Along with red blood cells, white blood cells and a panoply of hormones, every drop of your blood contains tiny shards of DNA spewed out of various cells in your body as they die. Recent massive increases in the speed and efficiency of the instruments used to analyze these fragments of genetic information have led to some impressive advances in the development of so-called cell-free DNA (cfDNA) tests—particularly when it comes to prenatal testing of a developing fetus. But the best may yet be to come.
“Whenever cells die for one reason for another, they’ll release DNA into the blood,” says Kun Zhang, professor of bioengineering at the University of California, San Diego. “If you can recognize where they come from, there are multiple possibilities to detect the damage in different parts of the body.” Because cfDNA tests only require a simple blood draw, they may one day greatly improve a physician’s ability to diagnose a wide range of illnesses at their earliest stages, when they are often easier to treat. They could also reduce the need for painful biopsies to monitor the health of a new organ after a transplant. In the words of one researcher, cfDNA could become the ultimate “molecular stethoscope” that opens up a whole new way of practicing medicine—in much the same way that the acoustic stethoscope forever changed diagnostic opportunities after its introduction in the 1800s.
The first commercial application of cfDNA sequencing debuted in 2011. New blood tests can identify Down’s syndrome and similar genetic conditions during the first months of pregnancy by checking the fetal DNA in the bloodstream of a pregnant woman. (Anywhere from 10 to 15 percent of the DNA in a pregnant woman’s blood comes from the placenta, which is genetically similar to the fetus.) These maternal blood tests are fast replacing less-accurate procedures, such as ultrasound plus blood analysis.
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More recently, researchers have started looking at cfDNA to develop so-called liquid biopsies, which analyze a tumor’s genetic makeup or look for evidence of a cancer recurrence. Tumors often spill DNA into the blood as they grow and divide, and because they are usually riddled with mutations, their scrambled DNA is clearly different from that found in normal DNA fragments. The first liquid biopsy test was launched only three years ago; although they are not yet part of routine care, the field is growing quickly. One company says it will give liquid biopsy tests to one million people in the next five years, and another has raised nearly $1 billion for its studies.
A similar cfDNA method is being tested for newly transplanted organs, which are at risk of being rejected by the recipient’s immune system. Currently, transplant doctors check a transplanted organ’s health by performing repeated biopsies, which are expensive and invasive. After a transplant small amounts of donor DNA from the new heart or kidney, for example, circulate in the blood as part of the normal process of cell birth and death. If the host immune system attacks the foreign organ, the proportion of donor DNA increases as more and more foreign cells die. One company, CareDx, already sells a test that picks up on that change for people who have had kidney transplants.
These tests could be just the beginning. Researchers are exploring the possibility that DNA fragments could also be used to find chronic infections or detect diseases before they cause symptoms. Technically, this is feasible. The real question is whether it can also be efficient, cost-effective and easy to use in routine care. The essential consideration, Zhang says, is this: “In the end, does this bring real benefit to patients?”
While working on transplant monitoring research at the Stanford University laboratory of bioengineer Stephen Quake, Mickey Kertesz and colleagues noticed genetic material from infectious organisms such as viruses in blood samples. They began researching whether cfDNA could reliably identify infections, a rather small needle in the haystack: Just one in 100,000 or one in 1,000,000 bits of DNA found in the bloodstream might actually come from viruses or other pathogens, Kertesz says.
The researchers invented a way to boost the signal by reducing human DNA in blood samples. Their spin-off company, Karius, launched a test earlier this year to identify bacteria, fungi, viruses or parasites in hospitalized patients. It can spot infections in organs that are too dangerous for biopsies, including the lung and the brain, Kertesz says—and it is most useful for people with mystery infections or who are too sick to endure a surgery.
In one recent case a patient’s CT and MRI scans revealed nodules in the brain, but traditional methods could not pinpoint the cause without taking out a bit of brain tissue. The newly launched Karius test pointed to the parasite toxoplasmosis, which is treatable. “Right now, the technologies are new and more expensive than a blood culture, so this is not the first line of defense,” Kertesz explains. “But I have no doubt that in a few years this will be the way to go.” Their test is offered in eight hospitals nationwide; the company has expanded its capacity and infrastructure, and plans to broaden access later this year.
But for cfDNA to deliver on its ultimate promise—monitoring the function of any part of the body—there’s a catch. In pregnancy, cancer and infection there is a separate genome to analyze (coming from the fetus, the tumor or the infectious organism), so figuring out which fragments to focus on is not so difficult. To use cfDNA in other diseases, researchers must first solve a trickier problem: identifying which tissue or organ the DNA comes from. Here sequencing does not really help, because all cells have basically identical genomes; one cannot immediately know if the fragments being examined come from heart, stomach or kidney.
One solution is to look at methyl groups, the chemical attachments to DNA that control how and when genes are turned on and off. They have distinct patterns in different organs, and even between cell types in the same organ. Zhang’s group mapped out methylation across the body, so that a fragment of DNA in the bloodstream can be traced back to its origins based on its characteristic pattern.
Using a similar method, an Israeli group demonstrated that people with emerging diabetes have elevated cfDNA from dying pancreatic islet cells, which are lost as the disease progresses. A cfDNA test could possibly flag a person’s ailing pancreas before it is seriously damaged, so that treatment can protect the organ and keep the person healthier. Similarly—although less consistently—the team found cfDNA from the brain in the blood of people with active multiple sclerosis, and in others who had suffered brain damage after a heart attack. The study, published last year, was just a first step toward a useful test.
Geneticist Jay Shendure of the University of Washington has called cfDNA a molecular stethoscope for the next 200 years, and has developed an alternative method to trace where cfDNA comes from. The tightly coiled strings of DNA in the genome are packaged differently in different tissues, so when cells die the DNA is chopped up in distinctive patterns. Heart muscle cfDNA, for example, comes in different lengths than cfDNA from brain cells.
In a recent study, Shendure’s group used the patterns to pinpoint the source of tumors in five cancer patients. They launched a company, Bellwether Bio, to apply the method in the 4 to 5 percent of invasive cancer cases in which the original site of the tumor is not known, because knowing the origin can help doctors select the best treatments.
Other conditions that could be suitable for cell-free DNA tests in the future include stroke, or autoimmune conditions such as lupus. But just being able to see a signal does not automatically make a good test, cautions Zhang. In addition to being accurate, a test must also be affordable and practical, which can require a lot of fine-tuning and clever engineering. But it offers an appealing possibility: Perhaps one day a mere vial of blood could lead the way to better health.