Science Friday - Meet The Doctor Who Solves Medical Mysteries

Episode Date: October 9, 2023

A news story was circulating a few months ago—a woman in Australia came into the hospital with abdominal pain. She was increasingly forgetful and struggling with depression. Her doctors were stumped for over a year. What was causing her symptoms? Turns out she had a three-inch parasitic worm living in her brain. They took it out, and she recovered.How do doctors crack cases like this? How do you even know to check for a brain worm? This is the specialty of Dr. Joe DeRisi. When doctors run into a diagnostic dead end they call him. In his world, brain worms aren’t even that rare. (Ask him about brain-eating amoebas.)Guest host Flora Lichtman talks with Dr. DeRisi, professor of biochemistry and biophysics at the University of California, San Francisco’s School of Medicine and president of the Chan Zuckerberg BioHub San Francisco, about his fascinating work solving some of the most vexing medical mysteries, and how it may even help detect the next pandemic-inducing pathogen.  To stay updated on all-things-science, sign up for Science Friday's newsletters.Transcripts for each segment will be available the week after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Hi, Ira here. A lot of you have said, hey, Ira, we like the podcast, but sometimes we just want to listen to one story at a time. And we hear you. So we're going to try something new. A topic or two a day spread out through Monday through Science Friday. Have a listen. Something like 40 to 50 percent of infections of the brain go without any known cause. So what do doctors do when they can't figure it out? They call Dr. Joe DeRisi. It's Monday, a October 9th. Not to worry, though, it's still Science Friday. I'm SciFRI producer Shoshana Bucksbaum. Remember that story from a few months ago about a woman who had a three-inch parasitic worm living in her brain? She's fine. They remove the worm. But in Dr. Durese's world, brainworms aren't even that rare. Wait till he tells you about the brain-eating amoebas. Flora Lickman goes behind the scenes of what it takes to crack medical mysteries. Dr. DeRisi is a professor of biochemistry and biophysics at the University of California, San Francisco, and the president of the Chan Zuckerberg Bio Hub, San Francisco. Welcome to Science Friday.

Thanks for having me on. So, Joe, let's get brainworms out of the way. Are brain worms yet another thing I need to worry about, like climate change and a democracy and now brainworms? Flora, let me ask you this. Do you wash your hands regularly? Yes. 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 brainworns are actually pork tape worms.

And if you really want to know the dirty truth, they're spread by contamination with fecal material. Okay, got it. Okay, well, I'm going to keep washing my hands. So thank you for that. Have you encountered a brainworm on the job? We have encountered our fair share of tapeworms in the brain. That headline that hit the news a couple months ago, that wasn't like a, a shocker for you. Not at all. Yeah. A couple of friends said, hey, did you see the article about

the brainworned the brain? I'm like, yeah, tell me something new. I saw a couple of those last month. Okay, Joe, are you like a real life house? Like, am I talking to an actual medical Sherlock right now? No, not really. You know, 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. How do you use data? 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. I'm guessing, though, that if you looked at everything in me that wasn't human, there would be like a lot of stuff that wasn't infecting me, too? Totally. So, you know, 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. I feel like there's so much in my brain. That's not me. That shouldn't be there. But you mean pathogen-wise. Exactly. The non-human part. And it's really the sanctuary of your body. Your cerebral spinal fluid, the fluid that bays your brain and 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, that's undoubtedly the cause of the infection most of the time. Oh, so does that mean that brain infections are actually easier to diagnose using this system than like a kidney infection?

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 99.9999% human. Got it. Okay, well, let's talk about this brain amoeba. Can you walk me through the case? 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-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 percent, 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 mandralis, which is something I'd never heard of. Oh, really? I'm an infectious disease gig, right? Like, I don't 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, you know, 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. Neglaria, the one you may hear about where a 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 Naglaria. And then Acamp amoeba, which is also found in the soil and or water. So there's three of these. And Balamutia is one of the evil trio. So these are free living amoeba. The humans are the dead end host. Like we're not intended to their 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. But, you know, 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? Right. Right. 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, right? The market's just too small. It's too rare in 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? Like, it's not going to happen. It's just like not on the cards. There's no incentive. There's no incentive. Capitalistic incentive, I guess I should specify. 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, right? So 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 has tested all the known approved drugs in the U.S. and Europe on this like 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? And what did you find? So we grew Valamuthi 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 nitroxylene. 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, like, that's sort of the end of the story, right? Okay, 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 Spaswood, 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 nitroxylene 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.

Wow. How did that feel for you? 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-one case study. You don't have a parallel universe where you withheld the drug, so where's your control? How do you know 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 pre-print 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 USSF, and we were able to get them the drug, nitroxylene. And she's now shown considerable improvement and is back out of the hospital. So that's Ennis II. Now, Enos 2 is not a big study, but I'll take it where I can get it.

It must be so gratifying. So, you know, in science, many times people think science is sort of like not a very emotional pursuit, but we keep beat up a lot of times. Like 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. It's a lot of disappointment, a lot of unfortunate experiments that never work. In fact, most of the time is 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,

like that's way better than getting any good review on a paper or a grant funded. I'll take that any day. You know, so this story is about someone who had a disease that was known, but people couldn't figure out what it was, right, and how to treat it. Are there unknown diseases? Like, is that a thing that this approach can also help us with? That's a great question for us. 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 lamp post 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, you, 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. If you're just joining me, I'm talking with Dr. Joe DeRisi about cracking medical mysteries. I'm Flora Lickman, 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... 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 a 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. 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. Yeah, that's a great question. You know, 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-resourced, 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.

And are there sort of signals where you're like, oh, I'm seeing characteristics that suggests that this is going to blow up? Like, are there, I don't know, things that we can look for? Yeah. So the things that you would look for is a 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 hospitals 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. 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's School of Medicine and President of the Chan Zuckerberg Bio Hub, San Francisco. Thank you for joining me.

Thank you, Flora. It was a blast. Thanks for coming on the show. That's it for today. Lots of people help make the show this week, including Lois Parsley, Ariel Zitch, Jordan Smudjick, Diana Plasker. And many more. On Tuesday, why more medical testing doesn't always mean a better prognosis.

I'm Shoshana Bucksbaum. Thanks for listening. We'll see you Tuesday on Science Friday.