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A sequel to one of the most popular NOVAs of all time, "Miracle of Life," this Emmy Award-winning program tracks human development from embryo to newborn using the extraordinary microimagery of Swedish photographer Lennart Nilsson.

Trace human development from embryo to newborn through the stunning microimagery of photographer Lennart Nilsson.

Life's Greatest Miracle

US & Territories

Water. Turn on the faucet and it’s always there. Without it we perish. But how safe is our tap water? In this special report narrated by Joe Morton, NOVA investigates what happened in Flint, Michigan, when local officials changed the city’s water source to save money, but overlooked a critical treatment process. As the water pipes corroded, lead leached into the system, exposing the community—including thousands of children—to dangerous levels of poison. NOVA uncovers the science behind this manmade disaster— from the intricacies of water chemistry to the biology of lead poisoning to the misuse of science itself. NOVA follows ordinary citizens and independent scientists who exposed the danger lurking in Flint’s water and confronted those who turned a blind eye. And discover the disturbing truth that reaches far beyond Flint—water systems across the country are similarly vulnerable. How can we protect ourselves from poisoned water? (Premiered May 31, 2017)

What exactly went wrong in Flint—and what does it mean for the rest of the country?

Poisoned Water

Whether they make you fat, fart, or freak out, microbes play a central role in your life. Right beneath your nose—on your face, in your gut, and everywhere in between—trillions of bacteria, viruses, and fungi are so abundant in your body, they outnumber your human cells. But these aren’t just nasty hitch-hikers. Many are crucial to your survival. Evidence suggests that a diverse microbiome can keep you healthy and, conversely, a damaged one could kill you. NOVA Wonders peers into this microscopic world to discover the fascinating, bizarre, and downright surprising secrets of the human microbiome, including the world’s largest stool bank, which transforms raw stool into life-saving poop pills.

Discover how a world of microbes living in and on you can make you sick-and keep you healthy.

What's Living in You?

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Why Experts Say Permanent Daylight Saving Time is Unhealthy

Early morning sunlight is the key to setting our internal clocks.
The misalignment of our internal clocks and the sun could result in a handful of heath concerns, experts say.
Why Experts Say Permanent Daylight Saving Time is Unhealthy Published November 8, 2022 Narrator: Are you more of an early bird or a night owl? If you prefer your sunlight in the evenings, permanent Daylight Saving Time might sound pretty good—and it could become a reality. In March 2022, the U.S. Senate approved a bill to make Daylight Saving Time permanent. But some experts say it could come at a price to our healthBeth Malow: I would love to have light in the morning and in the early evening all year round. If we were to be on permanent Daylight Saving Time, you could see where it would be pitch black, some places at eight o&#x27;clock in the morning.Ken Wright: Then people are going to be commuting to school and to work in the dark, and we&#x27;re going to be sending our kids to wait out for the school bus in the dark.Narrator: If the bill becomes law, it would mean later sunsets, but also later sunrises—an hour later than usual.Beth Malow: What people have found when people are going to work in the pitch black is it actually affects health. Genes get turned on that normally shouldn&#x27;t be. And some of those genes are not operating properly when we&#x27;re not in sync with our biological world.Narrator: Early morning light helps set our internal clocks, or circadian rhythms, which drive many systems in our bodies and even tell us when to sleep. Some research suggests morning light plays a role in determining when the body releases cortisol, a stress hormone that makes us more alert.Ravi Alla: We really think of circadian rhythms as really a fundamental part of life. That is, it&#x27;s critical that our biology is, if you will, in sync with the rising and setting of the Sun in our environment.Narrator: And when morning light is delayed, our internal clocks are out of step with the Sun, in what’s called circadian misalignment.Beth Malow: When we&#x27;re getting our light too late in the day, and not enough light in the morning, and we&#x27;re losing sleep, we call it circadian misalignment. And those things together can affect health in so many different ways.Narrator: And the effects can be more extreme depending on where you live in relation to your time zone. For example, let’s look at these two cities: Indianapolis and Chicago. Indianapolis is on the western edge of the eastern time zone—confusing, I know, but bear with me here—and Chicago is on the eastern edge of the central time zone. So even though they’re less than 200 miles apart, and they get similar amounts of sunlight, the time on the clocks is off by an hour. So when the Sun rises in Indianapolis at 7:00 am, it is only 6:00 am in Chicago.Ken Wright: If we look at the health of people on the western edge versus in the eastern edge that are adjacent to each other, the people on the western edge have more health problems.Ravi Allada: We know that those who are on the western part of the time zone have higher rates of cancer.Narrator: One study found that people living on the western edge of a timezone, and get more natural light in the evenings, got less sleep than their counterparts on the eastern side. And had higher rates of heart disease, diabetes, and breast cancer.Ken Wright: They get less sleep, higher risk of heart disease, higher risk of cancer, higher risk of type II diabetes. We think that if we shift to permanent Daylight Saving Time, that we&#x27;re going to increase the risk of these types of problems for our society.Narrator: So what does science say is the healthiest choice?Ken Wright: It&#x27;s clear that we should probably stop shifting every year. We know that spring forward shift is associated with increased risks of motor vehicle accidents, fatal motor vehicle accidents on our highways, as well as things like heart attacks and strokes.Ravi Allada: The ideal decision would be to select permanent Standard Time.Narrator: But if Standard Time becomes permanent, some places—like Boston—could see summer sunrises as early as about 4:00 am. But according to science, all that morning sunlight is critical.Beth Malow: Permanent Standard Time is the healthy choice because morning light is just critical to our health. It gets us up, it gets us going. It helps us fall asleep easier at night. So having that bright morning light is really, really essential, particularly for people who can&#x27;t control their schedules, like teenagers and some of our essential workers.Ken Wright: When we&#x27;re thinking about permanent Daylight Saving Time, we&#x27;re going to go ahead and gain light one way and lose light another. And so we have to decide as a society what is going to be the healthiest thing for our society.

Early morning sunlight is the key to setting our internal clocks.

A light blue brain scan against a black background with two purple C-shaped regions highlighted in purple

A brain scan from Fred Barrett's lab with the location of the claustrum indicated in purple. Image Credit: GBH/NOVA

How do psychedelics work? This brain region may explain their effects

Even if you’ve never used magic mushrooms, you may have heard what the experience can be like. People often hallucinate, seeing vivid colors or swirling patterns. And while not everyone has a positive experience, many users report feeling a deep sense of connection to the universe. Now, medical researchers are exploring ways to harness magic mushrooms and other psychedelic substances to help treat mental health conditions like depression, addiction, and PTSD—sometimes with dramatic results. But what actually happens in the brain during a psychedelic experience? Fred Barrett, a neuroscientist at Johns Hopkins University, is one of the scientists trying to figure that out. His work suggests that “a brain region called the claustrum may be at the center of all of this,” <a href="https://www.pbs.org/wgbh/nova/video/can-psychedelics-cure/">he told NOVA.</a>
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The claustrum is a set of two slight strips of gray matter–one tucked deep inside each brain hemisphere–that are connected to almost every other region of the brain. Francis Crick (of DNA fame) and neuroscientist Christof Koch suggested in 2005 that the calustrum’s position and connectedness made it a likely “conductor of consciousness.” Barrett compares it to a switchboard that tells other brain regions to turn on and off in response to changing stimuli.Take, for example, receiving an email, he said. You might hear the telltale ding, and your claustrum would coordinate each step you take next. You would read the text using your visual cortex. Then your claustrum-as-switchboard would recruit your prefrontal cortex to decide whether to send a response. Once you make your choice, your claustrum would tell the decision-making regions in the prefrontal cortex to turn off and mobilize your language region and motor cortex so you can start typing words.Knowing that the claustrum is crowded with receptors that psychedelics act on, Barrett and his colleagues wondered what happens to it when someone takes psilocybin, the hallucinogenic compound in magic mushrooms. In <a href="https://pubmed.ncbi.nlm.nih.gov/32454209/">a recent study</a>, he and his colleagues used a functional MRI machine to observe blood flow in the brain before and after 15 people took either psilocybin or a placebo. Neural activity in the claustra of study participants who took psilocybin was reduced by 15% to 30%, as if the switchboard operator had walked away.With the big boss out to lunch, Barrett said, different regions of the brain can interact in radically different ways. “Networks that normally don’t turn on at the same time may turn on and stay on, and they begin to fight for control,” Barrett said. “And other brain networks that would normally be involved in emotions or memories are firing on and off in an unpredictable fashion.” <h4>Watch: How Psychedelics Change the Brain</h4>
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With the claustrum turned down, Barrett said, his team has also noticed that a network of regions called the default mode network can go quiet as well. This network is active when we think about ourselves, so its dawdling may contribute to the feeling of egolessness that so many psychedelics users report. Research has shown that people who struggle with depression, anxiety, or other mental health conditions have difficulty recovering in part because their default mode networks are stuck in a rut—that “default” setting—which can include a powerful cycle of repetitive, negative thoughts and behaviors that only get stronger as they replay. But the sudden upheaval wrought by the claustrum’s mushroom-induced coffee break seems to have the potential to jolt the brain out of this cycle. “It may be that in this state, the normal repetitive thoughts that are baked into some neural circuits after years and years of use become less strong,” Barrett said. That may leave room for other, usually quieter circuits to have a say.
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He compares the situation to a theater production in which the director suddenly leaves. The actors don’t know what to do, so they just keep saying their lines, sometimes all at once or out of order. “You may come out with a performance that is just completely disorganized,” he said. “Or you may come out with a performance that’s rearranged in a very interesting way that nobody had thought of before.” Barrett points to this dynamic as one reason psychedelic therapy may have so much potential to treat mental health conditions. In normal talk therapy, “you’re battling the circuitry that you’ve built up over a long period of time,” he says—instead of radically reorganizing it.The profound transformations some study participants have experienced through psychedelic-assisted therapy may be possible because when the claustrum’s control is disrupted, the brain becomes more “plastic,” or flexible and open to change, Barrett said. Plasticity may be key to at least allowing that growth to happen, but it’s only the first step. “Simply making the brain more plastic itself doesn’t necessarily always lead to a positive outcome,” he added. A controlled environment with trained therapists to guide and support the person during and after the experience is crucial to promoting that plasticity, “which can lead to learning, which can lead to healing and growth.” <h4>Watch: Can Psychedelics Cure?</h4>
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The claustrum seems to act as a switchboard, telling different parts of the brain when to turn on and off. But what happens when the switchboard operator steps away?

How Psychedelics Change the Brain

Scientists found that psychedelic drugs may change how brain regions talk to each other.
Psychedelics might interact with the brain by turning off the brain’s default mode network and affecting a thin sheet of gray matter called the claustrum. This could shake up communication between different regions of the brain.
How Psychedelics Change the BrainPublished October 19, 2022NARRATOR: The default mode network activates when a person is introspective, and, under normal circumstances, becomes less active when a person shifts their attention to the outside world. But brain studies show that under the influence of a psychedelic, the default mode network is quieted, while other regions of the brain increase communication with each other. A mathematical model captures a normal brain’s activity. In contrast, a brain under the influence of psilocybin reveals a dramatic increase in global communication. Thousands of new connections form, linking brain regions that don’t normally talk to each other.ROBIN CARHART-HARRIS: So, one analogy I’ve used for how psychedelics work in the brain is this snow globe. When you pick up a snow globe, you know, the snow’s settled at the bottom, it’s sort of fixed, and then you pick it up, shake it, and things jiggle around, and there’s randomness and a kind of chaos, if you want, in the system.NARRATOR: The user experiences this as an altered and heightened sense of awareness. But what causes this?FRED BARRETT: Early in our functional brain imaging studies of psychedelics, scientists were finding that the default mode network was turning down or turning off during these experiences. And that was a really good place to start, but we began to then look one layer deeper. Why was the default mode network turning off?NARRATOR: New research led neuroscientist Fred Barrett to investigate a region of the brain called the claustrum.FRED BARRETT: The claustrum is a really thin sheet of gray matter in the brain, tucked deep within each of the hemispheres of the brain. Recent animal models have shown that it is incredibly highly connected to just about every other region of the brain. Understanding that the receptors targeted by psychedelic drugs are also really densely expressed in the claustrum, we began to wonder whether the claustrum may be at the center of psychedelic effects.NARRATOR: Fred believes the claustrum’s central location and shape suggest it regulates communication between the departments.FRED BARRETT: When it’s functioning normally, the claustrum is essentially acting like a switchboard. It’s trying to help other brain regions figure out when to turn on and when to turn off. But when we experience a psychedelic drug, we believe that it’s binding to specific receptors in the claustrum and, somehow, disrupting or disorganizing the claustrum. It’s almost as if the switchboard walks away. What happens next is that we seem to observe a, a radical change in the way that brain regions talk to each other. And it may be within this context that we’re experiencing learning and a possible, even, rewiring of the circuits that govern our behavior. And it may be that it’s that radical reorganization that allows people to encounter new psychological insights that they hadn’t encountered before.NARRATOR: Fred thinks the claustrum’s sudden abdication of control may help explain why rigid behavior and thought patterns have a shot at resetting.MATT JOHNSON: It’s almost like they’ve seen this kind of grand menu within their mind that they weren’t aware of. That this, this greater number of possibilities that they can explore.ERIC GOSS: It took a while to recover. I was having headaches and muscle pains. But it was the best headache I’d ever had in my life, because it told me that the psilocybin was working. It was actually physically restructuring my brain, something that I never imagined could happen before.ROLAND GRIFFITH: It’s like reprogramming the operating system of a computer. You’re getting down to very basic code-level changes that can enduringly change someone going forward.
EDITED BY:Ryan ShepheardWRITTEN, PRODUCED AND DIRECTED BYLarkin McPhee---NARRATED BYMercer BoffeyPRODUCTION MANAGERJaney KlebeCAMERAEzra WolfingerSamuel RussellThomas KaufmanVicente FrancoSOUND RECORDISTSEzra WolfingerMark MandlerIvan BasauriRay DayANIMATIONBrian OlsonMUSICAPM MusicScorekeepersRESEARCHJoan NolanASSOCIATE PRODUCERRachel NybergPRODUCTION ASSISTANTMike RoseONLINE EDITOR AND COLORISTDave BigelowAUDIO MIXHeartpunch StudioARCHIVAL MATERIALAlamyAP ArchiveGetty ImagesMultidisciplinary Association for Psychedelic StudiesPond5ShutterstockThe Royal SocietyEXPERT REVIEWERSDr. David E. NicholsDr. Natalie GukasyanSPECIAL THANKSJim MandlerKennedy Krieger Institute---NOVA SERIES GRAPHICSyU + co.NOVA THEME MUSICWalter WerzowaJohn LukerMusikvergnuegen, IncADDITIONAL NOVA THEME MUSICRay LoringRob MorsbergerCAPTIONING AND AUDIO DESCRIPTIONMedia Access Group at GBHPOST PRODUCTION ONLINE EDITORLindsey Rundell Denault---SENIOR DIGITAL PRODUCEREmily ZendtDIGITAL MANAGING PRODUCERKristine AllingtonDIGITAL PRODUCERSAlex ClarkAna AcevesDIGITAL PRODUCTION ASSISTANTShyla Duff---DIRECTOR OF EDUCATION AND OUTREACHRalph BouquetPROGRAM MANAGER, NOVA SCIENCE STUDIOLaura-Ashley AlegbeleyeDIGITAL EDITOR, EDUCATIONKara Norton---DIRECTOR OF PUBLIC RELATIONSJennifer WelshDIGITAL EDITORSAlissa GreenbergHanna AliAttabey Rodríguez BenítezSENIOR DIRECTOR OF AUDIENCE RESEARCHCory AllenNATIONAL PUBLICITYDKC Public Relations---ASSOCIATE RESEARCHERSChristina MonnenAbe MusselmanPRODUCTION COORDINATORLinda CallahanASSOCIATE PRODUCERAngelica Coleman---BUSINESS MANAGERElisabeth FrelePROJECT MANAGER, SCIENCE AND SOCIETYMaggie StevensonBUSINESS ASSOCIATESaron Admasu---LEGAL AND BUSINESS AFFAIRSSusan RosenRIGHTS MANAGERHannah GotwalsCONTRACTS MANAGERSarah ErlandsonTALENT RELATIONSSuzy Carrington---BROADCAST MANAGERNathan GunnerSENIOR SUPERVISING PRODUCERKevin YoungSENIOR PROMOTIONS PRODUCER AND EDITORMichael H. AmundsonPOST PRODUCTION ASSOCIATE PRODUCERJay Colamaria---SENIOR SCIENCE EDITOREvan HadinghamSCIENCE EDITORRobin KazmierSCIENCE AND EQUITY EDITORKrystnell Storr---BUSINESS DIRECTORElizabeth BenjesPROJECT DIRECTORPamela RosensteinSENIOR DEVELOPMENT PRODUCERDavid CondonNOVA PRODUCERCaitlin Saks---SENIOR DIRECTOR OF BRAND MARKETING AND AUDIENCE DEVELOPMENTNadia Petschek RawlsDIRECTOR, BUSINESS OPERATIONS &amp; FINANCELaurie Cahalane---EXECUTIVE PRODUCERSJulia Cort Chris Schmidt---A NOVA Production by Larkin McPhee Productions, LLC for GBH Boston.© 2022 WGBH Educational FoundationAll rights reservedThis program was produced by WGBH, which is solely responsible for its content. Some funders of NOVA also fund basic science research. Experts featured in this film may have received support from funders of this program.Original funding for this program was provided by Brilliant Worldwide, Inc., Consumer Cellular, the NOVA Science Trust and the Corporation for Public Broadcasting.

Scientists found that psychedelic drugs may change how brain regions talk to each other.

Psychedelics as Medicine: The History of Peyote

Indigenous communities use this small psychedelic cactus as a medicinal herb.
Peyote is an important medicinal plant that is used in rites of passage and in religious and healing ceremonies in Indigenous communities.
Psychedelics as Medicine: The History of PeyotePublished October 19, 2022NARRATOR: In many cultures, psychedelics have been used in rites of passage and to gain wisdom, usually administered in specific religious and healing ceremonies. In North America, some indigenous peoples use peyote, a cactus that grows in northern Mexico and a small region of south Texas.ADRIAN PRIMEAUX: I am Adrian Primeaux. I come from five generations of peyote people, myself being the sixth, and then my son being the seventh generation. To me, peyote it’s a very intimate medicinal herb. We use it as a guide; we use it as a means to synchronize with the universe. My grandparents explained to me, at a very young age, that we could acquire any means of success through medicine and peyote if we approached it with the right intent.NARRATOR: Peyote use can touch on many aspects of life.ADRIAN PRIMEAUX: How this medicine is able to heal, there’s a lot of complex facets. Within indigenous forms of thought, we believe that, like, the spirit exists somewhere back there in the subconscious, it’s connected to the universe. So, this plant medicine helps you reach those depths of your ability to manifest whatever it is you can picture in your mind. Maybe you’re picturing pain going away; maybe you’re picturing your cancer going away; maybe you’re picturing your body being healthy; maybe you’re picturing education. Whatever it is that you’re picturing, your subconscious brain has that power to create that for you. And this medicine is just the tool to help you to reach that point.YASMIN HURD: When we think about how native people have used these drugs, it was a ritual. So, there’s something still really important about the setting, the ritualistic aspect. You can see this positive outcome, you can hear the positivity around you, all of that then gets encoded into the brain, in a manner that, when you’re not in that hallucinogenic state it still stays with you.NARRATOR: A peyote cactus can take over 10 years to reach maturity. Since the arrival of Europeans, Native American tribes have often been persecuted for peyote use and had limited access to the plant. Now, commercial interests and poachers are putting undue pressure on peyote’s fragile ecosystem. Recently, a philanthropist purchased 605 acres of peyote land, here in South Texas, to provide access for members of the Native American Church, which teaches Native American traditions, sometimes elements of Christianity, and regards peyote as a sacrament.STEVEN S. BENALLY (Dine Nation): In order to assure that this medicine is going to be available, we have to have some kind of direct connection with this land. And this land, I think, is an answer to a prayer from years ago, that there will be medicine for our children.SANDOR IRON ROPE (Titonwan Lakota Oyate): This land now means the world to all of us. Mother Earth and what she has provided us, this represents the future. It’s about what you are going to teach your children, your grandchildren, and what you’re going to leave behind, the essence of, of generational responsibilities, you know? Words cannot suffice what the spirit feels in connecting with this land.

Indigenous communities use this small psychedelic cactus as a medicinal herb.

Four bright orange loops brand off of a dark blue blob

A transmission electron micrograph of HIV-1 virus particles (orange) replicating from the plasma membrane of an infected H9 T cell. Credit: NIAID, Flickr

How a select few people have been cured of HIV

Over the past year, news of two new people cured of HIV grabbed headlines, stirring hopeful talk of what these scientific wonders might portend for the four-decade fight against the virus. To researchers working in the HIV cure arena, these cases are inspiring because they prove it is in fact possible to eradicate this extraordinarily complex virus from the body. 
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That said, such cures are the result of treatments too toxic to attempt on all but a select few. So while they provide a scientific roadmap toward success, they do not necessarily make researchers’ job any easier as they work to develop alternatives: safe, effective and, crucially, scalable therapies to cure HIV.“HIV has been a tough nut to crack,” says Marshall Glesby, an infectious disease specialist at Weill Cornell Medicine in New York City and a coauthor of one of the recent HIV cure case studies. “But there is incremental progress being made in terms of our understanding of where the virus hides within the body and potential ways to purge it from those sites.”The HIV cure research field is yet quite young. And it likely never would have ballooned as it has in recent years were it not for the very first successful cure—one that served as a catalyst and guiding light for scientists.  
<h3>A transformative success</h3>During the late 1990s and early 2000s, the HIV research establishment focused the lion’s share of its energy and resources on treatment and prevention of the virus. Actually curing HIV was generally regarded as a distant dream, with only a small set of researchers pursuing such a goal. Then, in 2008, German scientists <a href="https://www.nytimes.com/2008/11/14/health/14hiv.html">announced</a> the first case of what would ultimately be deemed a successful <a href="https://www.nejm.org/doi/full/10.1056/nejmoa0802905">cure of the virus</a>. This proof of concept ignited the field and sent financial investment soaring—to <a href="https://www.avac.org/sites/default/files/resource-files/Global_Investment_HIV_CureResearch_and_Development2020.pdf">$337 million</a> in non–pharmaceutical industry funding in 2020, according to the HIV nonprofit AVAC.Clinicians were able to cure HIV in an American man living in Berlin named Timothy Ray Brown, by exploiting the fact that he had also been diagnosed with acute myeloid leukemia, or AML. This made Brown a candidate for a stem cell (bone marrow) transplant to treat his blood cancer. Brown’s treatment team relied on the existence of a rare genetic abnormality found among people with northern European ancestry. Known as the CCR5-delta32 mutation, it gives rise to immune cells lacking a certain coreceptor called CCR5 on their surface. This is a hook to which HIV typically latches to begin the process of infecting an immune cell and hijacking its machinery to manufacture new copies of the virus. The clinicians found a stem cell donor who was not only a good genetic match for Brown, but who also had the CCR5-delta32 mutation. First they destroyed Brown’s immune system with full-dose chemotherapy and full-body radiation. Then they effectively gave him the donor’s immune system through the stem cell transplant. This cured his HIV by ensuring that any remaining virus in his body was incapable of infecting his new immune cells.
<h3><a href="/wgbh/nova/video/ending-hiv-in-america/">Ending HIV in America</a> (2022)</h3>
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Variations of this method have yielded cures, or likely cures, in four other people during the years since. These cases provide researchers with increasing certainty that it is possible to achieve the ultimate goal: a sterilizing cure, in which the body has been rid of every last copy of virus capable of producing viable new copies of itself. “It was not a given that if you completely replace the immune system, even with a purportedly non-susceptible immune system, that you would cure infection,” says Louis Picker, associate director of the Vaccine and Gene Therapy Institute at the Oregon Health &amp; Science University. “It was possible that HIV could be hiding in non-immune cells, like endothelial cells, and still find targets to infect.” But the small cohort of people who have been cured or likely cured to date, Picker says, “show that’s not the case.”  Nevertheless, these successes have not opened the door to a cure for HIV available to much more than a few of the estimated <a href="https://www.unaids.org/en/resources/fact-sheet">38 million people</a> living with the virus worldwide. Critically, it is unethical to provide such a dangerous and toxic treatment to anyone who does not already qualify for a stem cell transplant to treat blood cancer or another health condition. Brown, for one, nearly died from his treatment. And a number of efforts to repeat his case <a href="https://www.nature.com/articles/nature.2013.14324">have failed</a>.
<h3>Why is HIV so hard to cure?</h3>Highly effective treatment for HIV hit the market in 1996, transforming what was once a death sentence into a manageable health condition. Today, the therapy, a combination of drugs called antiretrovirals, is so safe, tolerable and effective, that it has extended recipients’ life expectancy to <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081355">near normal</a>. But despite the fact that these medications can inhibit viral replication to such a degree that it’s undetectable by standard tests, they cannot eradicate HIV from the body. Standing in the way is what’s known as the HIV reservoir.This <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048589/">viral reservoir</a> is composed in large part of long-lived immune cells that enter a resting, or latent, state. Antiretrovirals only target cells that are actively producing new copies of the virus. So when HIV has infected a cell that is in a non-replicating state, the virus remains under the radar of these medications. Stop the treatment, and at any moment, any of these cells, which <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537114/">clone themselves</a>, can restart their engines and repopulate the body with HIV.
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This phenomenon is why people with HIV typically experience a viral rebound within a few weeks of stopping their antiretrovirals. And it is the reason why, given the harm such viral replication causes the body, those living with HIV must remain on treatment for the virus indefinitely to mitigate the <a href="https://www.nejm.org/doi/full/10.1056/nejmoa062360">deleterious impacts</a> <a href="https://www.nejm.org/doi/full/10.1056/nejmoa1506816">of the infection</a>.“A key new advance is the finding that those cells which harbor the virus seem resistant to dying, a problem with cancer cells,” HIV cure researcher Steven Deeks, a professor of medicine at University of California, San Francisco, says of the viral reservoir. “We will be leveraging new cancer therapies aimed at targeting these resilient, hard-to-kill cells.”
<h3>Follow-up acts</h3>Brown stood alone on his pedestal for over a decade. Then, at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, researchers announced two new case studies of men with blood cancer and HIV who had received treatments similar to Brown’s. The men, known as the <a href="https://www.croiconference.org/abstract/analytic-treatment-interruption-ati-after-allogeneic-ccr5-d32-hsct-aml-2013">Düsseldorf</a> and <a href="https://www.pbs.org/wgbh/nova/article/second-patient-has-entered-long-term-remission-hiv/">London patients</a>, were treated for Hodgkin lymphoma and AML, respectively. By the time of the conference, both had spent extended periods off of antiretroviral treatment without a viral rebound. To this day, neither man has experienced a viral rebound—leading the authors of the London and Düsseldorf case studies recently to assert that they are “definitely” and “almost definitely” cured, respectively.In February 2022, a team of researchers reported at CROI, held virtually, the first possible case of an HIV cure in a woman. The treatment she received for her leukemia represented an important scientific advance.Called a <a href="https://pubmed.ncbi.nlm.nih.gov/27788764/">haplo-cord transplant</a>, this <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595267/">cutting-edge approach</a> to treating blood cancer was developed to compensate for the difficulty of finding a close genetic match in the stem cell donor–which is traditionally needed to provide the best chance that the stem cell transplant will work properly. Such an effort is made even more challenging when attempting to cure HIV, because the CCR5-delta32 mutation is so rare. The American woman received a transplant of umbilical cord blood from a baby, who had the genetic mutation, followed by a transplant of stem cells from an adult, who did not. While each donor was only a partial match, the combination of the two transplants was meant to compensate for this less-than-ideal scenario. The result was the successful blooming of a new, HIV-resistant immune system.The authors of the woman’s case study, including Weill Cornell’s Marshall Glesby, estimate that this new method could expand the number of candidates for HIV cure treatment to about 50 per year. 
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<img alt="Close-up of green, purple, and red pills scattered on a countertop" class="richtext-image full-width" src="https://www.pbs.org/wgbh/nova/media/images/HIV_antiretrovirals.width-990.jpg"/>
<figcaption>A variety of antiretroviral drugs used to treat HIV infection. Image Credit: NIAID, Flickr
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In July, at the International AIDS Conference in Montreal, researchers announced the case of a fifth person possibly cured of HIV. Diagnosed with the virus in 1988 and 63 years old at the time of his stem cell transplant three years ago, the American man is the oldest to have achieved potential success with such a treatment and the one living with the virus for the longest. Because of his age, he received reduced intensity chemotherapy to treat his AML. Promisingly, he still beat both the cancer and the virus. The lead author of this man’s case study, Jana K. Dickter, an associate clinical professor of infectious disease at City of Hope in Duarte, California, says that such cases provide a guide for researchers. “If we are able to successfully modify the CCR5 receptors from T cells for people living with HIV,” she says, “then there is a possibility we can cure a person from their HIV infection.” Scientists also know of two women whose own immune systems, in an extraordinary feat, appear to have cured them of HIV. Both are among the approximately 1 in 200 people with HIV, known as elite controllers, whose immune systems are able to suppress replication of the virus to low levels without antiretroviral treatment. <a href="https://www.acpjournals.org/doi/10.7326/L21-0297">Researchers believe</a> that these women’s immune systems managed to <a href="https://www.nature.com/articles/s41586-020-2651-8">preferentially eliminate</a> immune cells infected with viral DNA capable of producing viable new virus, ultimately succeeding in eradicating every last such copy.
<h3>The search for the holy grail</h3>As they seek safer and more broadly applicable therapeutic options than the stem cell transplant approach, HIV cure researchers are pursuing a variety of avenues.Some investigators are developing genetic treatments in which, for example, they attempt to edit an individual’s own immune cells to make them <a href="https://www.croiconference.org/abstract/delayed-viral-rebound-during-ati-after-infusion-ccr5-zfn-treated-cd4-t-cells/">lack the CCR5 coreceptor</a>. “The science that I am particularly excited about and that we and others are working on is to make this treatment as an in vivo deliverable therapy that would not rely on transplant centers and could ultimately be given in an outpatient setting,” says Hans-Peter Kiem, director of the stem cell and gene therapy program at the Fred Hutchinson Cancer Center in Seattle.Then there is what’s known as the <a href="https://www.science.org/doi/10.1126/scitranslmed.abl3836">“shock and kill”</a> method, in which drugs are used to flush the virus from the reservoir and other treatments are then used to kill off the infected cells. Conversely, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019976/">“block and lock”</a> attempts to freeze the reservoir cells in a latent state for good. Researchers are also developing <a href="https://hivinfo.nih.gov/understanding-hiv/fact-sheets/what-therapeutic-hiv-vaccine">therapeutic vaccines</a> that would augment the immune response to the virus. “Progress will be incremental and slow,” Picker predicts, “unless there is a discovery from left field—an unpredictable advance that revolutionizes the field. I do think it will happen. My personal goal is to be a very good left fielder.”Correction: Dr. Glesby's quote in the fourth paragraph was initially published with a typo, saying "track" instead of "crack."This reporting was supported by the Global Health Reporting Center.
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Scientists have cured a handful of people of HIV by piggybacking on treatments they received for blood cancer. But does that bring a widespread cure any closer?

A hand in white latex glove adjusts two rows of rapid malaria tests on a tabletop

Blood tests designed to detect the presence of the malaria parasite Plasmodium falciparum, in Tak, Thailand in 2004. Image Credit: Thierry Falise, Getty Images

Malaria is outsmarting blood tests. Can a breath test help?

Since 2010, a biological drama has been playing out in the bloodstreams of humans from Peru to Ethiopia. Plasmodium falciparum, the parasite that causes the most common form of malaria, has managed to evolve away from the tests humans created to track it. These tests look a bit like the rapid antigen tests that have been deployed during the COVID-19 pandemic. “You put a little blood sample on them, and you get one or two lines,” explains parasitologist Audrey John. The tests are especially valuable in areas where lots of people come to hospitals or clinics with fevers, but only some of them have malaria. They make it possible for doctors to easily recognize malaria patients, so that only those <a href="/wgbh/nova/article/malaria-resistance-nigeria/">who need medication</a> receive it—and quickly.
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But there’s a problem: These tests work by detecting the presence of histidine-rich protein 2 (HRP2), a substance that the malaria parasite makes and disgorges as part of its metabolic process. Unfortunately, that protein isn’t strictly necessary for the parasite’s replication or transmission. The consequence is that, by helping doctors zero in on that protein, the tests inadvertently act as an evolutionary pressure. Any parasites that, by random mutation, don’t emit HRP2 pass under the radar. Their hosts are less likely to receive treatment, and the parasites live to fight another day.About a decade ago, scientists started to identify cases of malaria in Peru, then in India and East Africa, involving parasites that didn’t produce HRP2 and therefore generated false negatives on malaria tests. According to the <a href="https://www.who.int/news-room/feature-stories/detail/world-malaria-report-2019">World Health Organization</a>, of the 228 million cases of malaria in 2018, 93% were in Africa, and P. falciparum caused 99.7% of those infections, making the appearance of the mutation a big deal. The trend is strongest in places with comparatively few malaria cases and where sick people are likely to get treatment, John says. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411324/pdf/BLT.20.250621.pdf/">A review of world malaria studies</a> found that the mutant parasites had been reported from all major malaria-endemic areas. And while there are gaps in the data, analysis of multiple studies suggests that in parts of Eritrea, Ghana, Sudan, Nicaragua, and Peru, at least 20% of malaria cases may be caused by parasites that no longer make the protein, with numbers higher than 80% in some pockets.A <a href="https://elifesciences.org/articles/25008">2017 study</a> modeling the spread of the mutation in sub-Saharan Africa suggested that in many areas HRP2 tests will no longer be useful by 2030. “This is a total ‘Jurassic Park’ story,” John says. “Life finds a way.” In response, she and her team are working on a novel solution: a breathalyzer for malaria.Healthy human breath contains some 1,900 volatile organic compounds (VOCs). Generally speaking, VOCs are carbon-based molecules that drift around in the air, often shed from surfaces. They are what our noses pick up on when we smell a scent. The VOCs in human breath are emitted by the body as it functions—or by the menagerie of bacteria that call that body home—and become airborne when they rocket out of our lungs along with exhaled carbon dioxide. The membranes in our lung alveoli are extraordinarily thin, which allows oxygen in and carbon dioxide out of the bloodstream, and that provides an opportunity for these VOCs to escape as well. It is perhaps unsurprising that exhaled breath can include VOCs produced by (or in response to) the microbes that cause respiratory infections like tuberculosis and influenza, which burrow into the tissue around the alveoli. But studies also indicate that breath can include VOCs originating from microbes in other parts of the body, as those waste compounds make their way into the bloodstream and pass through the lungs.
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Since 2015, John and several colleagues have been running studies in Malawi and Kenya searching the breath of children with malaria for a so-called “breathprint” of the disease, a pattern of VOCs that can serve as a telltale sign that parasites are at work and the body is responding. They identified six compounds, four of which often form part of human breath but appear to shift in concentration in the presence of malaria. Hunting for those VOCs in specific combinations and concentrations, they were able to successfully diagnose malaria with 83% accuracy. (Remarkably, the other two VOCs are “terpenes,” a compound produced by P. falciparum. Terpenes are similar to chemicals given off by plants that the parasites’ mosquito hosts like to visit for nectar. That means the parasites are hijacking their human hosts’ biology to manufacture a chemical invitation to the mosquito that ferries the parasite from one human to another.)With the breathprint biomarkers established, the next challenge is designing a breathalyzer component known as an “electronic nose” to sniff out this complicated signature. “A breathalyzer for alcohol is really only trying to detect one thing—one thing that’s very rarely in your breath unless you’re drinking,” John says. It’s much more difficult to detect specific shifts in the concentration of multiple compounds, some of which are already there to begin with.  Still, John remains optimistic, in part because the COVID-19 pandemic has given the project extra momentum. Since she and her team already had a pipeline in place for a disease breathalyzer, it made sense to apply that principle for COVID, she says. Working with children coming to their emergency room, John and her colleagues at Children’s Hospital of Philadelphia set up a pilot study to find a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743102.1/">breathprint for juvenile COVID-19</a>. They ultimately settled on a set of biomarkers that allowed them to detect the virus with close to 90% accuracy. Both a COVID breathalyzer and its malaria-detecting cousin would contain material that can bind to the telltale sets of VOCs and change the resistance of a circuit, plus a little computer that can read the activity on that circuit. With that concept in place and the data in the process of validation, the next step is trying out a trial device in a real-world setting and comparing it to tests whose performance we already trust, John says. She also hopes to continue investigating new breathprints, starting with Plasmodium vivax malaria (the second most common type) and asymptomatic malaria, which is notoriously difficult to diagnose.All that requires more funding. But John hopes the technology needed for these tests could develop in tandem, with each project building on the other’s successes. With the pandemic raging on, “a lot more people are interested in screening for COVID than treating malaria,” she says. But all over the world, in the bloodstream of millions, life continues to find a way.
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A parasite that causes the most common form of malaria is evolving to be undetectable by current tests. Some scientists want to zero in on compounds in patients’ breath instead.

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