Meet The Doctor Who Solves Medical Mysteries

FLORA LICHTMAN: This is Science Friday, and I’m Flora Lichtman. Remember that story from a few months ago. A woman in Australia came into the hospital with abdominal pain. She was increasingly forgetful, struggling with depression, and her doctors were stumped for over a year. What was causing her symptoms?

It turns out she had a three-inch parasitic worm living in her brain. They took it, out and she was OK. But how do doctors crack cases like this? How do you even to check for a brain worm? This is the specialty of my next guest, Dr. Joe DeRisi. When doctors run into a diagnostic dead end, they call him.

And in his world, brain worms aren’t even that rare. Wait until he tells you about the brain-eating amoebas. Dr. DeRisi is a professor of biochemistry and biophysics at the University of California, San Francisco School of Medicine and the president of the Chan Zuckerberg Biohub San Francisco. Welcome to Science Friday.

JOE DERISI: Thanks for having me on.

FLORA LICHTMAN: So Joe, let’s get brain worms out of the way. Are brain worms yet another thing I need to worry about, like climate change, end a democracy, and now brain worms?

JOE DERISI: Flora, let me ask you this– do you wash your hands regularly?

FLORA LICHTMAN: Yes.

JOE DERISI: That’s a great thing because that’s one of the most important things you can do to prevent brain worms. A lot of these brain worms are actually pork tapeworms. And if you really want to know the dirty truth, they’re spread by contamination with fecal material.

FLORA LICHTMAN: OK, got it. OK, well, I’m going to keep washing my hands, so thank you for that. Have you encountered a brain worm on the job?

JOE DERISI: We have encountered our fair share of tapeworms in the brain.

FLORA LICHTMAN: That headline that hit the news a couple months ago, that wasn’t a shocker for you.

JOE DERISI: Not at all. Yeah, a couple of friends said, hey, did you see the article about the brain worm in the brain? I’m like, yeah, tell me something new. I saw a couple of those last month.

FLORA LICHTMAN: OK, Joe, are you like a real life House? Am I talking to an actual medical Sherlock right now?

JOE DERISI: No, not really. The whole Dr. House is an encyclopedic knowledge, where he uses his intuition to figure out infectious disease. We’re the opposite of Dr. House. We use data.

FLORA LICHTMAN: How do you use data?

JOE DERISI: So we use this technology called metagenomic sequencing. This is something we’ve been working on for years now. That is, every microbe, every virus, every fungal parasite, every worm in the brain has RNA or DNA. And because of that, we can leverage the technology of sequencing to sequence a person and understand what part of them is human and not human, the not-human part being the thing that could be infectious.

FLORA LICHTMAN: I’m guessing, though, that if you looked at everything in me that wasn’t human, there would be a lot of stuff that wasn’t infecting me, too?

JOE DERISI: Totally. So if you’re fans of Science Friday, you’ve heard about the microbiome and many other kinds of popular stories about all the bacteria that live in your guts and your lungs. So that’s actually true. And in certain locations, it could be a challenge to tell what is a normal bacteria that should be in your gut– a so-called commensal– or something that’s pathogenic.

However, when we’re talking about brain infections, there really should be nothing in your brain but you.

FLORA LICHTMAN: [LAUGHS] I feel like there’s so much in my brain that’s not me that shouldn’t be there. But you mean pathogen wise.

JOE DERISI: Exactly, the nonhuman part. And it’s really the sanctuary of your body, your cerebral spinal fluid, the fluid that bathes your brain in spinal cord, should be like Evian water. There really should be nothing in it. And so when we sequence some of that from a patient and we find there is something there that isn’t human, undoubtedly the cause of the infection most of the time.

FLORA LICHTMAN: Oh, so does that mean that brain infections are actually easier to diagnose using this system than like a kidney infection.

JOE DERISI: Yeah, actually, that’s true. So if you took like a sample from the gut, which is going to have thousands of different bacteria, unlike that, the brain is really, really clean. It should be like 99.9999999% human.

FLORA LICHTMAN: Got it. OK, well, let’s talk about this brain amoeba. Can you walk me through the case?

JOE DERISI: So when we first started doing this idea of metagenomic sequencing for infectious diseases of the brain, seriously, like in the clinic about a decade ago, one of the most memorable cases was this case of a 74-year-old woman who came into Zuckerberg General Hospital comatose. She got brain imaging. And what was revealed was massive progressive destruction throughout all territories of her brain. Basically, a doctor said it looked like a grenade went off.

Now, that’s really drastic. She wasn’t going to make it. But the key here is she’s not all that uncommon. Brain infections are one of the most underdiagnosed infections in the human body. Something like 40% to 50%, depending on the study that you look at, of infections of the brain go without any known cause.

Well, this is where metagenomic could really shine. We could use this technology and answer the question of what is going on. In this particular woman especially, we found out. And it was really surprising. When we did the sequencing, she wasn’t all human. It was like a few percentage points that weren’t her.

And when we matched it to the universe of all known microbes, it matched to an organism called Balamuthia mandrillaris, which is something I’d never heard of.

FLORA LICHTMAN: Oh, really?

JOE DERISI: I’m an infectious disease geek. You’d think I’d know it all. I don’t. And when I saw that name, I said, what is that? I have no idea.

A little bit of looking around on PubMed will reveal it’s one of the three brain-eating amoeba. So there’s three of them that are out there that people might be familiar with or maybe not. Balamuthia comes from the soil, eats brains. Naegleria, the one you might hear about, where child gets water up their nose in a warm lake in the south of the United States and a week later, they’re dead, that’s Naegleria. And then Acanthamoeba, which is also found in the soil and/or water, so there’s three of these.

And Balamuthia is one of the evil trio. So these are free living amoeba. The humans are the dead-end hosts. We’re not intended they’re target. But for some reason that I don’t think anyone really gets, amoebas grow really well in the human brain. So if it goes up the nose, it has a chance to get up in there.

And so that was all well and good. You’ve provided a diagnosis. In this case, we were not able to save the patient. She was too far gone. But it raised sort of an interesting point. It raised a point that, so what if you could do the diagnosis if you have no treatment for that patient?

FLORA LICHTMAN: Right, right.

JOE DERISI: Now, this is where we got interested. So this frustrated me. It’s no fun being told, so what if you could do this? No drug company in their right mind would fund an effort to develop a drug for amoebas. The market is just too small. It’s too rare an infection. We’re talking about a handful of cases per year.

So how would you ever do a clinical trial or a placebo controlled trial? It’s not going to happen. It’s like not on the cards.

FLORA LICHTMAN: There’s no incentive.

JOE DERISI: There’s no incentive.

FLORA LICHTMAN: Capitalistic incentive, I guess I should specify.

JOE DERISI: And these are super deadly. Over 90% of the people who get one of these amoebas are going to die. So that’s where an academic lab, like my own, can really play a role. We’re not a drug company or anything, but we can play around and ask other questions.

And the thing that we reasoned was, well, if no new drug can be developed, what if we screened, that is, tested, all the known approved drugs in the US and Europe on this small glimmer of hope that there might be an existing approved drug that’s already in the arsenal that might work against amoebas and we just don’t know it?

FLORA LICHTMAN: And what did you find?

JOE DERISI: So we grew Balamuthia in our lab, and we screened over 2,100 of such of these drugs. And I’ll be honest. Essentially nothing worked, not even the recommended drugs for the emergency treatment of amoeba that the Federal Government recommends, except there was one, one drug.

It’s called nitroxoline. It’s actually an old urinary tract infection drug that’s been used in Europe for decades. It’s not really popular here because there’s better drugs for that. It’s probably not on patent either. But it actually killed amoebas pretty darn well.

Now, for most academic labs, that’s sort of the end of the story. OK, I found this. I’m going to write a paper. We’ll get some credit for writing the paper and then sort of peace out.

Well, fast forward several years to just a few years ago, and a new patient showed up at UCSF, where I work, a male in his 50s, now diagnosed with Balamuthia and apparently in the same hopeless situation as that 74-year-old woman I mentioned earlier. Well, this is where things are different. So there’s a doctor here, Dr. Natasha Spottiswoode, an ID fellow here at our university, who is aware of the drug screen that we did in the paper that we wrote.

And she asked the FDA for an emergency approval to use nitroxoline in this patient. And look, there’s no other hope. So why not? They were totally accommodating. They made it happen.

Long story short, he got the drug. It’s now almost two years later, and the patient is back living in the community totally unassisted. And the last time he had an MRI, the infection had essentially disappeared.

FLORA LICHTMAN: Wow. How did that feel for you?

JOE DERISI: So that felt really good. Now, of course, the criticism, if you put your reviewer hat number three on, is well, that’s an n equals 1 case study. You don’t have a parallel universe where you withheld the drug. So where’s your control? How do the drug actually helped? Maybe this guy was just like super lucky.

And that’s a valid criticism. So it happens another case, six-year-old girl in this case, popped up in Texas, diagnosed with Balamuthia. And because we put the paper that we published on a preprint server, so long before it came out in the peer reviewed literature, the family and the clinical team were able to see this paper and contact us here at UCSF. And we were able to get them the drug, nitroxoline.

And she’s now shown considerable improvement and is back out of the hospital. So that n is 2. Now, n is 2 is not a big study. But I’ll take it where I can get it.

FLORA LICHTMAN: It must be so gratifying.

JOE DERISI: So in science, many times people think of science as sort of not a very emotional pursuit. But we beat up a lot of times. You submit a paper, and there’s always reviewer number three who hates your paper, maybe hates you, doesn’t really want your stuff published, just hates on your work. You submit a grant. The grant committee says, nah, not quite good enough. Try again later. No money for you.

So a lot of disappointment, a lot of unfortunate experiments that never work. In fact, most of the time, there’s failure in science, and you get these little successes now and then. And you have to live for those successes. And in this case, where you tried something completely wacky, you picked this drug off the shelf, it seems to work, and two patients walk out of the hospital, even though you don’t know their name, they don’t know you, that’s way better than getting any good review on a paper or a grant funded. I’ll take that any day.

FLORA LICHTMAN: So this story is about someone who had a disease that was known but people couldn’t figure out what it was and how to treat it. Are there unknown diseases? Is that a thing that this approach can also help us with?

JOE DERISI: That’s a great question, Flora. So yes, metagenomics doesn’t just find what you’re looking for. It’s not the classic problem of looking for your keys under the lamppost or the light shining. Metagenomics looks for everything. It doesn’t care what you think or not.

So if there’s a new virus, like another pandemic virus or something new, metagenomics can see everything that’s not human. And because viruses look a certain way, bacteria look a certain way, parasitic worms look a certain way, we can recognize those, even though we’ve technically never seen them before. And we’ve done that. We’ve discovered new viruses in a variety of different species– humans, veterinary animals, you name it– using metagenomics. So I think the tool has greater utility than just testing for the things you already know about.

FLORA LICHTMAN: If you’re just joining me, I’m talking with Dr. Joe DeRisi about cracking medical mysteries. I’m Flora Lichtman, and this is Science Friday from WNYC Studios. What are the chances I’ve had an unknown illness, like an unidentified virus, or bacteria, or?

JOE DERISI: Well, let’s put it this way. If you’ve ever had the common cold, my guess is you’ve had a version of the rhinovirus but a version one we’ve probably never seen because they’re almost limitless versions of the rhinovirus. So we might find something new, but it will probably fall into a family of relatedness with something we’ve seen before. So I would put the odds very high you’ve probably had a novel rhinovirus, just like everybody else. You’re not special, Flora.

FLORA LICHTMAN: [LAUGHS] I know that, Joe. thank you. So how do we find the next unknown illness that could become a pandemic? Are there clues that signal, oh, no, this disease isn’t going to stay rare? It’s rare now. It’s unknown now. But actually, this is going to blow up.

JOE DERISI: Yeah, that’s a great question. This gets to the point of, how are we going to detect the next pandemic? Or how are we going to protect the population from an unknown virus that pops up? And how do we know when it’s really going to start to spread?

And so my answer to that is, well, look, this sequencing technology has gotten super cheap. The cost has really fallen through the floor. It’s a commodity item now. And so why can’t we just deploy sequencing literally worldwide for infectious disease in clinics and hospitals everywhere, especially countries that have the highest burden of disease? Now, these tend to be countries that are low resource, low- and middle-income countries.

And so that’s traditionally not the way people have thought, like, oh, let’s put high technology in the place with low resources. But I’m saying that’s exactly what we should do because, by doing that, one, each country can monitor what’s going on inside their own borders to understand their own local problems. But if joined to a network, that could form the basis of like a worldwide monitoring system for new and emerging diseases. And that’s something, here at the Biohub, we’ve been trying to focus on by training people to use this technology and providing them the tools to do it.

FLORA LICHTMAN: And are there sort of signals where you’re like, oh, I’m seeing characteristics that suggest that this is going to blow up? Are there, I don’t know, things that we can look for?

JOE DERISI: Yeah, so the things that you would look for is easy route of spread. So respiratory virus checks that box. You would find it in multiple locations, not just one hospital. It may start in one hospital, but then it pops up at some other hospital some distance away or in another country nearly simultaneously. That would be a pretty strong signal that there’s unseen transmission that you haven’t clued into. That would be a strong signal.

And then the analysis of the microbe itself. Does it have pathogenic potential? Is it related to something that is known to cause human disease and illness? That would all be strong signals that we’ve got to watch out.

FLORA LICHTMAN: That’s all the time we have. I’d like to thank my guest. Dr. Joe DeRisi is a professor of biochemistry and biophysics at the University of California San Francisco School of Medicine and president of the Chan Zuckerberg Biohub, San Francisco. Thank you for joining me.

JOE DERISI: Thank you, Flora. It was a blast.

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