aimed at characterizing all genomic changes involved in human cancers. The initial goal of mapping three cancers—glioblastoma multiforme, lung, and ovarian—will expand four years later to encompass more than 20 cancers, which, combined, affect at least 10 million people in the United States alone.
     
  • The International HapMap is published, providing a powerful tool for linking genetic variation to disease susceptibility and treatment responses. This catalog gives scientists worldwide a first good look at the “order in variety” that is the human genome. “Built upon the foundation laid by the human genome sequence, the HapMap is a powerful new tool for exploring the root causes of common diseases,” says one of the corresponding authors, David Altshuler. “We absolutely require such a resource so that we can develop new and much-needed approaches to understand these diseases, such as diabetes, bipolar disorder, cancer, and many others.”

2006

  • George Church receives approval to enroll an initial group of ten volunteers in the Personal Genome Project, an initiative that aims to publish the complete genomes and medical records of all who participate. The web-accessible data of an eventual 100,000 volunteers will allow researchers worldwide to test hypotheses about the relationships between genotype, phenotype, and environmental factors.
     
  • Ting Wu, an HMS professor of genetics, and collaborators in her laboratory initiate the Personal Genetics Education Project to educate a range of audiences, from high school students to physicians, about the ethical, legal, and social issues that will arise in the era of personalized medicine.
     
  • Dana–Farber Cancer Institute researchers and their colleagues demonstrate that a genetic error so scarce it cannot be detected with some standard screening equipment is often responsible for the loss of effectiveness of frontline drugs against non–small cell lung cancer. Investigators led by Pasi Jänne find that many non–small cell lung cancer patients who become resistant to targeted drugs such as Iressa and Tarceva have a mutation in a single building block of the epidermal growth factor receptor, or EGFR, protein. “The implication of our study is that perhaps many more patients than previously thought have this as their mechanism of resistance,” says Jänne. “Identifying those patients will be important in the next generation clinical studies of drugs for non–small cell lung cancer.”
     
  • Researchers at Brigham and Women’s Hospital and elsewhere create a genetic diversity map that focuses on structural variations known as copy number variants. If the human genome represents the book of life, says principal investigator Charles Lee, an HMS professor of pathology, so far scientists have been looking for single-letter spelling mistakes. Work with copy number variants seeks to detect larger errors. “We’re finding sentences can be duplicated or completely deleted in some individuals,” Lee says, “sometimes paragraphs, sometimes whole chapters.”

2007

  • With collaborators, researchers at the Broad Institute of Harvard and MIT announce the completion of a genome-wide map of genetic differences in humans and their relationship to type 2 diabetes and other metabolic disorders. “The Human Genome Project, HapMap database, and new genomic tools have made it possible for the first time to screen the genome for DNA variations that contribute to common diseases,” says principal investigator David Altshuler. “Since diabetes and cardiovascular risk factors are influenced by many genes, environment, and behavior, these powerful new tools are required to pick up the effect of any one genetic risk factor.”
     
  • By the conclusion of the second phase of the International HapMap Project, Harvard contributions include new genetic clues to such conditions as type 2 diabetes, Crohn’s disease, elevated blood cholesterol, rheumatoid arthritis, multiple sclerosis, and prostate cancer. “The second phase has tripled the amount of genetic variation assessed,” says Mark Daly, co-senior author of the report, “and describes up to 95 percent of common single-letter variations in the human genetic code.”
     
  • The Partners HealthCare Center for Personalized Genetic Medicine creates a test that pinpoints genetic mutations associated with hypertrophic cardiomyopathy, a disorder that can lead to sudden cardiac death. The HCM CardioChip test offers information on the specific mutation—and thus the potential severity of disease. “Right now, we diagnose the disease,” says Christine Seidman, the Thomas W. Smith Professor of Medicine at Brigham and Women’s Hospital. “Personalized medicine means that we can also diagnose the disease risk.” In a series of studies spanning two decades, Christine Seidman and HMS professor Jonathan Seidman have identified the genetic roots of hypertrophic cardiomyopathy.
     
  • An international team led by researchers at the Dana–Farber Cancer Institute and the Broad Institute produces a comprehensive map of the molecular landscape of lung cancer, identifying more than 50 sites on the chromosomes of lung cancer patients that are genetically different from those in healthy individuals. About two-thirds of these sites harbor genes that hadn’t previously been suspected as playing a role in the disease. Among the Harvard scientists involved in this Tumor Sequencing Project are Matthew Meyerson and Eric Lander.
     
  • Science magazine unveils the 2007 Breakthrough of the Year—the realization that DNA differs from person to person much more than researchers had suspected. Science also offers a video presentation that looks at the previous year’s discoveries in human genetic variation; Harvard geneticist David Altshuler is featured in the video.

2008

  • The Genetic Information Nondiscrimination Act of 2008, or GINA, is signed into law, prohibiting health insurers and employers from discriminating based on genetic disease predisposition. The late Senator Ted Kennedy calls the act the “first major new civil rights bill of the new century.”
     
  • Two Dana–Farber Cancer Institute investigators—Matthew Meyerson and Lynda Chin—report initial results from The Cancer Genome Atlas. As the atlas expands, the researchers expect it to drive the development of new ways of categorizing tumors and of tailoring therapies accordingly.
     
  • Researchers at the Laboratory for Personalized Medicine at the HMS Center for Biomedical Informatics use cloud computing and clinical avatars for nearly 100 million virtual patients to test dosing of such drugs as the anticoagulant warfarin, often marketed as Coumadin. “We want to learn,” says Peter Tonellato, founder and director of the laboratory, “how to ensure better patient care and better results.”
     
  • The genome of James Watson, co-discoverer of the structure of DNA, is sequenced in two months at a cost of $1 million.
     
  • Scientists announce the results of the largest genomic study to date of lung adenocarcinoma. Led by researchers from the Broad Institute of Harvard and MIT, Dana–Farber Cancer Institute, and other research institutions nationwide, the collaborative study unearths a variety of genetic alterations in patient tumors and pinpoints 26 frequently altered genes, more than doubling the number already linked to the disease. The work draws on multiple large-scale approaches to highlight key molecular defects in lung tumors that are often found in other forms of cancer, a convergence that could open important avenues for treatment. “This work helps identify new targets that might show promise for treating broader groups of lung cancer patients,” says co-senior author Matthew Meyerson. With more than one million deaths worldwide each year, lung cancer ranks as the primary cause of cancer-related mortalities.
     
  • The ten pioneers of the Personal Genome Project—including George Church and HMS chief information officer John Halamka—post their genomic data and personal details, from vital signs to biopsy results, on the Internet.
     
  • Dana–Farber Cancer Institute scientists achieve a medical first when they use a targeted drug to drive a patient’s metastatic melanoma into remission. “This is the first proof of principle that we can find an Achilles’ heel in melanoma and, by targeting that gene with a drug, cause the cell to die,” says the study’s lead author, Frank Stephen Hodi, an HMS assistant professor of medicine at Dana–Farber. “It is especially exciting because there haven’t been any effective treatments for melanoma patients with metastatic disease.”
     
  • The Thrombolysis in Myocardial Infarction (TIMI) study group, based at Brigham and Women’s Hospital and led by chair Eugene Braunwald and now vice chair Marc Sabatine ’94, announces findings that one-third of people carry a genetic variation that prevents them from properly metabolizing clopidogrel, or Plavix, an antiplatelet medication commonly prescribed to prevent heart attacks.

2009

  • Massachusetts General Hospital becomes the nation’s first to make molecular fingerprinting standard practice in cancer treatment. This bold step helps avoid what Leif Ellisen, an HMS associate professor of medicine, calls “barely educated guesswork” in tailoring treatments to individual patients. “We needed a new way to think about cancer diagnosis and therapy,” Ellisen explains.
     
  • The Department of Pathology at Beth Israel Deaconess Medical Center establishes the country’s first mandatory residency training in personalized genomic medicine. A key aspect of the training: residents analyze their own genotype–phenotype associations. “We can bury our heads in the sand,” says one of their instructors, Mark Boguski, an HMS associate professor of pathology, “or we can figure out strategies to play a constructive role in this new era of personalized medicine.”
     
  • Children’s Hospital Boston launches the Gene Partnership Project, in which patients are given the opportunity to provide a DNA sample and enroll in a registry, giving researchers permission to include them in studies. The patients can then opt to receive the results of studies relevant to them, delivered through software that protects their anonymity. “Every single patient we encounter should be an opportunity to learn, and these are the first important steps,” Isaac Kohane, one of the project’s principal investigators, later tells the Boston Globe.

2010

  • Dana–Farber Cancer Institute researchers discover a gene-activity signature that predicts a high risk of cancer recurrence in women with certain breast tumors that have been treated with commonly used chemotherapies. Testing for this signature, say HMS assistant professors Andrea Richardson and Zhigang Wang, could help the 20 percent of women whose cancer recurs because of that gene activity.
     
  • An international research team announces the discovery of more than 100 genomic sites in which DNA from tumors is either missing or abnormally duplicated. The study shows, says senior author Matthew Meyerson, that most of these abnormalities—known as somatic copy-number alterations—are shared across cancers. Rameen Beroukhim, an HMS assistant professor of medicine, serves as first author on the paper.
     
  • Brigham and Women’s Hospital embarks on an ambitious study of the links among genetics, lifestyle, environment, and health. The study—OurGenes, OurHealth, OurCommunity—seeks to enroll 100,000 patients in a longitudinal study to set the stage for a new generation of personalized disease analysis and medical care.
     
  • A targeted drug used to treat metastatic melanoma with a specific genetic signature proves successful in more than 80 percent of patients enrolled in a trial. “Metastatic melanoma has a devastating prognosis,” says lead author Keith Flaherty, an HMS lecturer on medicine at Massachusetts General Hospital. “These findings can change the outlook for patients whose tumors are fueled by this mutation.”
     
  • David Altshuler, co-chair of the 1000 Genomes Project, coauthors two papers detailing initial findings from the project, which plumbs data from the third phase of the International HapMap Project. “Between these two types of genetic variants, very rare and fairly common,” Altshuler says, “we have a significant gap in our knowledge.” The 1000 Genomes Project aims to fill that gap.
     
  • Dana–Farber Cancer Institute researchers uncover a genetic clue that enables doctors to predict, for the first time, the likelihood that children with an aggressive form of leukemia—T-cell acute lymphoblastic leukemia—will benefit from standard chemotherapy. “This will help us determine,” says Alejandro Gutierrez, an HMS instructor in pediatrics, “which patients need different regimens.”
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