Front and center for this week’s jaunt into space is one of the most interesting—and possibly habitable—moons of our solar system. As the largest moon of Saturn, Titan measures about 3,200 miles in diameter, bigger than our own moon (which is a little over 2,000 miles wide). It’s covered in a thick atmosphere of clouds and haze that likely condenses onto the surface—and there might be organic compounds within.

So let us have a look at Titan like we’ve never seen before, thanks to the Cassini spacecraft’s Visual and Infrared Mapping Spectrometer. Earlier views were hampered by variations in resolution and lighting that reduced the surface clarity. (Blame tiny particles in the moon’s atmosphere called aerosols for scattering visible light.) But now astronomers are now able to peer below the clouds of Titan in the infrared spectrum, along with combining 13 years of image data—the entire length of time that NASA’s Cassini was in orbit.

It gets better. Titan has lakes and rivers, but unlike the lakes and rivers on Earth that are filled with actual water, Titan’s are made up of liquid methane and ethane. Scientists are still studying the provenance of these liquids and how they remain stable. Here’s a hint: Titan’s surface is a stone-cold -290 degrees Fahrenheit.

So put on a Mylar sweater, bring some oxygen, and enjoy pioneering to Titan!

Once you’re done dipping into a dwarf planet and beholding a nebula, peruse Wired’s full collection of space photos here.

This story was originally published by The Guardian and is reproduced here as part of the Climate Desk collaboration.

Greta Thunberg cut a frail and lonely figure when she started a school strike for the climate outside the Swedish parliament building last August. Her parents tried to dissuade her. Classmates declined to join. Passersby expressed pity and bemusement at the sight of the then unknown 15-year-old sitting on the cobblestones with a hand-painted banner.

Eight months on, the picture could not be more different. The pigtailed teenager is feted across the world as a model of determination, inspiration, and positive action. National presidents and corporate executives line up to be criticized by her, face to face. Her Skolstrejk för Klimatet (school strike for climate) banner has been translated into dozens of languages. And, most striking of all, the loner is now anything but alone.

On March 15, when she returns to the cobblestones (as she has done almost every Friday in rain, sun, ice and snow), it will be as a figurehead for a vast and growing movement. The global climate strike this Friday is gearing up to be one of the biggest environmental protests the world has ever seen. As it approaches, Thunberg is clearly excited.

“It’s amazing,” she says. “It’s more than 71 countries and more than 700 places, and counting. It’s increasing very much now, and that’s very, very fun.”

A year ago, this was unimaginable. Back then, Thunberg was a painfully introverted, slightly built nobody, waking at 6 am to prepare for school and heading back home at 3 pm. “Nothing really was happening in my life,” she recalls. “I have always been that girl in the back who doesn’t say anything. I thought I couldn’t make a difference because I was too small.”

She was never quite like the other kids. Her mother, Malena Ernman, is one of Sweden’s most celebrated opera singers. Her father, Svante Thunberg, is an actor and author (named after Svante Arrhenius, the Nobel Prize–winning scientist who in 1896 first calculated how carbon dioxide emissions could lead to the greenhouse effect). Greta was exceptionally bright. Four years ago, she was diagnosed with Asperger’s.

“I overthink. Some people can just let things go, but I can’t, especially if there’s something that worries me or makes me sad. I remember when I was younger, and in school, our teachers showed us films of plastic in the ocean, starving polar bears and so on. I cried through all the movies. My classmates were concerned when they watched the film, but when it stopped, they started thinking about other things. I couldn’t do that. Those pictures were stuck in my head.”

She has come to accept this as part of who she is—and made it a motivating force instead of a source of paralyzing depression, which it once was.

At about the age of 8, when she first learned about climate change, she was shocked that adults did not appear to be taking the issue seriously. It was not the only reason she became depressed a few years later, but it was a significant factor.

“I kept thinking about it, and I just wondered if I am going to have a future. And I kept that to myself because I’m not very much of a talker, and that wasn’t healthy. I became very depressed and stopped going to school. When I was home, my parents took care of me, and we started talking because we had nothing else to do. And then I told them about my worries and concerns about the climate crisis and the environment. And it felt good to just get that off my chest.

“They just told me everything will be all right. That didn’t help, of course, but it was good to talk. And then I kept on going, talking about this all the time and showing my parents pictures, graphs and films, articles and reports. And, after a while, they started listening to what I actually said. That’s when I kind of realized I could make a difference. And how I got out of that depression was that I thought: It is just a waste of time feeling this way because I can do so much good with my life. I am trying to do that still now.”


The WIRED Guide to Climate Change

Her parents were the guinea pigs. She discovered she had remarkable powers of persuasion, and her mother gave up flying, which had a severe impact on her career. Her father became a vegetarian. As well as feeling relieved by the transformation of their formerly quiet and morose daughter, they say they were persuaded by her reasoning. “Over the years, I ran out of arguments,” says her father. “She kept showing us documentaries, and we read books together. Before that, I really didn’t have a clue. I thought we had the climate issue sorted,” he says. “She changed us and now she is changing a great many other people. There was no hint of this in her childhood. It’s unbelievable. If this can happen, anything can happen.”

The climate strike was inspired by students in Parkland, Florida, who walked out of classes in protest against the US gun laws that enabled the massacre on their campus. Greta was part of a group that wanted to do something similar to raise awareness about climate change, but they couldn’t agree what. Last summer, after a record heat wave in northern Europe and forest fires that ravaged swathes of Swedish land up to the Arctic, Thunberg decided to go it alone. Day one was August 20, 2018.

“I painted the sign on a piece of wood and, for the flyers, wrote down some facts I thought everyone should know. And then I took my bike to the Parliament and just sat there,” she recalls. “The first day, I sat alone from about 8:30 am to 3 pm—the regular school day. And then on the second day, people started joining me. After that, there were people there all the time.”

She kept her promise to strike every day until the Swedish national elections. Afterward, she agreed to make a speech in front of thousands at a People’s Climate March rally. Her parents were reluctant. Knowing Thunberg had been so reticent that she had previously been diagnosed with selective mutism, they tried to talk her out of it. But the teenager was determined. “In some cases where I am really passionate, I will not change my mind,” she says. Despite her family’s concerns, she delivered the address in nearly flawless English and invited the crowd to film her on their mobile phones and spread the message through social media. “I cried,” says her proud dad.

People with selective mutism have a tendency to worry more than others. Thunberg has since weaponized this in meetings with political leaders and with billionaire entrepreneurs in Davos. “I don’t want you to be hopeful. I want you to panic. I want you to feel the fear I feel every day. And then I want you to act,” she told them.

Such tongue-lashings have gone down well. Many politicians laud her candidness. In return, she listens to their claims that stronger climate policies are unrealistic unless the public make the issue more of a priority. She is unconvinced. “They are still not doing anything. So I don’t know really why they are supporting us, because we are criticizing them. It’s kind of weird.” She has also been withering about leaders in the US, UK, and Australia who either ignore the strikers or admonish them for skipping classes. “They are desperately trying to change the subject whenever the school strikes come up. They know they can’t win this fight because they haven’t done anything.”

Such blunt talk has found a broad audience among people jaded by empty promises and eager to find a climate leader willing to ramp up ambition. Thunberg’s rise coincides with growing scientific concern. A slew of recent reports has warned that oceans are heating and the poles melting faster than expected. Last year’s UN Intergovernmental Panel on Climate Change spelled out the dangers of surpassing 1.5 degrees Celsius of global warming. To have any chance of avoiding that outcome, it said, emissions must fall rapidly by 2030. That will require far more pressure on politicians—and nobody has proved more effective at that over the past eight months than Thunberg.

The girl who once slipped into despair is now a beacon of hope. One after another, veteran campaigners and grizzled scientists have described her as the best news for the climate movement in decades. She has been lauded at the UN, met French president Emmanuel Macron, shared a podium with the European Commission president Jean-Claude Juncker, and has been endorsed by the German chancellor, Angela Merkel.

You may think this would put the weight of the world on the 16-year-old’s shoulders, but she claims to feel no pressure. If “people are so desperate for hope,” she says, that is not her or the other strikers’ responsibility.

“I don’t care if what I’m doing—what we’re doing—is hopeful. We need to do it anyway. Even if there’s no hope left and everything is hopeless, we must do what we can.”

In this regard, her family sees her singular focus as a blessing. She is someone who strips away social distractions and focuses with black-and-white clarity on the issues. “It’s nothing that I want to change about me,” she says. “It’s just who I am. If I had been just like everyone else and been social, then I would have just tried to start an organization. But I couldn’t do that. I’m not very good with people, so I did something myself instead.”

While she has little time for chitchat, she gets satisfaction from speaking to a big audience about climate change. Regardless of the size of the crowd, she says she does not feel the least bit nervous.

She seems incapable of the cognitive dissonance that allows other people to lament what is happening to the climate one minute, then tuck into a steak, buy a car, or fly off for a weekend break the next. Although Thunberg believes political action far outweighs individual changes to consumer habits, she lives her values. She is a vegan and only travels abroad by train.

At its best, this sharpness can slice through the Gordian knot of the climate debate. It can also sting. There are no comfortable reassurances in her speech, just a steady frankness. Asked whether she has become more optimistic because the climate issue has risen up the political agenda and politicians in the US and Europe are considering green New Deals that would ramp up the transition to renewable energy, her reply is brutally honest. “No, I am not more hopeful than when I started. The emissions are increasing, and that is the only thing that matters. I think that needs to be our focus. We cannot talk about anything else.”

Some people consider this a threat. A handful of fossil fuel lobbyists, politicians, and journalists have argued Thunberg is not what she seems—that she was propelled into prominence by environmental groups and sustainable-business interests. They say the entrepreneur who first tweeted about the climate strike, Ingmar Rentzhog, used Thunberg’s name to raise investment for his company, but her father says the connection was overblown. Greta, he says, initiated the strike before anyone in the family had heard of Rentzhog. As soon as she found he had used her name without her permission, she cut all links with the company and has since vowed never to be associated with commercial interests. Her family says she has never been paid for her activities. In a recent interview, Rentzhog defended his actions, denied exploiting Greta, and said that climate change, not profit, was his motive.

On social media, there have been other crude attacks on Thunberg’s reputation and appearance. Already familiar with bullying from school, she appears unfazed. “I expected when I started that if this is going to become big, then there will be a lot of hate,” she says. “It’s a positive sign. I think that must be because they see us as a threat. That means that something has changed in the debate, and we are making a difference.”

She intends to strike outside parliament every Friday until the Swedish government’s policies are in line with the Paris climate agreement. This has led to what she calls “strange contrasts”: balancing her math homework with her fight to save the planet; listening attentively to teachers and decrying the immaturity of world leaders; weighing up the existential threat of climate change alongside the agonizing choice of what subjects to study in high school.

It can be grueling. She still rises at 6 am to get ready for school. Interviews and writing speeches can leave her working 12- to 15-hour days. “Of course, it takes a lot of energy. I don’t have much spare time. But I just keep reminding myself why I am doing this, and then I just try to do as much as I can.” So far, this does not appear to have affected her academic performance. She keeps up with homework and is in the top five in her class, according to her father.

And now that she is active on climate change, she is no longer lonely, no longer silent, no longer so depressed. She is too busy trying to make a difference. And enjoying herself.

This Friday, when she takes her usual spot outside the Swedish Parliament, she will be joined by classmates and students from other schools. “It’s going to be very, very big internationally, with hundreds of thousands of children going to strike from school to say that we aren’t going to accept this anymore,” she says. “I think we are only seeing the beginning. I think that change is on the horizon and the people will stand up for their future.”

And then the activist slips back into being a teenager. “I’m looking forward to it and to see all the pictures the day afterwards. It’s going to be fun.”


Sean Parker, Napster cofounder


Alex Marson, biologist and infectious disease doctor at UC San Francisco

When Sean Parker was young, he cofounded Napster and changed the way we listen to music. In his twenties, he helped jump-start Facebook and changed the way we interact with each other. Now, at age 38, he’s set on changing something else: the way we treat disease. The Parker Institute for Cancer Immunotherapy, which he founded in 2016, has dedicated $250 million toward using new technologies like Crispr to teach the human body to vanquish cancer. Alex Marson is a scientist building the tools to do just that. His research at UC San Francisco and the Parker Institute rejiggers the DNA of T cells—your immune system’s sentinels—to better recognize and attack malignant mutineers. Parker and Marson sat down to talk about Crispr, genome editing, and the most exciting coding language today: DNA. —Megan Molteni

Sean Parker: I first learned about the therapeutic potential of Crispr a few years ago, and back then it really only allowed us to remove a gene or prevent it from functioning. The ability to completely reprogram a cell’s functions seemed like an ambitious, distant possibility.

Alex Marson: Yeah, for the past few years we could only use Crispr to make cuts inside of cells and snip away portions of DNA. But now we have a paste function. We showed in a Nature paper in July that if we mix our Crispr components in just the right recipe, we can zap the T cells with a bit of electricity to send in the genome-editing machinery. Then we can make edits that are about 750 nucleotides long at multiple sites, which starts to give us enough flexibility and real estate to give cells dramatic new functions. We’re now able to paste in a new T cell receptor, which is designed to recognize an antigen found on some cancer cells, giving us T cells that attack only the cells that carry that signal.

Parker: This was total science fiction up until very recently! But because of your breakthrough, we can now get into the source code and fundamentally alter the capabilities of not just T cells but any cell type. When I first started reading wired in the 1990s, one of the big ideas was that nanotechnology was going to cure all diseases with little silicon-based robots circulating in our bloodstream. Twenty years later it turns out those tiny machines are actually cells taken from our own bodies, reprogrammed, and put back in.

Alex Marson

Path not taken:
Culinary school

Marson: You’re making me realize that what I’m really trying to do in the lab is create tools that make a more flexible programming system for the field more broadly. That’s what Crispr has the potential to offer: to make it easier to write new code in the language of genetics.

Parker: You know, the advice I would give young people today is not to go into computer science; a much more exciting place to be is the world of biology. It’s going through the same kind of transformation right now that occurred in information technology 20 years ago.

This article appears in the October issue. Subscribe now.

MORE FROM WIRED@25: 1998-2003

  • Editor's Letter: Tech has turned the world upside down. Who will shake up the next 25 years?
  • Opening essay by Kevin Kelly: How the internet gave all of us superpowers
  • Melinda Gates and Shivani Siroya: Giving (micro)credit
  • Peter Thiel and Palmer Luckey: Remaking reality
  • Jill Tarter and Margaret Turnbull: The E.T. hunters
  • Marc Benioff and Boyan Slat: Betting on a cleaner ocean

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WIRED is turning 25! We are celebrating in San Francisco this October with four days of events honoring the ideas, innovations, and icons who have shaped the world we know today—and those who will shape it for the 25 years to come.

Not for the first time this year, Californians this week donned face masks to protect their lungs from the harmful airborne particles that have smothered the state in a sickly, sooty haze. The pollutants are products of three devastating infernos raging hundreds of miles apart, the largest of which, Butte County's Camp Fire, has swelled to become the deadliest and most destructive in state history. They join the more than 7,500 California wildfires that have this year consumed nearly 1.7-million acres of land—more than any fire season on record. The increasing intensity of California's blazes has many residents of the Golden State wondering: Is the smoke from wildfires also getting worse?


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That's a complicated question. On one hand, data suggests California's fires are burning hotter and consuming more land than they did in the past. "If you use intensity as a proxy for pollution—that is, if you assume stronger fires will produce more emissions like smoke—then by dint of that, yes, there ought to be more smoke," says atmospheric composition scientist Mark Parrington.

A senior researcher at the Copernicus Atmosphere Monitoring Service, Parrington tracks wildfires around the world to better understand their effect on pollution and public health. Most mornings he's in his office by 8 am, downloading the previous 24 hours' worth of fire data from a supercomputer operated by the European Center for Medium-Range Weather Forecasts. The data—thermal infrared radiation measurements from NASA's MODIS instrument—allow him to estimate the intensity of fires burning around the world; how many emissions (like lung-aggravating aerosols and greenhouse gasses like carbon dioxide) they're pumping into the atmosphere; and how those emissions affect global air quality. From his office in Reading, just west of London, he's kept closer tabs on California's current wildfires than most. "You really don't expect to see emissions of this magnitude, this late in the year," Parrington says. "Even on a global scale, it really stood out."

Parrington also compares each day's emissions data to past measurements, which is how he knows that California's current wildfires have pumped more schmutz into the atmosphere than any November blazes on record. In fact, this year's California wildfires have produced more emissions than all but 13 of the past 16 years. "It's not just the Camp Fire, but the wildfires from this summer," Parrington says. "The Carr Fire, the Mendocino Complex Fire—they've been devastating." If the state sees any major wildfires in December (the way it did in 2017), 2018 could become the year with the highest emissions ever recorded for California.

And yet, the question of whether smoke is getting worse is more complicated than many people realize. That's because smoke itself is pretty complex. For starters, it contains well beyond the 40 different "pyrogenic species" Parrington says his analyses account for, which include various forms of carbon, and toxic aromatic compounds like benzene and toluene. The relative and absolute quantities of said species can vary considerably, based on the conditions of the burn—like whether it's wet, dry, or has burned in the past. "All of these factors contribute to how much of those fire emissions get turned into smoke and how the pollutants interact with each other," Parrington says.

Determining how much smoke is actually in the atmosphere, let alone entering people's lungs, is also challenging. Parrington says it requires understanding how smoke interacts with large scale weather conditions like wind, ground temperature, air temperature, and cloud cover. In the Bay Area, for instance, high pressure atmospheric systems tend to produce inversion layers that, like a lid on a shallow pan, keep smoky air close to the ground. Determining the region's air quality has to do not just with the absolute quantity of smoke, but how much of it is is trapped at ground level.

There's also fuel sources to consider, variations in which produce different kinds of smoke. "The fact that more fires are happening at the wildland urban interface means that fires are encountering new materials," says Jessica McCarty, a geographer at Miami University specializing in fire-related air pollution.

When it comes to fuel, McCarty says, fires are agnostic. If it's hot enough, it doesn't care if it's a tree, a house, or your car. But as a rule of thumb, the emissions emanating from a burning shrub are less caustic than those of a burning Subaru. "Wood is far from clean, but it's nothing compared to something like burning rubber, which is downright toxic," McCarty says. Which is why, as people build deeper and deeper into wildland areas, the relevant question isn't just how much pollution these fires producing, but what kind of pollution they're producing.

Answers to both questions, Parrington says, could be found in computational systems like the Copernicus Atmosphere Monitoring service, which is capable of taking many of these variables into account and synthesizing the data across multiples wildfire seasons. CAMs has only been operational for three years, but the data it collects is openly available to scientists around the world who are increasingly interested in nuanced questions about wildland smoke.

For residents of California, answers to those questions can't come soon enough. In the meantime, hang on to any extra air masks you have lying around—there's no telling when you might need them again.

Today, cannabis continues its slow march toward nationwide decriminalization with voters deciding whether to allow recreational use in Michigan and North Dakota, and for medical purposes in Utah and Missouri. As states keep chipping away at federal prohibition, more consumers will gain access, sure—but so will more researchers who can more easily study this astonishingly complex and still mysterious plant.

At the top of the list of mysteries is how a galaxy of compounds in the plant combine to produce a galaxy of medical (and, of course, recreational) effects. For example, THC feels different when combined it with cannabidiol, or CBD, another naturally occurring compound in cannabis, but the reasons aren’t fully known. It’s called the entourage effect: THC, like a rock star, only reaches its full potential when it rolls with a crew, consisting of hundreds of other compounds in the plant that scientists know about so far.

But the problem with researching a schedule I drug is that the government doesn’t want you to do it. Yet as more states go legal, cannabis continues to climb out of the scientific dark ages. Because it’s not just about giving people a comfortable high, but about developing cannabis into drugs that could treat a massive range of ills.

First, some cannabis basics. THC and CBD are cannabinoids, which means they bind to receptors in the human body’s endocannabinoid system, specifically the CB1 and CB2 receptors. Researchers only discovered the endocannabinoid system in the early 1990s, but it appears to regulate things like mood and immune function.

You may have noticed that cannabis’ effects can differ wildly from experience to experience. Eat a weed brownie, for instance, and the THC goes straight to your liver, where it’s metabolized into 11-hydroxy-THC. That metabolite “has five times the activity at the CB1 receptor, the psychoactive one, as THC itself,” says Jeff Raber, CEO of the Werc Shop, a cannabis lab in California.

That’s why it’s so easy to overdo it with edibles. When you smoke cannabis, the THC at first skips the liver and goes straight to your bloodstream. It’s about five times less potent that way than if you eat cannabis, meaning that chowing down on 10 milligrams of THC is roughly equal to smoking 50 milligrams of the stuff.

Mode of ingestion, then, is a big consideration in the cannabis experience. But so too are factors beyond your control. “We're pretty aware that the endocannabinoid system is not a static picture throughout the day,” says Raber. “Why it changes, what causes those changes—those are other levels of complicated questions.” Cannabis might hit you differently during the day than at night, and can also depend on your mood or whether you’ve eaten.

But that’s not all. THC also interacts with other cannabinoids in your system, and it has a complicated relationship with CBD in particular. Anecdotally, cannabis users have reported that CBD can modulate the psychoactive effects of THC—think of it sort of like an antidote to the paranoia and anxiety that comes with being too high. That might be part of the reason edibles can feel so powerful: If you eat a brownie loaded with just THC, you aren’t getting the CBD you would if you smoked regular old flower. (Not that some manufacturers aren’t also adding CBD to their edibles. CBD is so hot right now, but it's hard to find flower with high CBD. Cultivators have over the decades bred highly intoxicating, THC-rich strains at the expense of CBD.)

With cannabis growing more legitimate as a medicine, researchers are finally putting hard data to these anecdotal reports. They’re beginning to understand how CBD might modulate the often unwelcome effects of THC.

Consider the drug Marinol, a synthetic form of THC available since the 1980s. It’s a good appetite stimulant, but it’s also good at getting patients high and paranoid. “When you just stimulate the CB1 receptor with this pure molecule, it's very intoxicating and patients don't tolerate it very well,” says Adie Wilson-Poe, who researches cannabis for pain management at Washington University in St. Louis.

However, give patients a drug like Sativex—which combines THC with CBD—or even pure cannabis flower or extracts, and they tolerate it much better. “We specifically see that CBD protects against the paranoia and anxiety and the racing heart that THC produces,” Wilson-Poe says.

It all comes back to the psychoactive CB1 receptor. THC is an agonist that fits nicely into CB1, activating it. “CBD can't do that at the CB1, but it does sort of sit in the pocket,” says Wilson-Poe. “It can compete with THC for the spot in the receptor.” Which means that if you take CBD with THC, there may be fewer receptors available for the THC to activate, thus modulating the psychoactive effects, like paranoia.

“But that's probably not the whole story,” Wilson-Poe says, “because CBD has at least 14 distinct mechanisms of action in the central nervous system. So it does a little bit of something at a whole bunch of places, and we probably can't attribute the anti-paranoia or anti-anxiety effects just to CB1 occupancy.”

Now let me add yet another complication to our growing list of complications: THC and CBD are far from alone in the cannabis plant when it comes to medicinal properties. Those two might be anti-inflammatory, for instance, “but if you were to vaporize a whole flower, you'd be consuming potentially a couple dozen anti-inflammatory molecules at once,” says Wilson-Poe. “In this sense I think of whole-plant cannabis as like a multivitamin for inflammation.” (Because there are so many important compounds at play, some researchers prefer the term ensemble effect over entourage effect. “Entourage” makes it sound like everything is supporting the rock star that is THC, when the reality might be more nuanced.)

There might also be medical applications when you don’t want the entourage effect at work. One of THC’s more famous treatments, for instance, is for lowering eye pressure to treat glaucoma. “We found that it works, and THC does a nice job,” says Indiana University, Bloomington researcher Alex Straiker, who studies cannabinoids. “But it's actually blocked by CBD. People often think, oh yeah, CBD and THC work together. But in terms of CB1 receptor signaling, they actually oppose each other, or at least CBD opposes THC.” That’s not to say, though, that CBD isn’t having some sort of beneficial effect on its own when it comes to treating glaucoma.

Plus, there are many other kinds of receptors in the endocannabinoid system that these compounds could be targeting. “It's messy,” Straiker says.

So while CBD seems to mitigate the unfun effects of THC, it also might get in the way of certain medical benefits that THC has to offer. But because there’s seemingly no end to the complexities of cannabis, CBD might also enhance THC’s anti-cancer properties. Research has found that if you apply THC and CBD to cancer cells in the lab, the combination is more effective than THC alone at both inhibiting the growth of those cells and outright killing them. The future of medical cannabis, then, depends in large part on teasing apart the entourage effect—leveraging it in some cases, and maybe breaking up the entourage (or ensemble) when THC or CBD alone is most beneficial.

“We need to understand which constellations of plant chemistry are best suited for which indications and which kinds of patients, and which form of the CB1 receptor you happen to carry, because there are lots of mutations in that gene,” says Wilson-Poe. “So understanding these mechanisms is absolutely crucial for providing these patients with personalized medicine that alleviates their symptoms without producing the unwanted side effects.”

Hate to do this, but we’ve got one last problem. For decades, cannabis users have claimed that different strains of cannabis produce different effects—maybe it makes them sleepy, maybe it gives them energy. And that’s been true even as CBD was largely bred out of cannabis in North America in favor of THC. “Well, if they're all high THC, it's got to be from something else,” says Ethan Russo, director of research and development at the International Cannabis and Cannabinoids Institute, who studies the entourage effect. “And that something else is terpenoids.”

Yes, another member of the entourage. Unlike THC and CBD, you can find terpenoids not just in cannabis, but across the plant kingdom. They’re handy little molecules that plants use to ward off insects, and they’re what give cannabis that characteristic smell (same for terpenoids in lemons and pine needles).

And science knows what some terpenoids found in cannabis do pharmacologically in the brain. For example, linalool is one that has sedating and anti-anxiety properties. “So it might make sense that when you combine its anti-anxiety effect with that of cannabidiol [CBD], then they boost each other,” says Russo.

The entourage effect, the ensemble effect—whatever you want to call it, the phenomenon might get more complicated before it gets clearer. But researchers continue to tease apart the chemistry of cannabis, unlocking its true potential as a medicine. Mystery … almost solved.

The theoretical physicist John Wheeler once used the phrase “great smoky dragon” to describe a particle of light going from a source to a photon counter. “The mouth of the dragon is sharp, where it bites the counter. The tail of the dragon is sharp, where the photon starts,” Wheeler wrote. The photon, in other words, has definite reality at the beginning and end. But its state in the middle—the dragon’s body—is nebulous. “What the dragon does or looks like in between we have no right to speak.”

Quanta Magazine


Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

Wheeler was espousing the view that elementary quantum phenomena are not real until observed, a philosophical position called anti-realism. He even designed an experiment to show that if you hold on to realism—in which quantum objects such as photons always have definite, intrinsic properties, a position that encapsulates a more classical view of reality—then one is forced to concede that the future can influence the past. Given the absurdity of backward time-travel, Wheeler’s experiment became an argument for anti-realism at the level of the quantum.

But in May, Rafael Chaves and colleagues at the International Institute of Physics in Natal, Brazil, found a loophole. They showed that Wheeler’s experiment, given certain assumptions, can be explained using a classical model that attributes to a photon an intrinsic nature. They gave the dragon a well-defined body, but one that is hidden from the mathematical formalism of standard quantum mechanics.

Chaves’s team then proposed a twist to Wheeler’s experiment to test the loophole. With unusual alacrity, three teams raced to do the modified experiment. Their results, reported in early June, have shown that a class of classical models that advocate realism cannot make sense of the results. Quantum mechanics may be weird, but it’s still, oddly, the simplest explanation around.

Dragon Trap

Wheeler devised his experiment in 1983 to highlight one of the dominant conceptual conundrums in quantum mechanics: wave-particle duality. Quantum objects seem to act either like particles or waves, but never both at the same time. This feature of quantum mechanics seems to imply that objects have no inherent reality until observed. “Physicists have had to grapple with wave-particle duality as an essential, strange feature of quantum theory for a century,” said David Kaiser, a physicist and historian of science at the Massachusetts Institute of Technology. “The idea pre-dates other quintessentially strange features of quantum theory, such as Heisenberg’s uncertainty principle and Schrödinger’s cat.”

The phenomenon is underscored by a special case of the famous double-slit experiment called the Mach-Zehnder interferometer.

In the experiment, a single photon is fired at a half-silvered mirror, or beam splitter. The photon is either reflected or transmitted with equal probability—and thus can take one of two paths. In this case, the photon will take either path 1 or path 2, and then go on to hit either detector D1 or D2 with equal probability. The photon acts like an indivisible whole, showing us its particle-like nature.

But there’s a twist. At the point where path 1 and path 2 cross, one can add a second beam splitter, which changes things. In this setup, quantum mechanics says that the photon seems to take both paths at once, as a wave would. The two waves come back together at the second beam splitter. The experiment can be set up so that the waves combine constructively—peak to peak, trough to trough—only when they move toward D1. The path toward D2, by contrast, represents destructive interference. In such a setup, the photon will always be found at D1 and never at D2. Here, the photon displays its wavelike nature.

Wheeler’s genius lay in asking: what if we delay the choice of whether to add the second beam splitter? Let’s assume the photon enters the interferometer without the second beam splitter in place. It should act like a particle. One can, however, add the second beam splitter at the very last nanosecond. Both theory and experiment show that the photon, which until then was presumably acting like a particle and would have gone to either D1 or D2, now acts like a wave and goes only to D1. To do so, it had to seemingly be in both paths simultaneously, not one path or the other. In the classical way of thinking, it’s as if the photon went back in time and changed its character from particle to wave.

One way to avoid such retro-causality is to deny the photon any intrinsic reality and argue that the photon becomes real only upon measurement. That way, there is nothing to undo.

Such anti-realism, which is often associated with the Copenhagen interpretation of quantum mechanics, took a theoretical knock with Chaves’s work, at least in the context of this experiment. His team wanted to explain counterintuitive aspects of quantum mechanics using a new set of ideas called causal modeling, which has grown in popularity in the past decade, advocated by computer scientist Judea Pearl and others. Causal modeling involves establishing cause-and-effect relationships between various elements of an experiment. Often when studying correlated events—call them A and B—if one cannot conclusively say that A causes B, or that B causes A, there exists a possibility that a previously unsuspected or “hidden” third event, C, causes both. In such cases, causal modeling can help uncover C.

Chaves and his colleagues Gabriela Lemos and Jacques Pienaar focused on Wheeler’s delayed choice experiment, fully expecting to fail at finding a model with a hidden process that both grants a photon intrinsic reality and also explains its behavior without having to invoke retro-causality. They thought they would prove that the delayed-choice experiment is “super counterintuitive, in the sense that there is no causal model that is able to explain it,” Chaves said.

But they were in for a surprise. The task proved relatively easy. They began by assuming that the photon, immediately after it has crossed the first beam splitter, has an intrinsic state denoted by a “hidden variable.” A hidden variable, in this context, is something that’s absent from standard quantum mechanics but that influences the photon’s behavior in some way. The experimenter then chooses to add or remove the second beam splitter. Causal modeling, which prohibits backward time travel, ensures that the experimenter’s choice cannot influence the past intrinsic state of the photon.

Given the hidden variable, which implies realism, the team then showed that it’s possible to write down rules that use the variable’s value and the presence or absence of the second beam splitter to guide the photon to D1 or D2 in a manner that mimics the predictions of quantum mechanics. Here was a classical, causal, realistic explanation. They had found a new loophole.

This surprised some physicists, said Tim Byrnes, a theoretical quantum physicist at New York University, Shanghai. “What people didn’t really appreciate is that this kind of experiment is susceptible to a classical version that perfectly mimics the experimental results,” Byrnes said. “You could construct a hidden variable theory that didn’t involve quantum mechanics.”

“This was the step zero,” Chaves said. The next step was to figure out how to modify Wheeler’s experiment in such a way that it could distinguish between this classical hidden variable theory and quantum mechanics.

In their modified thought experiment, the full Mach-Zehnder interferometer is intact; the second beam splitter is always present. Instead, two “phase shifts”—one near the beginning of the experiment, one toward the end—serve the role of experimental dials that the researcher can adjust at will.

The net effect of the two phase shifts is to change the relative lengths of the paths. This changes the interference pattern, and with it, the presumed “wavelike” or “particle-like” behavior of the photon. For example, the value of the first phase shift could be such that the photon acts like a particle inside the interferometer, but the second phase shift could force it to act like a wave. The researchers require that the second phase shift is set after the first.

With this setup in place, Chaves’s team came up with a way to distinguish between a classical causal model and quantum mechanics. Say the first phase shift can take one of three values, and the second one of two values. That makes six possible experimental settings in total. They calculated what they expected to see for each of these six settings. Here, the predictions of a classical hidden variable model and standard quantum mechanics differ. They then constructed a formula. The formula takes as its input probabilities calculated from the number of times that photons land on particular detectors (based on the setting of the two phase shifts). If the formula equals zero, the classical causal model can explain the statistics. But if the equation spits out a number greater than zero, then, subject to some constraints on the hidden variable, there’s no classical explanation for the experiment’s outcome.

Chaves teamed up with Fabio Sciarrino, a quantum physicist at the University of Rome La Sapienza, and his colleagues to test the inequality. Simultaneously, two teams in China—one led by Jian-Wei Pan, an experimental physicist at the University of Science and Technology of China (USTC) in Hefei, China, and another by Guang-Can Guo, also at USTC—carried out the experiment.

Each team implemented the scheme slightly differently. Guo’s group stuck to the basics, using an actual Mach-Zehnder interferometer. “It is the one that I would say is actually the closest to Wheeler’s original proposal,” said Howard Wiseman, a theoretical physicist at Griffith University in Brisbane, Australia, who was not part of any team.

But all three showed that the formula is greater than zero with irrefutable statistical significance. They ruled out the classical causal models of the kind that can explain Wheeler’s delayed-choice experiment. The loophole has been closed. “Our experiment has salvaged Wheeler’s famous thought experiment,” Pan said.

Hidden Variables That Remain

Kaiser is impressed by Chaves’s “elegant” theoretical work and the experiments that ensued. “The fact that each of the recent experiments has found clear violations of the new inequality … provides compelling evidence that ‘classical’ models of such systems really do not capture how the world works, even as quantum-mechanical predictions match the latest results beautifully,” he said.

The formula comes with certain assumptions. The biggest one is that the classical hidden variable used in the causal model can take one of two values, encoded in one bit of information. Chaves thinks this is reasonable, since the quantum system—the photon—can also only encode one bit of information. (It either goes in one arm of the interferometer or the other.) “It’s very natural to say that the hidden variable model should also have dimension two,” Chaves said.

But a hidden variable with additional information-carrying capacity can restore the classical causal model’s ability to explain the statistics observed in the modified delayed-choice experiment.

In addition, the most popular hidden variable theory remains unaffected by these experiments. The de Broglie-Bohm theory, a deterministic and realistic alternative to standard quantum mechanics, is perfectly capable of explaining the delayed-choice experiment. In this theory, particles always have positions (which are the hidden variables), and hence have objective reality, but they are guided by a wave. So reality is both wave and particle. The wave goes through both paths, the particle through one or the other. The presence or absence of the second beam splitter affects the wave, which then guides the particle to the detectors—with exactly the same results as standard quantum mechanics.

For Wiseman, the debate over Copenhagen versus de Broglie-Bohm in the context of the delayed-choice experiment is far from settled. “So in Copenhagen, there is no strange inversion of time precisely because we have no right to say anything about the photon’s past,” he wrote in an email. “In de Broglie-Bohm there is a reality independent of our knowledge, but there is no problem as there is no inversion—there is a unique causal (forward in time) description of everything.”

Kaiser, even as he lauds the efforts so far, wants to take things further. In current experiments, the choice of whether or not to add the second phase shift or the second beam splitter in the classic delayed-choice experiment was being made by a quantum random-number generator. But what’s being tested in these experiments is quantum mechanics itself, so there’s a whiff of circularity. “It would be helpful to check whether the experimental results remain consistent, even under complementary experimental designs that relied on entirely different sources of randomness,” Kaiser said.

To this end, Kaiser and his colleagues have built such a source of randomness using photons coming from distant quasars, some from more than halfway across the universe. The photons were collected with a one-meter telescope at the Table Mountain Observatory in California. If a photon had a wavelength less than a certain threshold value, the random number generator spit out a 0, otherwise a 1. In principle, this bit can be used to randomly choose the experimental settings. If the results continue to support Wheeler’s original argument, then “it gives us yet another reason to say that wave-particle duality is not going to be explained away by some classical physics explanation,” Kaiser said. “The range of conceptual alternatives to quantum mechanics has again been shrunk, been pushed back into a corner. That’s really what we are after.”

For now, the dragon’s body, which for a brief few weeks had come into focus, has gone back to being smoky and indistinct.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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On an uncommonly cold and gray Thursday in Los Angeles, in an empty alleyway outside her studio in Chinatown, Marawa Ibrahim—aka Marawa the Amazing—is preparing to spin what appears to be about 30 sparkly Hula-Hoops.

It looks like a preposterous number of Hula-Hoops, to most people anyway. But for Marawa, a virtuosic performance artist with a bachelor's degree from Australia's National Institute of Circus Arts and more than one hoop-related world record to her name, it's a warm-up.

The rings, each of which has been hand-wrapped in expensive glitter tape, start out stacked in a column. Marawa, who is wearing a leopard-print unitard, stands at their center. She scoops them up, presses them against the small of her back, and tips them over her head before leveling them before her, parallel to the ground. (Tilting the hoops like this is a habit, she says, like a basketball player's free-throw ritual.) With her feet planted wide, she twists her torso first to the right, then quickly to the left while setting the hoops in counterclockwise motion with her right hand.

The hoops are spinning now. With her arms straight above her head, her frame undulating like a vertical sine wave, they start to distribute themselves along cross sections of her body spanning from her shoulders to her knees. They loop around together at first, then shift slowly out of phase to form a spirographic pattern Marawa calls "skirting," then merge again, a couple hoops at a time. She beams, raises her eyebrows, turns in place.

The hoops are still spinning.

At one point, a hoop looks like it might escape her control, dip below her knees, and clatter to the ground. But Marawa, whose consciousness I imagine being distributed through her body, like that of an octopus, senses the wayward ring. With a wiggle (a word that utterly fails to capture the degree of somatic genius this act requires), she saves it, sending it spiraling up to meet the others.

Watching Marawa do this with 30 hoops is impressive, but it's nowhere near her limit. In 2015, she set the current world record by keeping 200 of them aloft simultaneously. "No one ever believes me when I tell them," she says. (See above, for video evidence.) For the record to count, she had to get the rings going under her own power and keep them rotating for a minimum of three revolutions. Her attempt lasted all of four seconds, and practically knocked her over. (Spinning 40 pounds of plastic on your 5-foot, 4-inch frame will set you off balance in a hurry.) But it counted.

Forget about the world record for a second. Because even more astonishing than her absolute limit is Marawa's command of intermediate numbers of hoops. When she sets in motion a stack of say, 100 hoops, she can keep them aloft for up to a minute. And it's in watching her keep that many rings going that you really start to appreciate what sets Marawa apart from the vast majority of people who have ever set hoop to hip.

A quick primer on the physics of this stuff: For a Hula-Hoop to continue spinning, one must apply force to the hoop in both the fore-aft and up-down directions. "The Hula-Hoop stays aloft thanks to conservation of angular momentum, but the system is extremely unstable—one little hiccup, and the hoop comes tumbling down," says Ramesh Balasubramaniam, a sensorimotor neuroscientist at UC Merced and an expert in how the brain and body work together to perform skilled tasks.

In a 2004 study titled "Coordination Modes in the Multisegmental Dynamics of Hula-Hooping," Balasubramaniam showed that most Hula-Hoopers apply the necessary forces through the coordination of two lower-limb "systems": The hips and ankles apply force in the fore-aft direction, while the knees add force in the up-down direction. When things are going smoothly, the hip-ankle system and the knee system oscillate in unison. But if you interrupt your hooper's flow and cause them to falter—say, by redirecting their attention from hooping to counting backwards from 100 in increments of seven—their knees will fall out of phase with the hips and ankles by pumping a little faster to try to restore order to the system.

This "corrective action," as Balasubramaniam calls it, is what amateur hoopers like you and me use to keep a single hoop from hitting the floor. What Marawa does to keep her many hoops looping involves the exquisite pairing of two things: While most people rely on their hips, knees, and ankles to keep their Hula-Hoop aloft, Marawa recruits her whole body. "Her brain has divided her body into other decoupled systems," Balasubramaniam explains. "For most people it's just the hip-knee and ankle systems. But she's added other oscillators in the form of her head, neck, shoulders, and chest."

Second, her body seems to be keeping track of all the hoops. "Every hoop needs to have its angular momentum conserved," according to Balasubramaniam. "What she’s learned to do is get the collective motion of all the hoops to follow the same conservation principle, and it’s a skill. The timing of all her oscillators must be so precise that she’s able to collectively see where all these hoops are, and she's able to control them."

Marawa says 200 hoops is probably her limit. While she might be able to move more than that with her body, she would first need to pick them up and get them started, "and I can't get my arms around them!" She thinks someone with the right physique—tall, strong core, long arms for optimal hoop-scoopage—could top her record.

But to match Marawa's skill would likely require untold hours of dedicated practice, amounting to a complete reformulation of one's life—and the odds of anyone besting her on that front anytime soon seem slim. Her latest stage production, an eight-woman variety act called Quality Novelty, blends hooping, high-heeled roller skating, and acrobatics. When she's not performing, she leads regular "Hoola Schoola" workshops for kids and adults with the Majorettes, her troupe of record-holding hoopers, and sells skate- and hoop-themed apparel and accessories of her own design through her online Hoopermarket. Last year, she distilled many of her experiences—not just as a performer, but as a woman—into The Girl Guide, a modern handbook for girls going through puberty. She promotes the book wherever she travels (which is all over the world), through pop-up parties replete with hoops, music, dancing, and roller skates.

Marawa, in other words, is more than a steadfast practitioner of hooping. She's a full-blown hula-vangelist. Back in her studio, while adding hoops to a stack already 150 rings high, she pauses to explain their appeal. "They're fun, you can take them anywhere, and with a little practice, anyone can do it."

Just, you know, not like her.

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The Devastating Allure of Medical Miracles

March 20, 2019 | Story | No Comments

Sheila Advento was not feeling well. It was July 6, 2003, and her mother’s house in northern New Jersey was filled with people. Sheila and her mom were there, along with Sheila’s boyfriend, sister, and brother-in-law—a slice of a huge extended family, many of whom, like Sheila and her parents, had immigrated to the US from the Philippines. They ate cheeseburgers and adobo and raised Pabst Blue Ribbon and San Miguel to toast one another, independence, good health, and freedom—almost all of which Sheila, who was 26, was about to lose.

For days she’d been having headaches. Her stomach wasn’t right. She was starting to think she had the flu. She trudged to a basement bedroom to lie down. Family members took turns checking on her. When her mother, Peachie, looked in around dinner time, she found Sheila lying on the bathroom floor. Peachie, who was a nurse manager at New York University’s Langone Medical Center, took one look at her daughter and knew she was in trouble. Sheila, she said, I have to take you to the hospital. Your lips are blue. In the car, Sheila had trouble breathing. Her last memory before blacking out was someone lifting her hand to put one of those white clips on her dusky blue finger.

Sheila was in acute septic shock. An infection in her bloodstream had unleashed an inflammatory storm. Her body was shutting down, starting with the limbs. The ER team blasted her with antibiotics and fluids and eased her into an induced coma. They wanted her body, undistracted by mind or maintenance, to focus on the fight ahead.

After about eight days on a ventilator, Sheila’s doctors unhooked the machine, stopped the sedatives, and waited. Later that day, she awoke and looked at her hands. They were nearly black, dull, dead as coal. She couldn’t move or feel them. They seemed no part of her. She nodded at her hands and said, “We have to take these off.” She was right. The hands had to go. So did her feet and legs, almost up to the knees.

Over the next three months or so, Sheila had five operations. After one, she remembers the surgeon saying something about wanting the muscles in her arm to work “if you get a transplant someday.” Sheila had never heard of hand transplants. At the time, just 20 had been done worldwide.

Over the years, Sheila gained mastery of prosthetic legs and the split hooks she used as hands. She lived for a while with her mother, then on her own. After a time, she returned to her job at a call center for a medical diagnostics company. She had work, family, a love life, friends. But like most hand amputees, she missed the fluid dexterity and perceptive power of her fingers, the ability to wipe her nose or scoop up a set of keys, to shuffle cards or remove an eyelash from the corner of her eye. She wanted hands.

In 2009, six years after losing her limbs, Sheila heard that the University of Pittsburgh was looking for patients for an experimental hand transplant program. She wrote to them immediately, and a few weeks later drove with Peachie to Pittsburgh. She spent a week there, taking physical and psychiatric tests and giving blood for lab work. The doctor heading the program, W. P. Andrew Lee, was charming and accomplished: He had done physics at Harvard, medical school and training at Johns Hopkins, and more training at Harvard and Massachusetts General. Like Sheila, Lee was an immigrant. He had come to the US as a teenager—in his case, from Taiwan. She liked his warm smile and gentle manner. “I thought he was fantastic,” she says.

Lee’s team called a few weeks later to tell Sheila that she had been accepted into the trial. They told her it might be months or years before they found a donor well-matched in size, skin color, and immune profile. Or it could be tomorrow, so pack a duffel. When things moved, they would move fast. She packed as soon as she got home. When the call came about eight months later, in September 2010, she was watching TV in her apartment. She hung up and called Peachie. Mom, she said, come get me.

When Sheila Advento arrived at the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh, the man for whom it was named was 84 years old and still a presence there. Starzl, who had done the first human liver transplant in the early 1960s, was acclaimed as “the father of transplantation.” Starzl himself insisted that the rightful owner of that title was a zoologist named Peter Medawar, who at midcentury had helped solve transplantation’s central puzzle—one not surgical but immunological.

The body has a fierce need to protect itself. It does so by turning its immune system against any foreign body—an obvious obstacle to accepting another person’s organ. In experiments on animals in the 1940s and ’50s, however, Medawar and his colleagues discovered a mechanism for preventing immune rejection of transplanted organs. In studies on mice, they found that if they introduced an eventual organ donor’s cells to the recipient in utero or just after birth, the mouse would develop an acquired tolerance—a diplomatic ploy to have the foreign flesh accepted as kin.

Alas, as a practical matter, introducing a future human donor’s cells in utero or infancy so one could later get a timely transplant from them would require super­human prescience. But by demonstrating that immunological tolerance could be acquired, Medawar had given the field hope.

In the 1960s, researchers began developing immunosuppressant drugs and launching transplant programs. Unfortunately, the side effects of early anti-rejection drugs were severe, and mortality rates were high. Organ transplants did not become viable as routine treatment until around 1980, when an anti-rejection drug called cyclosporine was introduced. A similar drug, tacrolimus, followed a decade later. With those drugs, five-year survival rates for organ transplant patients jumped. Most transplant patients are now treated with a three-drug cocktail that includes cyclosporine or tacrolimus along with steroids and a second, gentler anti-rejection drug. Such transplants, now routine, have saved or extended more than 750,000 lives in the US.

The next big leap came in 1998, when the world’s first initially successful hand transplant, in Lyon, France, accelerated the practice of vascularized composite-tissue allotransplantation, or VCA. (For complex reasons, the patient had it removed in 2001.) These transplants, mainly of hands but also of faces and genitals, differ in two important ways from solid-organ transplants: They involve multiple tissue types intricately tied together, and they don’t extend life—they enhance it.

That they improved lives rather than saving them posed a serious new ethical problem. Even today’s transplant drugs cause side effects ranging from passing nausea, dizziness, and weight loss to life-threatening conditions such as diabetes, infection, cancer, and kidney failure. In a 2003 study, up to 21 percent of transplant recipients experienced total renal failure within five years, forcing patients to have dialysis or a kidney transplant.

Most people readily accept such risks to get a new heart, lung, or liver: When the benefit is life itself, most find almost any cost bearable. But a hand transplant sharply changes this calculus. Is taking dangerous drugs for the rest of one’s life worth the satisfaction of tying a shoelace or moving a strand of hair from a child’s face? Such deeply personal questions test the boundaries of medical ethics.

Solid-organ transplants had been common for almost 20 years by the time doctors and hospitals started performing VCA. It had taken two decades to find the right levels of immuno­suppressants. Once this breakthrough arrived and the Lyon team gave their patient a new hand, doctors and major hospitals worldwide began to add VCA units. The hand transplant’s day had arrived. In 1999, Warren Breidenbach became the first US surgeon to perform a VCA transplant when he gave a new left hand to Matt Scott, a 37-year-old who’d lost his to a firecracker. Hand transplant teams started in Innsbruck, Paris, Pittsburgh, Los Angeles, Boston, and other cities. In less than two decades, there were dozens.

The University of Pittsburgh joined the field in 2002, with the hiring of Andrew Lee to lead its new program. A rising star in hand-reconstruction research, Lee came to Pittsburgh partly to work with Starzl, the legendary surgeon. According to Lee, Starzl may have seen in hand transplants a chance to revisit Medawar’s proposal to trick the body into accepting a donated organ as its own. Starzl began working with Lee to develop a new regimen that might open the way to such a safer, drug-free immune tolerance. (Starzl died in 2017, at age 90.)

This new treatment regimen was dubbed the Pittsburgh protocol. Its most distinctive feature was to infuse the recipient with bone-­marrow cells from the donor’s body two weeks after surgery. The idea was that those cells, leaving the marrow and spreading through the recipient’s bloodstream, would make the entire immune system receptive to the donated limb. Then, instead of taking three drugs, the patient would take a low dose of just one, tacrolimus. Lee’s hope—the hypothesis his protocol would test—was that the bone-marrow treatment would allow the patient to take only a minimal dose of tacrolimus or even give up the drug entirely.

The possibilities raised by Lee’s research and similar efforts elsewhere stirred keen interest at the US Department of Defense. Approximately 1,600 troops returned from Iraq and Afghanistan with amputations. If a safe way to transplant these multitissue limbs could be developed, it would bring life-changing treatment to these veterans. So in 2008, the Defense Department gave millions of dollars in grants to fund clinical trials, including one to test the Pittsburgh protocol.

In March 2009, Lee performed his first hand transplant in that DOD-funded trial. The patient was Josh Maloney, a likable, somewhat rambunctious 24-year-old who had lost his right hand to a stick of TNT during a Marine training exercise. A couple of weeks after the surgery, Lee held a press conference with Maloney at his side. According to the Pittsburgh Post-Gazette, Lee told the gathered reporters about the Pittsburgh protocol and said, “I think there’s clearly a chance of weaning Joshua off immuno­suppressants altogether.”

Eighteen months later, Sheila Advento, having become the fifth patient in Lee’s trial on September 18, 2010, woke groggily in the University of Pittsburgh Medical Center recovery area to find her new hands. “­People had said they might not seem like mine right away,” she told me. “But mine did. Right away they were mine.”

When she had recovered enough to get out of bed, she put on her leg prostheses to walk around the transplant program’s dedicated wing. One of the first people she met was Jessica Arrigo, a slender, friendly, and deceptively tough 27-year-old who had received a transplant of her right hand a week before Sheila’s operation.

Like Sheila, Jessica had almost died of septic shock. That was in 2004, when she was barely 21. She had been living with her father, Wayne, in West Virginia when the sepsis hit. It took both feet, her right fingers, and on her left hand, all but the stubs of her middle, ring, and index fingers. Alongside those, the surgeons fashioned a sort of thumb so she’d have a pinch-grip. It worked pretty well. She worked, drove, shot pool, even went skydiving with Wayne. Jessica met a man with whom she had a daughter, Cody, in 2009. Jessica and Cody moved in with Wayne, who by then was living in Millville, New Jersey. “She was living a pretty full life,” Wayne says. But like Sheila, Jessica wanted a hand.

The two women took to each other. Over the next four or five months, they would spend most of their time together, up to five hours a day in occupational therapy, walking the halls, talking, comparing notes on family, love, life, fate, and hands.

“I just loved her,” Sheila says. “We had so much fun. We had our own section, our own therapist. We were always laughing.”

It was good to have cheerful company, because the physical work the new hands demanded was grueling. The operations Lee had performed were enormously complex, lasting 10 to 15 hours and requiring microsurgery to connect dozens of tendons, muscles, bones, nerves, and vessels sometimes no bigger than vermicelli. These blood vessels promptly pinked the women’s new fingertips. But newly connected nerve fibers do not instantly carry current. The fibers in the recipient’s arm must grow from the transplant’s attachment points clear down into the new hand, at a rate of about an inch a month, to give the donated hands anything but the crudest sensations and movement control. Making her new fingers and hands pinch, flex, and grip was some of the hardest work Sheila had ever done.

Sheila and Jessica, for hours at a time, picked up peas, pennies, marbles, and weights, stacked cups, slid blocks into boxes like nursery school children, assembled things and disassembled them. They struggled to remaster buttons and laces. They came up with their own tasks. “You remember friendship bracelets?” Sheila says. “We started making them. Good for the fingers.” They took tests: Close your eyes and tell me which of your fingers I’m touching, then tell me what part of your finger I’m touching. “We found ways to make it interesting,” Sheila says. “But it was exhausting.”

Sometimes they were joined by Josh Maloney, who lived with his parents 40 minutes south of Pittsburgh. Eighteen months after his surgery, Maloney was Lee’s star patient. Sheila remembers seeing videos of Maloney lifting weights, Maloney screwing in a light bulb. He was taking a training course to become a car mechanic. He traveled with Lee to press events and medical meetings to promote the protocol. He even shook hands and chatted with Prince Harry on the USS Intrepid at an event honoring British and American veterans. CBS Evening News ran a spot about him. “I don’t feel broken anymore,” he told the reporter.

At times, two other trial patients would also return to the hospital for checkups. Jeff Kepner, Patient 2, had lost both hands to sepsis; Chris Pollock, Patient 3, destroyed his hands while reaching for an ear of corn in a corn picker. Pollock already dressed himself, drove, opened windows and doors. Kepner was struggling. He had trouble holding things or opening doors.

Sheila and Jessica made steady progress. But in December, while still in Pittsburgh recovering from the surgery, Jessica confessed to the transplant team that she had struggled with drug addiction since she was a teenager. This history would have barred her from participating in the trial had it come out during the screening process, interviews, or drug testing. (It “surprised us,” Lee told me. “I think this shows that even a detailed weeklong process is not perfect.” ) Jessica began getting addiction treatment, which would work better at some times than others.

In early 2011, after several months of intense work, Sheila and Jessica had progressed enough to go home. The team reviewed with them what would come next: The women would need to keep up the rehab work at home; return to the hospital monthly or quarterly for a while, and then less as time passed; and for the rest of their lives, or as long as they had the transplant, get regular blood tests that would be sent to the transplant team to monitor for complications and drug side effects. On this everyone agrees. The details of those discussions, particularly about specific dangers from the drugs, would later become a matter of dispute. Sheila packed up and moved into her mother’s house. Jessica returned to Cody and Wayne in Millville.

In the fall of 2010, about two months after he performed Jessica’s and Sheila’s transplants, Andrew Lee took a position running the new Department of Plastic and Reconstructive Surgery at Johns Hopkins University School of Medicine, in Baltimore. Some of his Pittsburgh team later joined him, others stayed behind. His transplant trial patients could be treated in either location. In Baltimore, Lee would eventually perform three more transplants, in 2012, 2015, and 2017, bringing the trial’s total to eight.

A year after her operation, a CNN report about Sheila showed her putting on eye makeup, driving, and talking about what it meant to be able to feel the fabric of her jeans under her fingers. Other patients found life with the transplanted hands full of complications, some quite challenging. Nearly 16 months after Jeff Kepner’s surgery, he also appeared on a CNN broadcast, but he showed far less progress: He had trouble writing with a marker, picking up small balls, and doing tasks that Lee’s other transplant patients had accomplished just weeks out. Progress in transplant patients is variable, depending on how quickly the nerves regenerate and the patient’s commitment to rehab.

Maloney, the ex-Marine, was still in auto-­mechanic school. He was also driving two hours round-trip to Pittsburgh, two times a week, for lengthy evening rehab sessions. Sometimes he didn’t protect his hand well enough while working on cars, he said, and the injuries or rejection episodes forced him to rest it, stalling both schooling and rehab. “You’re supposed to keep from getting infections, getting a cold, getting sick, getting cuts and dirt in it,” Maloney told me. “I wasn’t the best at that. I was trying to go back to my old life.” He grew discouraged and at times too disheartened to go to rehab; sometimes he lacked the money to make the trip.

He also grew less vigilant about his twice-daily drug regimen. In that, he had company: Some 20 to 25 percent of all transplant patients miss doses. It can be difficult to remember to take the drugs, and side effects ranging from hair loss and heartburn to headaches, confusion, and mood changes can be hard to tolerate. One hope for the Pittsburgh protocol was that by reducing the number of immunosuppressants from three to one, it would be easier for patients to comply.

Maloney’s body increasingly tried to reject the transplanted hand. “When it finally started to go downhill,” Maloney told me, “it went fast.” A particularly nasty rejection put Maloney in the hospital for about a week. His hand turned red, rashy, and blistery. Afterward it didn’t work as well. The realization that set in took him weeks to say out loud: I no longer want this hand. On March 14, 2013, four years to the day after he got his transplant, he had the surgeons take it off.

Jessica Arrigo had gone home in decent health in early 2011. Her hand was working well, allowing her to take care of Cody and work at a series of jobs at Toys “R” Us and Kmart. In 2012, she met a man named Robert Doak, whom she would marry two years later. Jaimie Shores, the Lee team’s clinical director, was impressed with her rapid progress. “She really surprised us in some ways with how well she did early on,” he says. “She started taking private pilot lessons. She sent us a video of her flying a plane. I was just like, ‘Oh my goodness. That’s incredible.’ ”

Complicating Jessica’s case, however, were two foreboding factors. The first was the history of illicit drug use she’d confessed to the team three months after the transplant: cocaine in her teens, she said, and more recently, struggles with an on-and-off addiction to opioids—a class of drugs that sometimes cause symptoms easily confused with possible immunosuppressant side effects and which she was prescribed periodically for hand pain. (Joseph Losee, a surgeon who helped oversee Jessica’s care at Pittsburgh, declined to comment on her case.)

The other factor was that Jessica’s kidneys began to quickly decline. Just seven months after her transplant, a Pittsburgh nephrologist diagnosed her with early chronic kidney disease. The next year, another nephrologist at Pittsburgh gave Jessica her second diagnosis of chronic kidney disease and told her that her kidney function would most likely worsen as long as she continued to take tacrolimus. Managing immuno­suppressive drugs, says Yale transplant nephrologist Richard Formica, is a delicate art. You want to give enough medication to restrain the immune system from attacking the transplanted organ, but not so much that it harms the kidneys or other organs. In some patients, you find this sweet spot easily; in others, you find it elusive.

Jessica was one of the latter. Physiologically, Shores says, “she was a little bit more challenging in terms of dosing.” All the transplant patients took weekly blood tests to monitor for signs of infection, diabetes, organ damage, or other treatment side effects. Of particular interest was creati­nine, a waste product that is cleared by the kidney and whose presence in the blood can be used to derive an estimated glomerular filtration rate, or eGFR, the standard lab measure of kidney health. A healthy GFR is around 90 to 100. Scores below 60 signal mild to increasingly severe kidney damage, with the likelihood of permanent damage or total kidney failure rising greatly with sustained scores below 30. A sustained score under 15 usually means you need dialysis or a new kidney.

Jessica’s medical records, which her father shared with me, show her scores first dipping below 60 for weeks at a time in 2011, less than a year after her transplant. In 2012 they dropped steadily through the 50s and 40s, plunging to 17 one day that December—which led to a weeklong hospital stay in Pittsburgh to get her kidney function on track. The following year Jessica moved her treatment to Johns Hopkins, which was closer to her home and because Lee was there. After that point the Pittsburgh team no longer received regular updates about her kidney health, says Vijay Gorantla, a surgeon who was at Pittsburgh at the time.

Apart from her kidney issues, Jessica had also been suffering bouts of abdominal pain that were sometimes so severe, Wayne says, that she curled up on her bed. She’d have spells of vomiting or diarrhea; other times she’d be constipated for days. Jessica had suffered similar episodes before the transplant, Wayne says, but her GI issues now came more frequently and with more fury. Most dispiriting of all, her hand was having more painful rejections, requiring more trips to the hospital.

In March of 2015, a livid rejection sent Jessica to Hopkins. Her hand was in terrible shape. The biopsy revealed areas of deep necrosis in her skin, the tissue below riven with blisters and signs of infection. Everyone agreed it was time. Shores and a surgical team removed the graft later that day.

Shores, who helped oversee Jessica’s post-transplant care at Hopkins, says he viewed her particular mix of problems—the stubbornly recurring rejections; the rising creatinine levels; the gastric torments—as arising both from her distinct physiology and from what appeared to be an inconsistent adherence to diet and drug regimens. To the team, it seemed that Jessica often failed to drink enough water, courting dehydration that strained her kidneys, and took her tacrolimus doses erratically. Both Shores and Lee acknowledge her kidney issues but said that when they adjusted her medication and care, the episodes would pass. Shores noted that patients like Jessica and Sheila who have had episodes of sepsis are more predisposed to kidney problems.

Once her arm healed, Jessica resumed using her short thumb and finger stubs on her left hand and made do with her right. She cared for Cody and looked for work. She was free of the tacrolimus, and, according to Shores, her creatinine levels improved immediately after the reampu­tation. But her GI issues persisted. According to Robert Doak, meals would often put her in excruciating pain. She usually tried to tough it out at home, but every few weeks, it seems, the pain was so bad that Wayne or Doak took her to a nearby emergency room.

On November 21, 2017, just before Thanksgiving, Jessica had another painful episode. That evening, Doak took Jessica to the ER while Wayne stayed home with Cody. At the hospital, the ER team worked furiously as Jessica grew weaker. By this time, Doak told me, “She was in absolute agony.” Doak says that as a former EMT and combat veteran, “I’ve seen men shot on the battlefield. I’ve seen all kinds of things. I’ve never seen somebody in quite that much pain.” Doak called Wayne and told him to come. By the time Wayne got there, his daughter was still. “I was there when she died,” he says. “But I don’t think she knew.”

The attending doctors, consulting with the medical examiner, ruled the cause of death to be mesenteric ischemia, although there was no autopsy. Mesenteric ischemia is a rare, painful condition in which the blood supply to the small intestine slows or closes off. It sometimes creates a toxic sludge that fills the gut and spreads sepsis through the body. The disease, which generally arises from multiple factors, is notoriously difficult to diagnose. Much of Jessica’s long, complicated medical and drug history likely put her at risk.

While Jessica Arrigo’s health was declining, Sheila Advento was doing well. Her new hands let her work, cook, drive. She got her annual checkups (like Jessica, she’d moved her care to Johns Hopkins, for the shorter trip and because Lee was there), and she says she faithfully took her drugs each day. She gave talks and did press events. “Everyone loved her,” says Vijay Gorantla, who was a former member of the Pittsburgh team and is now director of the VCA program at Wake Forest School of Medicine, “because she was the perfect patient. She did everything asked of her.” She got more headaches than before, and they were worse—a common side effect of tacrolimus that she accepted as the price of her wondrous hands. She passed the five-year mark, in September 2015, in good health.

But in the two years after that, Sheila’s blood tests began to show a decline in kidney health. Around October 2017, Thomas Salazer, a New Jersey nephrologist who often had been Sheila’s primary care provider since her original 2003 sepsis episode, was concerned enough about her blood tests that he recommended a kidney biopsy. He suggested that she schedule one as soon as possible.

As it happened, Sheila didn’t have that biopsy until five months later. The Hopkins team says they told Sheila her kidneys were declining and tried to schedule the biopsy starting in November. Sheila, they said, was unable to make any appointments before March. According to Sheila, Salazer’s biopsy recommendation was her first notice that her kidneys were declining, and if she delayed or canceled appointments, it was because she had trouble taking time off work.

In any event, Peachie dropped Sheila off in Baltimore on March 13, 2018, for the biopsy. That same day, Sheila says, she remembers learning about Jessica’s death. She hadn’t talked to Jessica in two or three years. “It came to me as a complete shock,” she says.

A few weeks later, Sheila received the biopsy results: It seemed her kidneys had lost about three-quarters of their function. Stunned, Sheila called Gorantla, who had counseled her through tough patches before. He urged her to call the Hopkins team immediately and ask for an appointment with their nephrologist to discuss a treatment plan—the sooner, the better. Text messages between Sheila and a patient coordinator show that Hopkins offered to set up an appointment or a conference call. Sheila said she was too tired to make the trip and preferred to speak alone to a nephrologist over the phone. Scheduling efforts continued into June. Meanwhile, the pain in her lower back surged. She was always tired and often nauseous. Her legs swelled, her head hurt. It had been more than six months since Salazer first told her to get a biopsy. She wanted a plan.

Six months. There were things I could have been doing,” she said, to try to slow what was now her kidney’s inevitable decline. It was July 2018, and we were eating dinner in a Mexican restaurant near her house, an hour from New York City. Sheila, who walked with only a slight limp and looked sharp in a simple black top and slacks, was animated, funny, smart, and personable. She was also clearly still shocked by the diagnosis she had received only weeks before. She said she felt certain she had never been told the drugs could destroy her kidneys. “I had no idea this could happen,” she told me.

Jaimie Shores, who was involved in Sheila’s care from the beginning, says he tried to convey the threats to kidney health vividly and regularly to all patients, including Sheila, starting at the screening process and continuing through all pre- and post-transplant care. According to Hopkins, other team members did too. “She may not have received the message that I thought I was communicating,” Shores says. When I asked the Hopkins team to send me any written records documenting such conversations with Sheila, they said they couldn’t provide any, and added in a statement, “We do not document every conversation with patients.”

Sheila and the other patients did sign a 27-page consent form that included a warning about the drug’s possible “toxicity to the nervous system (brain, nerves), kidneys, or liver.” An appendix further warned of side effects like nausea, vomiting, diarrhea, headache, abdominal pain, and “kidney injury.” The patients themselves report varying experiences: Jeff Kepner says he doesn’t recall being warned that his immunosuppressants could lead to kidney failure, nor does Wayne Arrigo feel that Jessica was adequately informed. However, Chris Pollock and two others, Jeff Swedarsky and Eric Lund, say they were fully told of the consequences. “The main thing I recall is the fact that there’s a possibility of kidney failure,” Pollock says. “I will remember that until I die.” Gorantla says he’s dismayed that the risks were not unambiguously clear to Sheila. “Informed consent is not just a form you sign,” he says. “It’s an ongoing process in which you keep the patient informed and involve them in every significant decision.”

On May 15, 2018, nine weeks after the biopsy, Hopkins sent Sheila a letter. It said she had stage 3b chronic kidney disease, which the letter attributed in part to the tacrolimus she’d been taking for more than seven years, along with her sepsis episodes 15 years before, her hyper­tension, and other issues. The letter recommended switching from a twice-daily dose of tacrolimus to an extended-release form taken once a day. Then it said, “Even with these changes and continuous monitoring, it is possible that at some point, you may require a kidney transplant” and suggested she check in at least yearly with the Hopkins hand transplant team and a transplant nephrologist. “As you know from the last seven plus years,” the letter concluded, “our most important priority is your overall health.” It was signed, “The Johns Hopkins Hand Transplant Team.”

A few weeks later, Gorantla referred Sheila to a kidney transplant team at the University of Maryland. Around the same time, she says, a transplant physician told her there was a possibility, small but real, that the challenge posed by a new kidney to her immune system might spark a rejection episode that could affect her hands. “I don’t know what to do,” she told me. “I don’t want to lose my hands.”

It was early in my reporting for this story, in May 2018, when I first interviewed Andrew Lee. At that point, I planned to write a story about the emotional challenge of making a new hand one’s own. I hadn’t yet met Sheila Advento or Wayne Arrigo. I had learned of Jessica’s death only a few weeks before, when Jessica’s mother, Janet Carpenter, returned my third call to Jessica’s cell number and told me that her daughter had died in November. She sounded so pained that I didn’t ask how it happened. As I was soon to meet Lee, I figured I’d ask him. 
Lee, wearing an elegant gray suit, showed me into his office on the Johns Hopkins medical campus in Baltimore. We started by discussing where he saw hand transplants in their arc of development. He said that he believed hand transplants were almost mature enough to be routinely covered by insurance. I asked him what surprised him most about doing hand transplants. He said it was the bond one forms with the patient. “You keep a lifelong close relationship with the patient … You get to know one another really well, you stay in close touch, you have their cell phone number, you text one another. It’s a long-term and close relationship.”

He spoke with animation about Brendan Marrocco, his sixth patient, an irrepressible soldier who’d lost both arms and legs to an IED in Iraq. In public appearances, Marrocco seemed delighted with the double hand transplant Lee did for him in 2012; in a 2014 episode with Lee on the Late Show With David Letterman, Marrocco pretty much stole the show. “He’s still driving his car,” Lee told me, smiling, “going all over the country. He does everything a young man does.”

When I asked him about Jessica Arrigo he became far more circumspect. I asked how he’d heard of her death. He said through word of mouth. Then he offered, “We really don’t know the cause of death. We don’t think it’s related to her transplant. But we don’t know the cause of death.”

Perhaps I’d misheard him. I asked, “Is that because you didn’t know of any existing medical issues?”

“Well, after her hand was removed, we did not follow her,” he said. “But the last we heard she was in good health.”

A few months later, I got Jessica’s death certificate. I shared with Lee that the certificate listed mesenteric ischemia as the cause of death; it seemed to be news to him. When asked about Arrigo’s cause of death recently, Lee said that he wasn’t aware of any evidence of association between transplantation or immunosuppressive drugs and mesenteric ischemia.

Of Lee’s eight transplant patients, I have spoken with six of them and the father of a seventh, Jessica. As one would expect, some have fared better than others.

The most recent patient, Patient 8, Eric Lund, 35, lost both arms above the elbows in 2012 to an IED in Afghanistan and had a double transplant in November 2017. When I recently talked to Lund, he said his two-year rehab program to bring his arms and hands to full function was on schedule. He could lift his arms and push things around with his hands, but he couldn’t grab anything with them yet. The hands still provided only faint movement and sensation, as the nerve fibers still had a ways to grow to reach his fingers. He expects better sensation will come. He’s glad he had the operation.

Jeff Swedarsky, Patient 7, received a bicep-level transplant of a left arm in mid 2015 and has regained fair function. At 38, he does weight training daily, has built a busy food-tourism business, and is so thrilled with his transplant that he encourages others to apply for the program. “Best decision I ever made,” he says.

Brendan Marrocco, Patient 6, did not return my calls but appears to be doing well.

Sheila Advento is on the kidney transplant waiting list.

Patient 4, Jessica Arrigo, is survived by her husband, Robert Doak; her father, Wayne Arrigo; and her daughter, Cody, who made third-grade honor roll last fall.

Chris Pollock, Patient 3, is doing great. When I called him at his home in Pennsylvania, he was mowing his lawn. He easily takes care of himself, makes toast and eggs (scrambled or fried), drives, and much more. He feels blessed.

Jeff Kepner, Patient 2, wakes each day to two transplanted hands that he feels are utterly useless. “I could do almost everything with my prosthetics,” he says. “Now I can’t do anything.”

Patient 1, Josh Maloney, the Marine who had his transplant amputated in 2013, started a course in turf management last year—a step toward working in golf course greenkeeping. With his soldier’s acceptance of bad outcomes, he does not question his original decision to get a transplant. Yet when asked if he feels he made the right decision in having it removed, he says, “Absolutely.”

On a cloudy Thursday afternoon last November, about 150 members of the American Society for Reconstructive Transplantation, the main organization that represents the VCA field in the US, gathered at the Drake Hotel in Chicago for the society’s biennial meeting. As a cold wind swirled outside, transplant surgeons, rehab specialists, immunologists, and others gathered in a ballroom with two-story ceilings and ornate columns—the Gold Coast Room—to hear Gerald Brandacher, the scientific director of Lee’s team and the incoming president of the society, give the opening speech.

Brandacher was taking over at a pivotal moment for the VCA field. For one thing, just two weeks earlier, news broke that Andrew Lee, Brandacher’s longtime mentor, a cofounder of the ASRT, and one of the VCA field’s most public faces, was leaving Hopkins to take a job as dean of the huge medical education complex at the University of Texas Southwestern Medical School. Brandacher later told me that this came as a “complete surprise” to his team.

In addition, the VCA field was facing something of an existential crisis: The Department of Defense grants that funded many of the US clinical trials of hand transplants were running out. “The field is running on fumes,” says L. Scott Levin, a prominent surgeon and former ASRT president who runs the VCA program at the University of Pennsylvania.

To keep money flowing, the field must now persuade the industry and government bodies that set health insurance and reimbursement standards that hand and face transplants are relatively safe, effective, and financially justified. Only then can the procedures be routinely covered by insurance. The bureaucratic bodies the field must convince include the American Medical Association, the private insurance industry, and the US Centers for Medicare and Medicaid Services, known as CMS. The process of getting these approvals is daunting.

But success was the theme of the conference that day, and Brandacher underscored that idea in his opening speech. Just as solid-organ transplants had moved 30 years earlier from doubt to acceptance, he said, so reconstructive transplants were poised to do the same. Challenges remained. Now that many patients had been on immuno­suppression for years, Brandacher noted, they were suffering more renal complications and chronic rejection of the grafts. (Later, in his talks at the conference, Jaimie Shores would say what Sheila Advento already knew—that the Hopkins team had a patient in stage 4 renal failure.) Yet reconstructive transplants, Brandacher said, had already shown their power to restore normalcy to people’s lives. Given the progress being made in animal research at Harvard, Hopkins, and elsewhere on convincing the body to tolerate grafts rather than fight them, he said, “I think we are getting closer to this holy grail, and hopefully can see tolerance in VCA in the not too distant future.” VCA was almost ready to join conventional transplants as established practice. But to accomplish this, he said, “we need to have a unified voice to the public and policymakers, as well as third-party payers.”

However, it’s not clear that the VCA field has accumulated the evidence that policymakers and payers normally want to see. Several experts described the tough path the field faces in gathering the evidence to make their case.

A recent Canadian government examination of the hand transplant field suggested there was much research work to be done. In 2016, Health Quality Ontario, a government body that evaluates new therapies, used a widely adopted standard to examine all available hand-transplant outcome data. While the report found that successful transplants improved function, it found the outcome evidence itself of “very low quality” because of the small number of studies and poor study designs. It concluded: “There is considerable uncertainty as to whether the benefits [of hand transplants] outweigh harms.”

Other observers see similar problems. Francis Perry Wilson, a nephrologist at Yale, read the two most complete studies of global hand transplant outcomes, written by Lee, Shores, and Brandacher in 2015 and 2017, as well as a third study from 2013. The papers “read OK,” he says, and raised no red flags. But they lacked several measures he would have wanted to see. The studies, for instance, were sparse on patients’ own assessments of hand function or quality of life, had little about how the VCA centers chose their patients, and sometimes presented outcome data that was several years old. (The Hopkins team says they plan to include this type of data in future papers.)

This past fall, drawing on conversations and data from patients and clinicians, recent papers, and oral histories collected by Emily Herrington, a doctoral student in communications who is also pursuing a masters in bioethics at the University of Pittsburgh, I was able to compile information on 24 of the 31 known US hand transplant patients. Of these, at least 12 have had serious setbacks. These include seven patients with grafts removed and others who have had kidney problems and poor hand function. In addition to Jessica, Louisville patient Rich Edwards died from suicide, and another patient died of metastatic skin cancer.

This tally is hardly a scientific study, of course. But when I ran these numbers by Scott Levin, who is currently compiling a quality-of-life report for all US patients, he did not dispute the breakdown.

Some of the people in the Gold Coast Room in November weren’t as eager to speak with one voice about VCA’s success. One such person was Warren Breidenbach, the surgeon who led the team that performed the very first hand transplant in the US and is one of the field’s most accomplished, complicated, and confounding figures. After the 1999 operation in which he gave Matt Scott the first hand transplant in the US at the Louisville Jewish Hospital, Breidenbach followed with five more hand transplants over six years. He became the king of a revolutionary medical practice.

Then he fell. By his own account, he tried and failed to get 2008 grants from the Defense Department. Despite serving as a founder of both the field and the ASRT, he felt increasingly alienated at Louisville, which he left in 2011. He hasn’t done a transplant since. He now works as a researcher at the US Army Medical Research and Materiel Command in San Antonio.

As the field has developed—and has gone astray, in his view—Breidenbach has grown increasingly vocal about what he describes as its lack of rigor, transparency, and integrity. He feels that practitioners should publish more information about their patients’ experiences and acknowledge how profoundly these experiments disrupt their lives. Herrington agrees. “It is odd,” she says, “that in a discipline whose entire justification and purpose is quality of life, almost no one adequately emphasizes actual patients’ experiences or includes them in their outcome measures.”

Breidenbach wants his colleagues to publish more and be more transparent. “The rules have always been simple,” he says. “When you do experimental medicine, you must publish—and you must publish what actually happens.” Some of Breidenbach’s colleagues see him as out of touch. “I love Warren Breidenbach,” Scott Levin says. “But this idea that people are hiding things—you have to put his criticisms in perspective.”

Levin does agree with Breidenbach and several others I talked to that Lee’s Pittsburgh protocol has not proven to be better than the three-drug model. As Kadiyala Ravindra, a former Louisville VCA team member who’s now a transplant surgeon at Duke, puts it, the protocol “unfortunately has not worked.” Lee counters that the protocol is designed to reduce immuno­suppression and spare patients some of the corrosive effects of the steroids used in the more common three-drug therapy.

Several people I talked to lamented that the discipline has no established protocol for following patients like Josh Maloney and Jessica Arrigo who have had their transplanted hands removed. There are now six people in the US who no longer have their hand transplants but who took immunosuppressive drugs for various periods. But because the DOD grants that funded much of this work didn’t require following patients after a graft was removed, their care and monitoring fell to the discretion of the institutions and research teams.

Francis Perry Wilson, the Yale nephrologist, says VCA teams should follow their patients for the full length of the trial to provide proper care and to track the experiments’ long-term effects. “The patients who are going to do worse in general are going to be more likely to have the graft removed,” he says. “So all the more reason to keep track of them.” Or, as Levin puts it, “If somebody says, ‘Three months after my hands were amputated, I got liver cancer and died,’ we’d want to know that.” Which is why Levin plans to follow any of his patients who lose their grafts.

The Hopkins team’s research protocol does not include a way to do this. The team says they always intended to follow up with patients who had their grafts removed. Shores says he tried to reach both Jessica and Maloney to do a follow-up study around 2016. He couldn’t get ahold of Maloney; he says he talked to Jessica on the phone but couldn’t get her to come in for a follow-up. As a result, the trial has very little data on either of those subjects’ health after the grafts were removed.

In some senses, the field is still struggling with two linked problems that have dogged it at least since that operation in Lyon in 1998: the cost-­benefit ratio of VCA transplants and the failure to develop gentler anti-rejection treatments that have been proven to resolve the issue by reducing the risks.

Back in 1999, Andrew Lee and a colleague, writing of this quandary in the wake of the Lyon surgery, concluded that the “deficiency of experimental evidence” then available, along with the known dangers of immuno­suppression, “renders precarious the risk-benefit balance of hand transplantation at present.” Still, they believed the VCA field represented “the next frontier” in reconstructive surgery. By 2010, having done three transplants and witnessed 37 worldwide, Lee and others in his team wrote that while much work remained to reduce immuno­suppression’s costs, they had faith that the experimental protocols being tested—including their own Pittsburgh protocol—“will surely undergo further evolution during the next decade.”

Yet the burden borne by today’s hand transplant patients seems to be essentially no lighter than that assumed in 1999. Levin believes that the operation’s proven capacity to “give people back their dignity” makes hand transplants justified even now. Of Levin’s three patients, all have functioning hands, although one has begun having renal issues and may need a kidney transplant in the future. “We have enough data that, in my heart of hearts, I can say that we can continue in this field ethically and forcefully … There will be people who have horrible complications, but that’s called medicine.”

Others are less sanguine. Herrington believes the field may need to hit the pause button to gather and weigh more carefully the progress so far. Some surgeons have chosen to wait. Vishal Thanik, a member of the hand transplant team at NYU Langone whose lab is among many trying to develop gentler ways to calm the immune system, does not plan to do any transplants until he has “something really new to bring in terms of immunosuppression.”

To lose a hand—or, God forbid, both—is a catastrophe that inflicts physical, emotional, and psychological consequences that, as one paper on the ethics of hand transplants put it, “are notoriously difficult to overcome.” As that 2012 paper, published in a journal of the Royal Society of Medicine, also notes, the transplant procedure’s experimental nature, along with the temptation for physicians chasing the “thrill of medical advancement” to exaggerate the benefits, “casts doubt on how informed a patient’s decision can truly be.”

Consent in hand transplants is devilishly slippery: Can a person who has lost a hand properly weigh the allure of soon regaining such a vital part of themself against the seemingly distant probabilities of suffering treatment’s possible harms? Levin says this is best addressed by confronting the patient with the grimmest picture possible of the risks and by appointing them an independent patient advocate. James Benedict, a bioethicist at Duquesne University who has studied consent and the US hand transplant community for more than seven years, has a different concern. At this point, he says, “I’m not even sure it’s possible to give informed consent, because the outcome data is so sparse. How can you give consent about accepting risks if you don’t even know what they are?”

In his opening talk at the conference, Brandacher acknowledged that the VCA field had not resolved all its issues. But his main message was one of success and the need to move forward. Most of the day’s talks followed this lead. The last speaker of that after­noon’s long opening session, a bioethicist, in fact, ended by crying, “Let us plow forward with this incredible field!”

Sitting in the room for most of the afternoon was Sheila Advento. She had listened to one speaker after another talk about success and the importance of including patients in its definition. She was sicker than ever. Within a month, she would be put on the waiting list for a kidney. She had flown to Chicago because she wanted to ask a question of Gerald Brandacher, in front of this crowd. She had worked it all out beforehand with Breidenbach, she told me. Breidenbach would station himself near the microphone that was generally in the center aisle at such conferences for audience questions, and when Brandacher finished his introductory talk, Breidenbach would quickly move to the mic and introduce Sheila as she made her way up the aisle. Then she would tell the room that she was in stage 4 kidney failure and ask Brandacher the question that was eating at her: “Why didn’t anyone tell me this was happening to me?”

The plan didn’t work. When Brandacher finished, he left the stage, and a moderator announced that a tight schedule precluded questions, then called the next speaker. Sheila, waiting for her cue in the back of the room, never even stood up. It remained so for the rest of the session. She never got a chance to be heard.

Line art by Claudia de Almeida

David Dobbs (@david_dobbs) writes on science, medicine, and culture.

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The reason you are so strong in the water is because of the buoyancy force. This is a force that every object in water or even in the air has pushing up on it. OK, you rarely notice this buoyancy force in the air, but it's there (just small) To help you see it, here's a quick experiment to show how the buoyancy force works in water.

Let's say you have a glass of still water sitting on a table. It's important that the water is still. Now imagine a small section of water inside that water. Maybe it's a cube of water that is 1 cm on a side. Here's a diagram that might help.

I put a dotted line around the special water-in-the-water so you can see it. I mean, it's still just water (even though it's special). But what happens to this special water in the rest of the water? This is not a trick question. The answer is that that water just sits there. It's in water, it doesn't move. You could say it floats in water. Really, it has to float. Otherwise it would accelerate down and then the water wouldn't be still. But this is still water.

If the water is just sitting there with zero acceleration, the total force on it must be zero—that's the nature of forces. This total force is a sum of two forces. The first force has to be the gravitational force pulling down. There is a gravitational force because the special water has mass. Objects with mass have a gravitational interaction with the Earth. The magnitude of this gravitational force is equal to the mass (in kilograms) multiplied by the local gravitational field (g = 9.8 N/kg).

Now suppose I replace this cube of water with some other object—let's use a metal block of the exact same dimensions. Like this:

Since the metal has the exact same shape and size as the water cube, the rest of the water in the cup should interact with the metal block in exactly the same way. The net buoyancy force on this block would be equal to the net buoyancy force on which the special water floated. That means that if I calculate the gravitational force on the water that the block displaces, that would be equal to the buoyancy force. I can write this as the following expression:

If you are wondering what that heck that p-looking symbol is, it's the greek letter ρ (pronounced rho) and it's the variable for density. Chemists often use "d" for density—but that's just because they aren't as cool as physicists. Oh, and if you put something in water it has a density of around 1000 kilograms per cubic meter. The V in the above formula is the volume of the water displaced and g is the gravitational field.

OK, now for an experiment. What happens if you partially submerge an object in water? Is there a way to measure this buoyancy force in a fun way? Yes, there is. Here's what I'm going to do. I have an aluminum cylinder. I can partially put it in water and suspend it from a scale.

In this case, there are three forces acting on the aluminum cylinder: the gravitational force pulling down, the spring scale pulling up, and finally the buoyancy force from the part of the cylinder that is underwater. What happens when the cylinder is lowered even more into the water? The scale reading decreases and the buoyancy force increases. Since the volume of water displaced by the cylinder will increase with the depth of the cylinder in the water, I can get the following expression for the total force.

This looks bad, but really it's not so bad. Let me go over the key parts.

  • The Fs term is just the force the scale pulls up on the mass. This is something that I will read off the scale.
  • Again, the ρ is the density of water and g is the gravitational field.
  • The h is the distance of the cylinder that is under the water. If I know the cross-sectional area (A) of the cylinder, then hA is the volume of the water displaced.
  • The mg is just the weight of the cylinder.

Notice that as I lower the the cylinder in the water, the depth changes and the scale reading changes—everything else is constant. Since the force from the scale and the height have a linear relationship, I should be able to plot Fs vs. h and get a straight line. That's exactly what I'm going to do. Here is what I get.

Boom. That looks pretty linear to me (as it should be). But wait! There's more. When I fit a linear equation to the data, I get a slope of -5.1335 Newtons per meter and a vertical intercept of 1.088 Newtons. Both of these values mean something related to the experiment. With a tiny bit of algebra (just a tiny bit), I can modify the force equation above to look like this:

In this more familiar form (remember I am plotting Fs vs. h), it's easier to see that the slope should be ρgA and the intercept should be the weight (mg). I can check these two things. If I measure the diameter of cylinder, I can get a calculated cross-sectional area of 0.00049 m2 for an expected slope of 4.81 N/m. That's pretty close. For the intercept, I get an expected value of 1.079 N. Again close.

See. Graphs are our friends. It is a great way to show a linear relationship between two things. I try to tell my students this all the time, but they don't believe me.

Friends, have you thought about your insurance lately?

[Reader clicks close tab.]

Dammit! Wait, no, look: Climate change makes natural catastrophes worse, in both intensity and frequency, and insurance might be a significant way to pay for recovery. International aid can be unreliable; government money really is just taxpayer money. Corporations and nations have, for at least a decade, had access to quick infusions of post-disaster cash; now they might be common for regular people too—and if you’re in a disaster zone, a cash bonanza could be the difference between staying and rebuilding or having to just leave, permanently.

Typical insurance, the kind you probably have on your car or home, helps with this, but it is slooooow. It pays out only after you make a claim and get a valuation of the damages—and then you still have to wait for the check. That’s not much help if you’re wading through floodwater.

Insurers have figured out a way to speed that up—by restructuring the system. Forget about claims and adjustment; with these new kinds of policies, all it takes to get the financial ball rolling is the occurrence of a trigger, a previously agreed-upon event: an earthquake of sufficient size, say, or a hurricane with winds of a given speed. It’s called “parametric insurance,” and if one of those hazard parameters gets met, every policy holder downrange of the trigger gets an automatic payment of a set amount. Pow.

Governments and corporations are into it. The investment world originated the idea, probably because large organizations that incur complex damages appreciate a fast, predictable payout. And catastrophes can make deploying claims adjusters unsafe or outright impossible—the Nepal earthquake of 2015, for example, killed 9,000 people and incurred losses in the range from $6 billion to $10 billion. Only a fraction of that was insured, and even getting help to the region was a challenge. A big, all-at-once infusion of cash would have helped.

Since 2007, countries in the Caribbean and beyond have together operated the Caribbean Catastrophe Risk Insurance Facility to deal with the problems developing countries typically face after hurricanes, earthquakes, and floods. The African Union has one, as does Hong Kong in case of typhoons. “If you have good enough data and good enough sensing technologies, such as the seismometer network in California or the hurricane-hardened WeatherFlow anemometer stations on the East Coast, you can get that data and very quickly work out whether someone should be getting paid,” says Samuel Jay Gibson, of the Capital and Resilience Solutions Group at the catastrophe risk modeling firm RMS. “This allows post-event, initial injections of cash for immediate disaster recovery.”

Until recently, individual consumers didn’t have access to parametric insurance in the US. That’s changing: In October 2018, a company called Jumpstart started offering earthquake coverage to Californians. The trigger is a quake that reaches 30 centimeters per second of peak ground velocity, a measure the US Geological Survey uses to create “shake maps” of intensity.

So if a quake hits and you’re in the “red zone” of 30 cm/sec PGV, you get an automated text message asking if you want your money. Confirm—you have to confirm for regulatory reasons—and you get a direct deposit of $10,000. “Even if there’s no damage to your stuff, your life is going to be messed up in an earthquake that big,” says Kate Stillwell, Jumpstart’s founder and CEO, a structural engineer who spent a decade building computer models of earthquake risk. That money can pay for a hotel after evacuation, for child care if schools close, for a quick car repair, or to make up for lost work days because the roads are too damaged to drive and transit is suspended.

Well, actuary

Insurance and risk are primarily about math. The basic principle of just about all insurance is that enough people pay premiums over time to cover the big payouts after an event. In California, everyone knows a big earthquake is coming. But only 10 percent of homeowners have quake insurance; the same goes for commercial buildings. Even if you survive a disaster, even if most of your stuff survives, you still face consequences. And those hit poor people—less likely to have ready cash or stable support networks—the hardest. Watching New Orleans after Hurricane Katrina, Stillwell realized that those social vulnerabilities can be as much a problem as the actual disaster. “As structural engineers, we are not doing our job if the other pieces of the resilience puzzle are not in place, and one of those pieces is getting enough money into the system,” she says. “What good are safe buildings if nobody stays to live in them?”

In business school, Stillwell learned about “catastrophe bonds,” a financial tool pegged to disasters. Parametric insurance fits that category. She also realized that new technologies—more accurate hazard models, automated financial services, and a robust text-messaging system—could actually sustain a parametric consumer business. “Fundamentally the motive was to get more money into the system,” according to Stillwell. That let her incorporate as a public benefit corporation, a so-called B-corp, to do post-disaster stimulus. Originally the company was going to pay $30,000; she says California regulators told her that amount was large enough that people might think Jumpstart was meant to cover all their losses, rather than serve as “gap coverage” in a disaster’s aftermath. So she lowered the payout. (The premiums, ranging from $11 to $33 a month depending on zip code, cover the business and the cost of paying for the collateral—a pool of money at the insurer Lloyds of London that makes sure Jumpstart can always pay out.)

The key to making parametric insurance work is dealing with “basis risk,” the match (or mismatch) between a trigger and the damage it can actually cause. If you model damages for a magnitude 7 quake and set that as a trigger, but then suffer damages at magnitude 4, you’ve blown it. “So how you design that trigger could vary depending on which of the different types of coverage you’re looking for,” Gibson says. “It starts with understanding the problem space and then moving backwards to an optimal parameter.”

Natural hazards are particularly amenable to this, because there are so many sensors monitoring them. New York’s MTA uses a tidal gauge; satellite images combined with topography might eventually work for flood levels. Wildfires have a distinct burn area regardless of whether your house, specifically, gets destroyed. “What you’re trying to do is say, what level of damage am I going to have, given this trigger?” says Matt Junge, head of property solutions, US and Canada, at Swiss Re, a global reinsurer and disaster information clearinghouse.

The obstacles, then, are “education”—telling people this thing is on sale—and regulation. Outside California, state regulators are still chewing on how and whether to give parametric policies the green light for consumers. They’re new, and bureaucracies are justifiably cautious. But if Jumpstart is successful, Stillwell says it will expand to other states and other perils next year. “You can imagine: summertime, East Coast.” We can indeed imagine. Every season, someone new is thinking about their insurance.