photograph by Ramin Rahimian

Innovative Thinking on Genetic Tests

Monitoring health and disease with next-generation sequencing.

Stephen Quake wants to use the power of DNA sequencing to monitor health. His ideas have already led to a blood test to tell a pregnant woman whether her fetus has Down syndrome. Now, the HHMI investigator is pushing further, to track the success of heart transplants and diagnose autoimmune diseases and allergies.

Genome sequencing is a potentially powerful approach to understand one’s inherited risk of disease. There is much excitement and research surrounding this prospect. I was among the first handful of people in the world to see their own genomes, and my colleagues in the Stanford Medical School enthusiastically assembled a team to provide a clinical annotation for me. But the information you get from this once-in-a-lifetime test tends to be limited—it offers risk assessments rather than diagnoses.

I began to think about other ways to use high-throughput sequencing to monitor health, beyond what one learns from the genome. An important potential source of material to analyze for this purpose is DNA from dead cells, which the body chews up into little pieces as it circulates in the blood. This ever-changing signal of the health of one’s organs can give clinicians a glimpse into a patient’s health at one particular moment in time. Though first discovered in 1848, this phenomenon of circulating cell-free DNA has not been exploited.

In the context of cancer, cell-free DNA has been widely studied. Tumors shed cells into the bloodstream and these cells contain altered genes that differ from those found in the rest of a person’s body. Identifying these mutations can help doctors determine what’s causing a tumor to grow and perhaps even guide treatment. HHMI investigator Bert Vogelstein is a pioneer in this area. Others are following his lead, identifying the kinds of cells and genetic material that slough off of tumors.

This is only the tip of the iceberg of how genetic tests can help diagnose disease, monitor health, and inform treatment plans. When my wife became pregnant with our daughter, she underwent amniocentesis—the risks involved in this procedure are difficult for any prospective parent to consider. I realized that prenatal testing would be a perfect place to start using noninvasive genetic testing. The fetus has a distinct genome from its mother, and I hypothesized that perhaps that could be measured through sequencing cell-free DNA. My lab developed a way to detect whether a fetus had Down syndrome, which is caused by an extra copy of chromosome 21, by counting chromosomes in a sample of maternal blood. We figured that as we sequenced cell-free DNA, we would be able to detect extra chromosome 21 material from the baby in the mother’s blood if a fetus had this disorder. A company called Verinata Health launched a commercial diagnostic test based on this discovery earlier this year.

There are other instances in which foreign, or changeable, DNA circulates through a person’s body, and genetic tests could provide ways to quantify or study this DNA. When someone receives a heart transplant, for example, the genome of the donor’s heart is different from the genome of the recipient—so a heart transplant is really also a genome transplant. After a transplant, doctors need to monitor how the new organ is doing. The best way to do this, currently, is to biopsy the heart every few months. This is incredibly painful for the patient, expensive, and not always a good measure of transplant success. But if the immune system is attacking the new heart, DNA will be released from the damaged heart cells and circulate in the blood. We can use sequencing to measure the amount of that foreign DNA—if it spikes, the transplanted heart is being rejected. We’ve shown that our method is very sensitive at detecting heart transplant rejection, and we believe it can be applied to other transplanted organs as well. A startup company has taken over the project and is raising money to develop it commercially.

Pregnancy and heart transplants are two very specific situations. The truly radical change will come when we can monitor the entire immune system—which defends the body against foreign cells that can make you sick—using genetic tests.

The immune antibodies circulating in your body are constantly changing depending on your environment, not based on the genes your parents gave you. And each antibody has a different genetic sequence. When you’re exposed to a pathogen, anything from the flu virus to Escherichia coli bacteria, your body makes a corresponding, unique antibody against that pathogen.

Developing a way to sequence the antibodies in a person’s blood at any given moment in time can potentially give valuable information on what that person has been exposed to. This could help diagnose an infection. It could also tell doctors whether someone has responded to a vaccine correctly, or whether they have an allergy or an autoimmune disease. A condition like lupus, which is very hard to diagnose and constantly fluctuates in terms of symptoms and severity, could be confirmed and then monitored by sequencing antibodies as the immune system changes over time.

As genetic sequencing becomes faster, cheaper, and more accurate, we’ll start seeing new ways to monitor the changing genes in a person’s body. These revolutionary sequencing technologies will help us understand the fluctuating state of a person’s health. In the future, I think genetic testing won’t mean a once-in-a-lifetime test that gives you some odds for developing certain diseases. A genetic test will be something that you can get any time. A quick finger prick and you’ll know whether you have a tumor, an infection, or an allergy. Such a test, I believe, will transform medicine.

Stephen Quake is a professor of bioengineering at Stanford University.

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Stanford University