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Vol. LXI, No. 23
November 13, 2009

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Genetics Offers Promise of Personalized Medicine

On the front page...

Genetics is not a new field, but for many researchers, the possibilities for study presented by unraveling genetic sequences, sequence variants and their potential relationship to specific illnesses are ever-changing. For as far into the future as anyone can project, scientists will have plenty to study, courtesy of the intricacies of the human genome.

One of the most beneficial aspects of having the human genome mapped, investigators contend, is that it offers a picture of what “normal” is supposed to look like. However, any scientist knows that “normal” is a relative and transient term. We have millions of interactions and lesser mutations occurring in our bodies at any given time. It’s the genetic alterations that aren’t minor or self-corrected that can cause problems and result in disease, experts note.


  Dr. Santa Tumminia (l) of NEI and Dr. Anna Barker of NCI are both using genomic information to develop patient-specific therapies, a major goal of modern medicine.  
  Dr. Santa Tumminia (l) of NEI and Dr. Anna Barker of NCI are both using genomic information to develop patient-specific therapies, a major goal of modern medicine.  

Several institutes are using the template of “normal” to record when particular gene sequences go bad, thereby providing a whole new dimension of understanding to certain illnesses. In the process, they’re also opening new doors for treatment and discovery.

“The relationship between genes and disease may, at first glance, appear to be relatively straightforward, but the relationship between a gene and disease is more complex than a simple one-to-one correspondence,” says Dr. Paul Sieving, director of the National Eye Institute. “A single gene may have a mutation at any one of a hundred different positions, and each mutation may give a different manifestation or aspect to the disease. Different mutations on a single gene can yield progressive global blindness while other mutations on that same gene result in a clinical state that preserves vision into advanced age. Also, mutations in multiple different genes can lead to the same clinical disease state with only subtle differences.”

Overall, the result of genetic mutations varies. They can either cause no disease, mild disease or be more devastating, Sieving says. “They can cause the breakdown of organs or loss of vision, cause cancer or cause heart or kidney problems.”

To get a better handle on the many mutations that can occur—at least those in the human eye—NEI has spent the last 3 years nurturing a research and clinical program known as eyeGENE, which is shorthand for the National Ophthalmic Disease Genotyping and Phenotyping Network. The program receives patient blood samples from eye health care providers such as ophthalmologists, optometrists and genetic counselors, all across the country. The samples are coded for anonymity and genetically tested by one of several NEI-affiliated network labs. The findings are then reported back to the clinicians who can work with their patients to determine next steps in their care. EyeGENE maintains an ever-growing database of information about scientifically vexing eye disorders. The network surpassed 1,000 samples this summer.

Officially, eyeGENE is testing samples for mutations in about 70 genes that cover about 30 specific disorders. If the genes in the sample don’t get a hit on one of the diseases they’re tracking, the eyeGENE team will bank the sample until new tests become available. “Genetic testing is like getting a second opinion, only through your genes,” says Dr. Santa Tumminia, project officer for the endeavor. “We must make sure that the genetic tests are both clinically valid as well as clinically useful. We can test for a particular genetic condition based on an initial diagnosis, we may uncover a new condition, or we may discover new genes causing the vision disorder. This network is a true partnership between individuals with inherited vision disorders, their eye health care professionals, the research community and the government.”

A similar venture is under way at the National Cancer Institute with the Cancer Genome Atlas, now emerging from a pilot program and turning toward a new set of cancers. The Atlas is managed in collaboration with the National Human Genome Research Institute, and the program has collected thousands of tumor samples for study from academic and private institutions across the U.S. It is the first time a large-scale project involving disease genomics has ever been attempted.

The idea is to create a catalogue of genetic signatures from all the variations that occur in specific cancers to set the stage for understanding the changes and how they differentiate from others. It is in these often subtle differences that scientists believe new possibilities for intervention may be discovered or new strategies for treatment could be revealed.

“Through genome characterization and sequencing we are identifying the complexity of molecular changes in these tumors,” says Dr. Anna Barker, NCI deputy director. “Cancer is an obvious choice for large-scale genomic characterization since it is a disease of genomic alterations. In cancer, the genes are disrupted significantly. Knowing all of the relevant changes will help to define targets for intervention. We hope to learn enough about these tumors, as well as the pathways that are disrupted, in order to approach the diagnosis, treatment and prevention of cancer in an ever more rational manner.”

Such information could help to simplify the treatment process, leading to customized courses of action dependent on tumor subtype, unlike today’s treatment methods that approach nearly every cancer the same way.

The medical reality of eliminating cancer as the second leading cause of death is still a ways off, but the concept is sound, NCI says. The pilot program started with glioblastoma, ovarian cancer and squamous cell lung cancer, and researchers were able to determine multiple subtypes for glioblastoma using the data gleaned from high-quality samples. This means treatments could one day be tailored to fit each cancer based on what sets them apart, not what makes them similar.

NIH will invest $275 million over the next 2 years in the Atlas (including $175 million in Recovery Act funds), focusing on more than 20 types of cancer. Barker is excited by the prospect of providing the research community with the complex data gained from such intense study, hopefully accelerating progress against all cancers.

“Personalized cancer medicine isn’t going to be a reality for everyone tomorrow,” she says. “But we want to get to the point where we can perhaps treat cancers as chronic diseases, and hopefully cure some outright based on the knowledge we are building. In an era of personalized cancer medicine, cancer could become a disease you live with successfully as opposed to dying from it. Projects such as the Atlas will enable this paradigm shift.” NIHRecord Icon

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