Show notes
Russ Altman: Today on The Future of Everything, the future of detecting DNA in your blood.Now DNA is the building block of life. It is a relatively simple long molecule or polymer made out of four components or DNA bases which have one letter abbreviations, the famous ATCG, which stand for their chemical names. It’s like a string of beans, beads, beads, but it is long. A human genome is made of about three billion DNA bases, divided into 23 chromosomes. So if you add up the beads in each chromosome, you get about three billion. You get a genome from mom and you get one from dad. So you have two copies of the genome, mostly the same but obviously not identical, or six billion total.Now DNA contains the blueprints for how your cells live, how they grow, how they interact with other cells, and like a computer program, it allows the cell to perform simple computations to make decisions about when and where things happen.If this goes wrong, you can get cancer. Mutations in the DNA cause the computations and decisions to go wrong.Other things can happen too. In the last ten years, researchers have learned that they can detect DNA in the blood. Now we knew that the cells in the blood had DNA, so that was not surprising, but what was surprising is that there is sometimes DNA from other cells in the body, often cells that have died and just released their DNA into the bloodstream. This is sometimes called cell-free DNA because it is floating in the blood and it’s not really part of a cell. Although this may seem like it’s junk, it offers evidence of lots of other processes going on in the body, processes diverse as cancer, pregnancy, stress on organs, or even death and many others.Dr. Stephen Quake is a professor of Bioengineering, Applied Physics and Physics and Stanford University. Steve pioneered the detection of DNA in the blood and some its first applications.Steve, what drove your interest in detecting DNA, and what was the first demonstration that this would actually be useful?Stephen Quake: Well, my interest came actually when I became a father. My wife and I were in to see the doctor, and the doctor says you guys should think about getting amniocentesis. And it was seemed like a theoretical question and something we have time to think about. We said yeah, okay, that sounds like the right thing if recommending it.Russ Altman: And this is a super risky procedure in many ways. A needle goes into the uterus near the baby to extract fluids.Stephen Quake: Big needle right in the mom’s belly, right next to the fetus to try to grab a few cells, and so to do genetic testing. And we said yeah, it sounds like a good idea, thinking we schedule another appointment for it. Next thing we knew, the guy was turning around with a giant needle, plunges it right into my wife’s belly,Russ Altman: Whoa.Stephen Quake: Yeah, whoa, exactly. That was our response. And it’s the response of many people who undergo that certain invasive testing. And not surprisingly, there’s risk associated with doing that testing. Sometimes, you lose the baby and other health problems that might happen.Russ Altman: How far into the pregnancy were you?Stephen Quake: That’s typically done, I don’t know, around 14 weeks, something like that, 15 weeks, somewhere around there. And so that sensitized me to holy cow, there’s a problem here that you’re asking a diagnostic question, and there’s a lot of risk associated with it. And so I began to think are there ways to ask these genetic questions and do diagnostics without adding risk? And I eventually stumbled upon this old scientific literature about this cell-free DNA that you were mentioning, which, as it turns out, was first discovered as a phenomenon in 1948.Russ Altman: That’s before Watson and Crick even articulated the importance of DNA for genetics.Stephen Quake: It’s before the structure, and it’s before people knew. It’s roughly contemporary people first realized that DNA was the molecule of inheritance.Russ Altman: Right.Stephen Quake: Oswald Avery just that same year was working that out. So it was blood chemistry to those guys who did it. But the field stayed alive, and it was mostly people doing cancer research. And eventually, it was figured out that when you’re pregnant, some of the DNA in your blood comes from the fetus, and that was worked out in the late 1970s. And –Russ Altman: And so this is not a large amount, I’m guessing.Stephen Quake: It’s not much, just a few percent of what’s there, so it’s a very challenging measurement problem and the decade-long search to try to figure out how to really use that to build a diagnostic that would allow you to understand the genetics of the baby without having to risk the baby’s life. And we saw that at Stanford, and it was through the work of a really terrific graduate student in my lab when the bioengineering department was young, Christina Fan. And that has now been the first real clinical application of cell-free DNA in diagnostics, and that’s how I got into it, to answer your question.Russ Altman: So in that initial demonstration or in your first industrial translation, what are the things that we can actually detect from the DNA of a fetus in the mom’s blood?Stephen Quake: Well, when we published the paper on this, started getting press inquiries. When is this gonna be available in the clinic? I said, I don’t know, decades, something like that.Russ Altman: That’s usually the answer.Stephen Quake: It takes a long time, right. It turns out people jumped on like you wouldn’t believe. Clinical trials were launched immediately. Within three years, the first real commercial diagnostic products had been launched, and now it’s four million women a year, something like that, get the test, and the use of amniocentesis has plummeted.Russ Altman: And so now you do this as a screening before you make the decision about the amnio. Is that the general use of it?Stephen Quake: That was the initial indication, and it’s very quickly moving to replacing amnio completely.Russ Altman: Completely, yeah. And what kind of things can we diagnose in the fetus these days?Stephen Quake: So the major genetic disorders you have for live births are things like Down syndrome; that’s number one. And it’s an aneuploidy is what it’s called technically, means the extra copy of a chromosome. And there’s a few other disorders, which are extra copies of chromosomes that are also detected with this approach.Russ Altman: Awesome. So that has had big-time market impact, and it’s changing people’s lives. I think it’s on the street now. People know you can get this blood test instead of the amnio, so it didn’t stop there. Now you had this hammer, and it worked. You hit one nail. What was the next nail you guys turned your attention to?Stephen Quake: Well, after we published that, word got around Stanford that I was interested in non-invasive diagnostics. And I got a call one day from Hannah Valantine, who’s a cardiologist –Russ Altman: Great cardiologist.Stephen Quake: Yep, and she says, well Steve, we got a similar problem in heart transplants. We give people a new heart, and after the operation, we then go biopsy that new heart and rip out pieces of the tissue to make sure it’s not being rejected by the body. And we’re doing that every couple of months. And so is there a blood test that could replace that? Same sort of problem, patients were having this painful, risky procedure, and there was a question of whether it could be replaced by a simple blood test. And so we thought about that a bit, and –Russ Altman: The key opportunity here is that the DNA and the heart that belongs to the donor is not gonna match the DNA of the person who received the heart, and, like the baby and the mom, because those are different DNAs, you have a chance of picking it up.Stephen Quake: Yeah, the key there is that the DNA is different. A little different with the baby and the mom because we don’t use differences in their DNA. But in the case of the transplant, absolutely. The whole principle is based on there being different genomes of every cell in the heart compared to other cells in the recipient’s body. And we monitor those so-called polymorphisms, those changes.Russ Altman: And so you went after this, and you were indeed able to show that people who were in rejection were spilling, so to speak, the heart DNA into the blood, and maybe we can avoid some of those biopsies.Stephen Quake: Absolutely. So we did a proof of principle study with some bank samples she had, and then we wrote a grant together and were able to do a very large study on both heart and lung transplants where pretty much every transplant patient at Stanford for those two organs was enrolled in our study over a period of three years, and were able to validate it. It was amazing. One of my kids was in elementary school at the time, and there was a new family who was in the class that year. And at the end of the year, we got a note around saying that, well, there’s a family that’s in town because they were at the Ronald McDonald House. One of their kids was in the hospital and very ill, and would anyone wanna put them up for the last couple of months because their time had run out there. And so we invited them –Russ Altman: Took them in.Stephen Quake: to our house, yeah, and very interesting family. They were immigrants from Africa. The father had been a nurse there, had some medical training and knew that when his son was infant and very ill that needed serious help and eventually got him to Stanford where the son had had a heart transplant.Russ Altman: Whoa.Stephen Quake: And we were talking around the dinner table one night, and the dad says well, and we’re just so proud to be part of this study where people are trying to figure out if they can replace the biopsies. And we enrolled our son in it and drew the blood. I said that’s my study. It was amazing and felt very good about it.Russ Altman: Of course, of course.Stephen Quake: And now that’s available. So there’s now tens of thousands of people every year who are getting that test, and it’s saving a lot of pain and suffering for those patients.Russ Altman: This is The Future of Everything. I’m Russ Altman. I’m speaking with Dr. Steve Quake about detecting DNA, and at this moment, detecting DNA in transplant, hoping to detect rejection. So does the test detect rejection potentially earlier than the old-fashioned biopsy approach would?Stephen Quake: It does, and we’ve proved that, absolutely. You see rejection weeks, if not a month, earlier than the biopsy.Russ Altman: And then presumably, that gives the docs more option for changing the immunosuppression.Stephen Quake: Oh, absolutely because yeah, as you mention, all these patients are immunosuppressed to try to prevent rejection, and too much of that, and they’ll get an infectious disease. Too little of that, you have rejection. So they can dial up the immunosuppressants a little bit and try to avoid the rejection event, and that’s much better for the patients. Once they hit rejection, all sorts of bad things happen, and so the whole thing is trying to keep them properly suppressed.Russ Altman: And just to flesh it out a little bit, how frequently are they getting these blood draws? Is this every six months or every three months or –Stephen Quake: The standard of care for the invasive biopsies was every two months, and that’s where they initially matched it. But this is the sort of thing that can and should be done more frequently, and I think it’s gonna change the way people treat the patients over time.Russ Altman: I know that there are more applications, and I’m interested to know which ones you wanna talk about, but let’s talk about one that fascinates me, which is the detection of infectious agents in the blood. Can you tell me how this technology has been used in that regard and what’s the future look like?Stephen Quake: Yeah, so when we were doing the large transplant study, my post doc at the time, Ian De Vlaming, was looking at all the sequencing data very carefully and realized that not all of the sequence reads off the sequence that were mapping to the human genome. And he said maybe 98% of it’s mapping; there’s one or 2% that aren’t. And I said that’s great. It means we’re not having a lot of contamination and it’s all good, and he didn’t let it go with that, thank goodness. And he started looking at those things that weren’t mapping, and he realized it wasn’t contamination, and they actually were not human, and it was part of the microbiome of these individuals. So the bacteria and the viruses and funguses that live in our body also release cell-free DNA, and we were measuring that as well. And he realized that we could use that to monitor things like what happens to your microbiome when your immune system gets turned offRuss Altman: Right, because a lot of folks —Stephen Quake: Because a lot of patients are immunosuppressed, exactly.Russ Altman: Right.Stephen Quake: And then we realized ‘cause some of them are getting infectious disease, we could also see infectious disease. And so that has evolved into a new kind of infectious disease diagnostic, which is hypothesis free. You don’t have to test for a particular thing. You’re essentially testing for a thousand infections all at once, and it’s just now reached commercial development. We’re seeing the first peer-reviewed studies showing how to use it, and it’s a very exciting innovation for infectious disease.Russ Altman: People might find this surprising so let’s just unpack this a little bit. We know that there are some bacteria that live in our gut, and we’ve always expected to see them there. Many of us have assumed that my blood should be pretty much infection free. That’s not where the bacteria and the viruses live. I guess the first question is how much of a surprise, what do you see in normal people who are not immunosuppressed, and how do we interpret this? Do we know that these are diseases? Are these pathogens causing problems, or might they be part of some ecosystem of health?Stephen Quake: Yeah, all good questions. So a fun way to think about it is to do an order of magnitude calculation. Could we talk about calculations here?Russ Altman: Yes, this is something that physicists do, folks.Stephen Quake: So there’s a statistic going around by the microbiome people. You’ve got 10 times more bacterial cells in your body than you do human cells. If you take that at face value and you say well, the human genome is 1,000 times longer. You said three billion base pairs, then the typical bacterial genome, which about three million base pairs. You do the math on that, and you say by mass, all the DNA in our body is 99% human, 1% bacterial. And so if you were to mush this all up in a blender, purify the DNA out, that’s what would come out.Russ Altman: And that matches what your post doc found.Stephen Quake: Yes, exactly.Russ Altman: So are these normal signs? Are these normal organisms, or are these things that we have to run to the doctor and get treated for?Stephen Quake: The vast majority of it, the vast majority of is our normal microbiome, bugs that live with us commensally and happy, equilibrium, with us as humans.Russ Altman: I’m guessing you saw viruses or bacteria that were either entirely novel or not appreciated as living in humans?Stephen Quake: Absolutely, we have discovered traces of novel organisms that is an area of ongoing research in the group to try to understand what they are and where they fit into the tree of life.Russ Altman: This is The Future of Everything. I’m Russ Altman. I’m speaking with Dr. Steve Quake, and now we’re talking about infectious disease detection.As a doctor, I know that we have patients come into the emergency room or into the clinic with what we call FUO, fever of unknown origin. They look sick, they have a fever, it’s not normal to have a fever, and they look infected, but we can’t find an infection. And…
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