Medicine gets a makeover by adopting a more personalized approach that enhances doctors’ ability to redict, diagnose, and treat disease.
When Robert S. was 1 year old, he was starting to speak and could crawl, cruising around his home in the suburbs of Washington, D.C. But after a fever, he suddenly and mysteriously lost those developmental skills. Doctors performed all the diagnostic tests at their disposal—MRIs, a spinal tap, amino acid and mitochondrial assays—but no abnormalities showed. He improved with physical therapy, but by 18 months Robert had lost control of the muscles in both arms, a condition known as dystonia. At 2 he lost more skills and has never regained them. For the next decade his parents sought specialist after specialist around the country to no avail.
A few years ago, they heard about whole exome sequencing, which was then at a research stage. Ada Hamosh, MD, MPH, the clinical director of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins Hospital who worked closely with Robert, explains that it only came on the clinical scene in January 2012. An exome is the portion of a genome that codes for proteins, and it comprises only 1.5 percent of the DNA in the entire genome. Most of the known genetic mutations exist in this portion of the genome right now, so rather than sequence each gene, which is precise but painstaking and very expensive (up to $3,400 for just a single gene), or the entire genome, which yields many uninterpretable results, researchers can now sequence an entire exome (with about 80 percent coverage) much more efficiently and economically, Hamosh says.
Now at 15, Robert has been wheelchair bound for years and is much brighter than his muscular abilities allow him to show—he moves his right arm to say yes and his left to say no. With his decline progressing and a tracheotomy a fast-approaching necessity, his family’s search for answers was growing increasingly urgent. When they were approached by the Rare Genomics Institute, which was looking for pilot patients for their whole exome program, they signed up right away. It returned results: Robert has two mutations on the PRKRA gene, one an inherited mutation from his mother and the other, a novel mutation. This recessive and very rare disease has a name: Dystonia 16, or DYT 16. Despite the degenerative nature of his disease, “his parents were thrilled,” Hamosh says. “His mother finally has a name to put on it, and it’s not her fault, as she had secretly feared. We didn’t have a way to make this diagnosis 14 years ago. Or even three years ago. Just labeling something is totally empowering.”
As Hamosh points out, the science behind genomic medicine is moving fast, whether doctors are unraveling medical mysteries like Robert’s or developing unique treatments for known diseases. With increasing velocity, medical treatments are becoming more tailored to an individual patient’s needs, based on one’s biological blueprint. The trend has become known as personalized or individualized medicine. While many top health institutions have adopted this approach, several lead the charge—MD Anderson Cancer Center, Mayo Clinic, and Johns Hopkins all have dedicated centers devoted to a more bespoke approach. What made it all possible was the mapping of the human genome and the incredible progress science has made in translating genetic research into clinical practice.
The field of genomics is exploding in every direction—in the lab, in research hospitals, and in the individual offices of oncologists and internal medicine specialists. For the first time, doctors can look at a patient’s DNA and read the genetic mutations that may make a patient more susceptible to certain illnesses and more likely to respond to certain drugs. They can diagnose rare, familial diseases they have not been able to identify before and can even use nutrigenomics to ensure one’s diet is a good match for one’s genome, especially in cases of celiac or Crohn’s disease. In fact, so much new information gets discovered and published every day that doctors struggle to keep up. Research hospitals affiliated with the National Institutes of Health are scrambling to hold conferences at which researchers can share with each other new developments and innovative uses for this information. Researchers continuously ask themselves how to use gene-mapping to give patients better care.
Cancer patients will likely be the most direct beneficiaries of the study of genomics. Researchers are mapping the genomes of cancerous tumors to determine which mutations patients have. What causes cancer cells to switch on, to produce proteins that cause them to continually reproduce? No one knows, but researchers can now map and cross-reference thousands of samples of tumors.
Jeff Engelman, MD, director of Molecular Therapeutics, and director of Thoracic Oncology at Massachusetts General Hospital (MGH), says that by studying a cancer’s genetics, researchers can identify new treatments. “One of the major emerging ways that we are treating cancer is to treat the specific molecular abnormality that is in cancer,” he says. Dr. Engleman says previously only a few such examples of this existed, the earliest of which was chronic myelogenous leukemia. Researchers matched a specific therapy with that specific abnormality. “It has revolutionized the treatment for that disease,” says Dr. Engleman. Similar examples of success stories include the HER2 mutation in breast cancer and ALK lung cancer. A number of cancers have a specific genetic mutation that can be targeted by treatment. Researchers study the genetic makeup of the biopsy cells, rather than the patient’s own cells, because the mutation exists in the tumor cells and not in the patient’s body. Dr. Engleman says that this has had a huge impact on the treatment of lung cancer. Currently, about 20 percent of patients in the United States have this treatable ALK mutation. “Ten years ago, it was zero patients,” says Dr. Engleman.
Developing new drugs and new therapies for patients by studying the genetic makeup of a patient’s cancer cells has become a priority at several medical centers. Mayo Clinic’s Center for Individualized Medicine, the New York Genome Center, and MD Anderson’s Center for Genetics and Genomics carve the path as clearinghouses on genetic maps for cancer cells. They are undertaking numerous studies in which scientists do DNA sequencing on cancerous cells before treatment to identify the specific mutations. Then if the regimen stops working, researchers biopsy the tumor cells again to see how they have changed. “Then we can think of what the next therapy might be to overcome that change,” says Dr. Engleman. Several centers are developing their own platforms for studying these mutations and creating therapies that might be effective against them.
The Cancer Genome Atlas (TCGA) is a collaborative research effort to study the genomic mutations that drive the growth of tumors in 12 organs. The project does this by comparing the DNA of normal tissue to that of cancerous tissue samples. By doing so, doctors hope to identify what turns a normal cell into a cancerous one and then craft treatments that are most effective against the mutation. TCGA is a national effort to coordinate research, and then share and integrate that information. Now in its eighth year, the research has already changed the field for the study of cancer cells.
“Eight years ago, if I wanted to study the genomics of a tumor type, I’d have to do the screening myself and I wouldn’t have much of a cohort,” says Lynda Chin, MD, chair of the Department of Genomic Medicine at MD Anderson. TCGA has changed that. It is studying more than 20 cancer types including breast cancer, lung cancer, brain tumors, and prostate cancer. All of this information becomes a shared resource for research, clinical, and pharmaceutical communities; researchers are not just sequencing the DNA of a single tumor sample, but hundreds. For example, more than 500 samples of breast cancer have been studied by TCGA. “Because every cancer genome is different. There’s a lot of noise,” explains Dr. Chin.
Melanoma, for example, is a cancer type that has one of the highest basal mutation rates. After looking at the data from many tumor samples, researchers discovered a recurrent mutation in a single amino acid on the BRAF gene in 60 percent of the melanoma patients sequenced. That gene helps control cell growth and division, so this particular mutation causes it to turn on the switch telling cells to grow and divide aggressively. Within nine years of the mutation’s discovery, the FDA had approved a drug that could target it. “That’s the kind of thing we are looking for with systematic sequencing,” says Dr. Chin. “TCGA was the first in pushing the idea of multi-dimensional analysis. We’re looking at different aspects of the genome to get a view of what these changes are. These can help us identify new biomarkers for cancer.” And Dr. Chin notes that TCGA has fundamentally changed the way scientists conduct cancer research. “TCGA data has led and will lead to new diagnostic and therapeutic targets for the treatment of cancer,” says Dr. Chin. “It may allow physicians to group patients into those who will respond to treatment and those who won’t.”
More recently, TCGA has embarked on the Pan-Cancer Initiative, in which scientists search for similarities in cancer cells across different types of tumors and ask questions about what makes some cancers similar to each other. Researchers will be able to collaborate in new ways because of this database, leading to even more tailored treatments for individual patients.
These data warehouses are possible now because new technologies in gene-mapping have emerged, including massive parallel sequencing methods. Parallel sequencing can produce thousands of sequences concurrently, which has caused the cost of gene sequencing to plummet. “Like anything else in the marketplace, it is driven by demand,” says Dr. Chin. “We can now sequence a normal genome, and we can do it in one day, depending on how much you want to know about the genome.” Some commercial companies produce results in a day or even an hour. And this technology has caused the base cost of sequencing to drop dramatically. “Some ads out there claim they can map your genetic code for $2,000 to $3,000, which is cheap relative to the billion it cost the first time,” says Dr. Chin, who notes that the real bottleneck still exists in the analysis. Emerging technologies will make sequencing even faster in the next decade.
A lot of research has focused on tumor cells and their mutations, even though doctors know that metastases are what kill the patient. As the technology continues to evolve in sequencing and the costs continue to drop, researchers will be able to obtain detailed analyses of many kinds of mutations and which treatments work on them.
“We need to fully integrate the genomic data from research with clinical data in real time,” says Dr. Chin, “and develop a new model of collaboration between clinical care and research.” She has launched one such initiative, nicknamed APOLLO, for Adaptive Patient-Oriented Longitudinal Learning and Optimization. MD Anderson has enrolled more than 1,300 patients who will have all their clinical data and genetic data collected and analyzed multiple times.
Institutions around the world are attempting similar projects. The Mayo Clinic has multiple clinical trials underway to study the genetic mutations in cancer cells. In these studies participants have biopsy cells sequenced at multiple times during treatment. One such study is called PROMOTE, and its participants have metastatic prostate cancer. Researchers take a biopsy of the tumor before starting a particular regimen and then another three months later to see if the cells have been affected by treatment and if so, how they have changed.
Doctors know that some patients do not do well on certain chemotherapy drugs. The field of pharmacogenomics is beginning to explain why. Some patients have genetic mutations that affect the way their bodies metabolize a drug. In some cases patients have trouble flushing a certain type of toxin from their systems, which means that they will eventually overdose. New genetic tests can predict which patients will struggle on which drug regimens. “We do those tests and put the results into the patient file, and the doctor will know that they have ordered a drug that will cause a problem with this variation,” says Richard Weinshilboum, MD, who heads the pharmacogenomics program in the Center for Individualized Medicine at the Mayo Clinic. Researchers have found 84 genes so far that play a role in drug metabolism and delivery.
In fact, there are many conditions for which pharmacogenomics will help define a patient’s treatment options. For example, 11 percent of younger adults who present with irritable bowel syndrome cannot tolerate the standard medications. Not only does it not relieve symptoms, the standard drug course can worsen the condition. A simple genetic test can identify which patients should have standard drug therapy and which should try an alternative one. Doctors hope similar tests will help them tailor medications to better control a patient’s blood pressure and blood sugar levels in other chronic conditions such as heart disease and diabetes.
While it is not yet clear how healthy patients may benefit from complete genetic screenings, physician-scientists like Dr. Chin believe this burgeoning field will immediately benefit the critically ill. When asked if she thinks that the field of genomics has changed the practice of medicine, she says, “Yes. Profoundly.”
The DNA decision: should you have your genome sequenced?
Researchers at the Mayo Clinic predict that an individual genomic signature may one day be as important as a blood type in determining care. But right now, even as genetic sequencing becomes more common, most hospitals refrain from complete gene-sequencing on healthy individuals, reserving the process instead for the patients who need it most.
Although fees have come down, the screening still has significant costs and the interpretation of results remains challenging and time-consuming. Other hospitals may provide this screening for a fee of several thousand dollars (a fee not covered by insurance) or on the condition that the individual enroll in a study. One such study is The MedSeq Project, run by Robert C. Green, MD, and his colleagues at Harvard Medical School. Dr. Green’s primary research interest is in how healthy individuals cope with all this information about their DNA and their alleged genetic destiny. How does this genetic over-sharing affect an individual’s health-care choices? “We are dancing in the dark here in terms of what happens with this information,” says Dr. Green.
Complete gene sequencing differs widely from the genetic information provided by some companies, such as 23andme.com, which do not sequence the entire genome. Instead they look for certain biomarkers known to correlate with the potential to develop particular conditions. This could be described as reading the chapter titles of a novel, while complete gene sequencing involves reading the book itself. When companies offer to generate genetic information from a spit test for a few hundred dollars, they are offering just a sampling of your DNA.
The trouble with getting one’s genome mapped at this point is that for most people the data file will contain very little actionable information. Like many scientists in this field, Dr. Green has had his genome mapped, as well as his wife’s. “We haven’t found anything interesting,” he says. He notes that about one percent of people will find themselves flagged for some mutations that signal a high predisposition to develop cancer or Alzheimer’s. More likely they will find correlations with markers that indicate a slightly elevated risk for conditions such as multiple sclerosis or colon cancer. In the latter case, the patient’s risk is tied far more closely to his or her lifestyle or exposure to toxins than it is to any genetic predisposition.
Other healthy adults will find that they have mutations about which researchers know nothing. The potential for panic outstrips the potential for finding useful diagnostic information. Never mind the potential for mistakes in the analysis of the information—if, for example, a doctor reports a false negative for the BRCA gene. “At every level, there is the potential for false reassurance,” says Dr. Green.