One of the biggest cheerleaders for personalized medicine is Michael Snyder, Ph.D., director of the Stanford University Center for Genomics and Personalized Medicine. He is quite possibly the most intensively monitored human in history. He has not only had his own genome sequenced but also has his RNA, proteins, metabolites, and antibodies repeatedly screened in what is called integrated personal omics profiling (iPOP) , and he is now beginning to have the microbiota in and on his body, including bacteria, scrutinized (Figures 1 and 2).
The purpose of this across-the-board monitoring study is to set the stage for personalized health care—to learn how all of these different factors independently and in concert affect an individual’s likelihood of developing disease and to identify the best treatment for that person when disease does surface. As studies like Snyder’s proceed, and as technological innovations make monitoring easier and less expensive, personalized medicine will become part of the health care industry. And it will happen soon.
“The revolution in DNA sequencing started in about 2005–2006 when new technologies emerged to drive down the cost of genome sequencing,” Snyder said. “Sequencing the first human genome cost a half a billion to a billion (U.S.) dollars. Today, we pay less than US$3,000 for human-genome sequencing.” Of course, he noted, interpretation of the genome is another beast altogether. “That is still a challenge. Some of the interpretation can be run by algorithms, but a lot of it is still done manually by curators.”
Technological innovations will improve the speed and accuracy of interpretation and will probably drive the cost of sequencing even lower, he said. “Any day now, we could well have genome sequencing that costs US$1,000. And some people are saying we can get that down to US$100. That is possible and probably likely at some point.”
Spotting and Treating Disease
Although it is becoming possible to begin selecting cancer-fighting drugs based on an individual patient’s genome sequence, very few cancer patients are having their genomes sequenced. That is starting to change, he said. “Even today and even though we don’t know everything there is to know about oncogenes (cancer genes), I cannot imagine being a cancer patient and not getting your genome sequenced. It hasn’t yet hit mainstream, but my own prediction is that within a few years, this will be the standard of care.”
The other area that is already benefitting from genome sequencing encompasses the so-called mystery diseases—the rare diseases that individually occur infrequently but that collectively affect more people than does cancer, Snyder said. Several percent of the population has one of the 7,000 or so rare diseases, and most of these diseases are genetic in origin. “Thousands and thousands of kids are born every year with some sort of serious problem, and their doctors can’t figure out what’s wrong. If more than one child in the family is affected, the children and parents will often undergo genetic sequencing to identify the mutated gene,” he said. The success rate is about 25% for identifying the disease, he noted, but of those, currently only a fraction has a cure or a therapy.
Successes are few, he acknowledged, but when they happen, they can be spectacular. “One success was a child, Nic Volker, who had been in and out of the hospital hundreds of times and was almost certainly going to die. His genome was sequenced, they found he had an immune deficiency, they gave him a bone-marrow transplant, and they essentially cured him. He’s a normal kid now,” Snyder said. Another case involved a set of twins, Noah and Alexis Beery, who were so-called floppy babies, infants without muscle tone. Through her own Internet research, their mother was instrumental in diagnosing the babies with dystonia, a nervous system defect that was treated with the neurotransmitter dopamine. The children were still experiencing some health issues, and they eventually underwent genome sequencing. It identified a second problem: a defect in the pathway that makes serotonin, another neurotransmitter. By treating them with a serotonin precursor, the problems cleared up. “Again, genome sequencing led to a diagnosis that they otherwise wouldn’t have had,” he said.
Identifying and treating disease is not all personalized medicine can or should do, Snyder said. “A lot of us are pushing to sequence the genomes of healthy people, so we can predict disease risk and therefore manage people’s health based on that information,” he continued. “In my vision of a future world, we will sequence the DNA of fetuses in pregnant women. I truly think that is the direction that the field will go.” He added, “My view is that it’s your genome. When you become of age, you should have access to it if you want to.”
Snyder’s research group was one of three involved in a study that sequenced the genomes of 12 healthy people. The sequence of one of the 12 revealed the BRCA-1 breast-cancer gene mutation. “She didn’t have a family history, so her genome told her something she would not have known otherwise,” he said. Information like that provides vital insight that patients can use to have a positive impact on their health care.
The researchers have also found that genome sequencing is not falling into the more-harm-than-good scenario predicted by some critics. The critics’ fear is that sequencing will encourage patients and possibly health care providers to seek millions of dollars in unnecessary follow-up tests for misidentified or infinitesimal disease risks. That hasn’t transpired, Snyder said.
“When we analyze the genome of healthy people, we’re finding that it costs somewhere between US$400 and US$1,500 in follow-up tests.” And these are good tests to have, he said, because patients who have a clear understanding of their disease risks can take precautionary measures to help ensure they remain as healthy as possible. In fact, he remarked, “I would argue that the insurance company should pay you to get your genome sequenced because I think those who do will be able to manage their health care better than those who don’t.”
About two decades ago, Snyder’s lab developed the first large-scale analysis of genes and has since begun characterizing other -omes, such as proteomes and transcriptomes, from blood samples. “We ended up developing technologies that I thought would be useful for clinical application,” he said. He even spun out some of that research into a few biotech companies.
To show proof of principal for the different monitoring approaches, he and his research group needed a subject who was both accessible and motivated. That’s when Snyder switched from being a researcher to being both a researcher and a study subject. “We wanted to be able to collect samples when a person was healthy and when that person wasn’t, and giving blood when you’re sick isn’t always a fun thing to do,” Snyder said. “It just made sense to roll out the first tests on me.”
Snyder is excited about the results on a personal and professional level. Genomics sequencing identified that Snyder had a high risk for a bone-marrow disorder, called aplastic anemia, which further tests showed he doesn’t have. Nonetheless, he said, he will still keep an eye on the potential for that disease as the years go by. More notably, personal omics profiling picked up a risk for type 2 diabetes, which Snyder has since developed. “We caught the diabetes early, simply because we were following the molecules in my blood,” he said, commenting that he is now taking steps, such as adjusting his diet and exercise regimes, to counter the disease. The finding also led him to look at his brothers and sisters. “We discovered that many of them have high glucose levels as well, indicating that there is some sort of glucose misregulation that occurs within my family history.” Had he not gone through iPOP, none of his siblings would have been aware of the impending danger. Now that they know, however, they can also make lifestyle changes to remain healthy.
To reap the full benefit of iPOP, considerable research will be needed. “In my case, I got type 2 diabetes after a very nasty respiratory syncytial viral infection. That’s when my glucose shot through the roof,” he said. “Our hypothesis is that my genome predisposed me for the disease, and the viral infection triggered it.” Snyder is among a growing number of researchers who have similar hypotheses that outside factors can turn a predisposition for a disease into actual acquisition. While the correlations mount, conclusive evidence will require more data, much of which will be collected through genome sequencing and iPOP, he said.
Snyder’s lab is contributing to the data pool by expanding their study to include other subjects. “We hope to enroll 50 people who are at high risk for diabetes, and we’re focusing on diabetes not only because I have a newfound interest in it, but also because it’s a disease that’s really poorly understood,” Snyder said. Like many other researchers and medical professionals, he believes diabetes is a collection of hundreds of diseases that have similar outcomes. “These omics technologies are perfect for trying to understand diabetes because they let us carefully monitor different molecules, and discover what leads to diabetes,” he said. If all goes well, he hopes the study will also begin to identify signatures that inform medical professionals about which treatment is the best choice on a patient-by-patient basis.
Snyder and his research group are now beginning to add the microbiome to the list of monitored -omes. “There are more cells in you that are not you than are you,” Snyder stated. “We have several pounds of bacteria living in our gut, many of which are important for digesting nutrients, and we have bacteria living in our mouth and nose, and on our skin.” Like other -omes, the microbiome can differ from one person to another. “It’s been found, for example, that people with diabetes have a certain microbiome and that if you can change it, you can actually improve their health,” he said. For that reason, his research group has now added the gut, urinary, nasal, oral, and dermal microbiomes to Snyder’s monitoring program.
Together, genome sequencing and iPOP will become very valuable tools in the personalized-medicine arsenal, Snyder said. As the cost for genome sequencing drops with technological innovation, and when insurance companies realize its benefit for preventing and treating disease, it will become routine. Personal omics profiling will be further down the road. He added, “I’ll stick my neck out and say that I’ll bet you’ll see some portion of this within ten years, but I don’t know for sure. Nobody does. Still, I think that is where this very fast-moving field of personalized medicine is headed.”
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