A decellularized small porcine liver.
Jennifer Cisneros was 18 years old, commuting to college from her family's home outside Annapolis, Maryland, when she came down with what she thought was the flu. Over the following weeks, however, her fatigue and nausea worsened, and her weight began to plummet. Alarmed, her mother took her to see a pediatrician. "When I came back with the urine cup, it was orange," Cisneros recalls. "He was like, 'Oh, my God. I've got to send you for blood work.'"
"Eventually, we'll be better off than with a human organ."
Further tests showed that her kidneys were failing, and at Johns Hopkins Hospital, a biopsy revealed the cause: Goodpasture syndrome (GPS), a rare autoimmune disease that attacks the kidneys or lungs. Cisneros was put on dialysis to filter out the waste products that her body could no longer process, and given chemotherapy and steroids to suppress her haywire immune system.
The treatment drove her GPS into remission, but her kidneys were beyond saving. At 19, Cisneros received a transplant, with her mother as donor. Soon, she'd recovered enough to return to school; she did some traveling, and even took up skydiving and parasailing. Then, after less than two years, rejection set in, and the kidney had to be removed.
She went back on dialysis until she was 26, when a stranger learned of her plight and volunteered to donate. That kidney lasted four years, but gave out after a viral infection. Since 2015, Cisneros—now 32, and working as an office administrator between thrice-weekly blood-filtering sessions—has been waiting for a replacement.
She's got plenty of company. About 116,000 people in the United States currently need organ transplants, but fewer than 35,000 organs become available every year. On average, 20 people on the waiting list die each day. And despite repeated campaigns to boost donorship, the gap shows no sign of narrowing.
"This is going to revolutionize medicine, in ways we probably can't yet appreciate."
For decades, doctors and scientists have envisioned a radical solution to the shortage: harvesting other species for spare parts. Xenotransplantation, as the practice is known, could provide an unlimited supply of lifesaving organs for patients like Cisneros. Those organs, moreover, could be altered by genetic engineering or other methods to reduce the danger of rejection—and thus to eliminate the need for immunosuppressive drugs, whose potential side effects include infections, diabetes, and cancer. "Eventually, we'll be better off than with a human organ," says David Cooper, MD, PhD, co-director of the xenotransplant program at the University of Alabama School of Medicine. "This is going to revolutionize medicine, in ways we probably can't yet appreciate."
Recently, progress toward that revolution has accelerated sharply. The cascade of advances began in April 2016, when researchers at the National Heart, Lung, and Blood Institute (NHLBI) reported keeping pig hearts beating in the abdomens of five baboons for a record-breaking mean of 433 days, with one lasting more than two-and-a-half years. Then a team at Emory University announced that a pig kidney sustained a rhesus monkey for 435 days before being rejected, nearly doubling the previous record. At the University of Munich, in Germany, researchers doubled the record for a life-sustaining pig heart transplant in a baboon (replacing the animal's own heart) to 90 days. Investigators at the Salk Institute and the University of California, Davis, declared that they'd grown tissue in pig embryos using human stem cells—a first step toward cultivating personalized replacement organs. The list goes on.
Such breakthroughs, along with a surge of cash from biotech investors, have propelled a wave of bullish media coverage. Yet this isn't the first time that xenotransplantation has been touted as the next big thing. Twenty years ago, the field seemed poised to overcome its final hurdles, only to encounter a setback from which it is just now recovering.
Which raises a question: Is the current excitement justified? Or is the hype again outrunning the science?
A History of Setbacks
The idea behind xenotransplantation dates back at least as far as the 17th century, when French physician Jean-Baptiste Denys tapped the veins of sheep and cows to perform the first documented human blood transfusions. (The practice was banned after two of the four patients died, probably from an immune reaction.) In the 19th century, surgeons began transplanting corneas from pigs and other animals into humans, and using skin xenografts to aid in wound healing; despite claims of miraculous cures, medical historians believe those efforts were mostly futile. In the 1920s and '30s, thousands of men sought renewed vigor through testicular implants from monkeys or goats, but the fad collapsed after studies showed the effects to be imaginary.
Research shut down when scientists discovered a virus in pig DNA that could infect human cells.
After the first successful human organ transplant in 1954—of a kidney, passed between identical twin sisters—the limited supply of donor organs brought a resurgence of interest in animal sources. Attention focused on nonhuman primates, our species' closest evolutionary relatives. At Tulane University, surgeon Keith Reemstma performed the first chimpanzee-to-human kidney transplants in 1963 and '64. Although one of the 13 patients lived for nine months, the rest died within a few weeks due to organ rejection or infections. Other surgeons attempted liver and heart xenotransplants, with similar results. Even the advent of the first immunosuppressant drug, cyclosporine, in 1983, did little to improve survival rates.
In the 1980s, Cooper—a pioneering heart transplant surgeon who'd embraced the dream of xenotransplantation—began arguing that apes and monkeys might not be the best donor animals after all. "First of all, there's not enough of them," he explains. "They breed in ones and twos, and take years to grow to full size. Even then, their hearts aren't big enough for a 70-kg. patient." Pigs, he suggested, would be a more practical alternative. But when he tried transplanting pig organs into nonhuman primates (as surrogates for human recipients), they were rejected within minutes.
In 1992, Cooper's team identified a sugar on the surface of porcine cells, called alpha-1,3-galactose (a-gal), as the main target for the immune system's attack. By then, the first genetically modified pigs had appeared, and biotech companies—led by the Swiss-based pharma giant Novartis—began pouring millions of dollars into developing one whose organs could elude or resist the human body's defenses.
Disaster struck five years later, when scientists reported that a virus whose genetic code was written into pig DNA could infect human cells in lab experiments. Although there was no evidence that the virus, known as PERV (for porcine endogenous retrovirus) could cause disease in people, the discovery stirred fears that xenotransplants might unleash a deadly epidemic. Facing scrutiny from government regulators and protests from anti-GMO and animal-rights activists, Novartis "pulled out completely," Cooper recalls. "They slaughtered all their pigs and closed down their research facility." Competitors soon followed suit.
The riddles surrounding animal-to-human transplants are far from fully solved.
A New Chapter – With New Questions
Yet xenotransplantation's visionaries labored on, aided by advances in genetic engineering and immunosuppression, as well as in the scientific understanding of rejection. In 2003, a team led by Cooper's longtime colleague David Sachs, at Harvard Medical School, developed a pig lacking the gene for a-gal; over the next few years, other scientists knocked out genes expressing two more problematic sugars. In 2013, Muhammad Mohiuddin, then chief of the transplantation section at the NHLBI, further modified a group of triple-knockout pigs, adding genes that code for two human proteins: one that shields cells from attack by an immune mechanism known as the complement system; another that prevents harmful coagulation. (It was those pigs whose hearts recently broke survival records when transplanted into baboon bellies. Mohiuddin has since become director of xenoheart transplantation at the University of Maryland's new Center for Cardiac Xenotransplantation Research.) And in August 2017, researchers at Harvard Medical School, led by George Church and Luhan Yang, announced that they'd used CRISPR-cas9—an ultra-efficient new gene-editing technique—to disable 62 PERV genes in fetal pig cells, from which they then created cloned embryos. Of the 37 piglets born from this experiment, none showed any trace of the virus.
Still, the riddles surrounding animal-to-human transplants are far from fully solved. One open question is what further genetic manipulations will be necessary to eliminate all rejection. "No one is so naïve as to think, 'Oh, we know all the genes—let's put them in and we are done,'" biologist Sean Stevens, another leading researcher, told the The New York Times. "It's an iterative process, and no one that I know can say whether we will do two, or five, or 100 iterations." Adding traits can be dangerous as well; pigs engineered to express multiple anticoagulation proteins, for example, often die of bleeding disorders. "We're still finding out how many you can do, and what levels are acceptable," says Cooper.
Another question is whether PERV really needs to be disabled. Cooper and some of his colleagues note that pig tissue has long been used for various purposes, such as artificial heart valves and wound-repair products, without incident; requiring the virus to be eliminated, they argue, will unnecessarily slow progress toward creating viable xenotransplant organs and the animals that can provide them. Others disagree. "You cannot do anything with pig organs if you do not remove them," insists bioethicist Jeantine Lunshof, who works with Church and Yang at Harvard. "The risk is simply too big."
"We've removed the cells, so we don't have to worry about latent viruses."
Meanwhile, over the past decade, other approaches to xenotransplantation have emerged. One is interspecies blastocyst complementation, which could produce organs genetically identical to the recipient's tissues. In this method, genes that produce a particular organ are knocked out in the donor animal's embryo. The embryo is then injected with pluripotent stem cells made from the tissue of the intended recipient. The stem cells move in to fill the void, creating a functioning organ. This technique has been used to create mouse pancreases in rats, which were then successfully transplanted into mice. But the human-pig "chimeras" recently created by scientists were destroyed after 28 days, and no one plans to bring such an embryo to term anytime soon. "The problem is that cells don't stay put; they move around," explains Father Kevin FitzGerald, a bioethicist at Georgetown University. "If human cells wind up in a pig's brain, that leads to a really interesting conundrum. What if it's self-aware? Are you going to kill it?"
Much further along, and less ethically fraught, is a technique in which decellularized pig organs act as a scaffold for human cells. A Minnesota-based company called Miromatrix Medical is working with Mayo Clinic researchers to develop this method. First, a mild detergent is pumped through the organ, washing away all cellular material. The remaining structure, composed mainly of collagen, is placed in a bioreactor, where it's seeded with human cells. In theory, each type of cell that normally populates the organ will migrate to its proper place (a process that naturally occurs during fetal development, though it remains poorly understood). One potential advantage of this system is that it doesn't require genetically modified pigs; nor will the animals have to be raised under controlled conditions to avoid exposure to transmissible pathogens. Instead, the organs can be collected from ordinary slaughterhouses.
Recellularized livers in bioreactors
(Courtesy of Miromatrix)
"We've removed the cells, so we don't have to worry about latent viruses," explains CEO Jeff Ross, who describes his future product as a bioengineered human organ rather than a xeno-organ. That makes PERV a nonissue. To shorten the pathway to approval by the Food and Drug Administration, the replacement cells will initially come from human organs not suitable for transplant. But eventually, they'll be taken from the recipient (as in blastocyst complementation), which should eliminate the need for immunosuppression.
Clinical trials in xenotransplantation may begin as early as 2020.
Miromatrix plans to offer livers first, followed by kidneys, hearts, and eventually lungs and pancreases. The company recently succeeded in seeding several decellularized pig livers with human and porcine endothelial cells, which flocked obediently to the blood vessels. Transplanted into young pigs, the organs showed unimpaired circulation, with no sign of clotting. The next step is to feed all four liver cell types back into decellularized livers, and see if the transplanted organs will keep recipient pigs alive.
Ross hopes to launch clinical trials by 2020, and several other groups (including Cooper's, which plans to start with kidneys) envision a similar timeline. Investors seem to share their confidence. The biggest backer of xenotransplantation efforts is United Therapeutics, whose founder and co-CEO, Martine Rothblatt, has a daughter with a lung condition that may someday require a transplant; since 2011, the biotech firm has poured at least $100 million into companies pursuing such technologies, while supporting research by Cooper, Mohiuddin, and other leaders in the field. Church and Yang, at Harvard, have formed their own company, eGenesis, bringing in a reported $40 million in funding; Miromatrix has raised a comparable amount.
It's impossible to predict who will win the xenotransplantation race, or whether some new obstacle will stop the competition in its tracks. But Jennifer Cisneros is rooting for all the contestants. "These technologies could save my life," she says. If she hasn't found another kidney before trials begin, she has just one request: "Sign me up."
Doctors used new eye drops to treat a rare genetic disorder.
The gene therapy: In May 2023, the FDA approved Vyjuvek, the first gene therapy to treat DEB.
Vyjuvek uses an inactivated herpes simplex virus to deliver working copies of the gene for collagen 7 to the body’s cells. In small trials, 65 percent of DEB-caused wounds sprinkled with it healed completely, compared to just 26 percent of wounds treated with a placebo.
“It was like looking through thick fog.” -- Antonio Vento Carvajal.
The patient: Antonio Vento Carvajal, a 14 year old living in Florida, was one of the trial participants to benefit from Vyjuvek, which was developed by Pittsburgh-based pharmaceutical company Krystal Biotech.
While the topical gene therapy could help his skin, though, it couldn’t do anything to address the severe vision loss Antonio experienced due to his DEB. He’d undergone multiple surgeries to have scar tissue removed from his eyes, but due to his condition, the blisters keep coming back.
“It was like looking through thick fog,” said Antonio, noting how his impaired vision made it hard for him to play his favorite video games. “I had to stand up from my chair, walk over, and get closer to the screen to be able to see.”
The idea: Encouraged by how Antonio’s skin wounds were responding to the gene therapy, Alfonso Sabater, his doctor at the Bascom Palmer Eye Institute, reached out to Krystal Biotech to see if they thought an alternative formula could potentially help treat his patient’s eyes.
The company was eager to help, according to Sabater, and after about two years of safety and efficacy testing, he had permission, under the FDA’s compassionate use protocol, to treat Antonio’s eyes with a version of the topical gene therapy delivered as eye drops.
The results: In August 2022, Sabater once again removed scar tissue from Antonio’s right eye, but this time, he followed up the surgery by immediately applying eye drops containing the gene therapy.
“I would send this message to other families in similar situations, whether it’s DEB or another condition that can benefit from genetic therapy. Don’t be afraid.” -- Yunielkys “Yuni” Carvajal.
The vision in Antonio’s eye steadily improved. By about eight months after the treatment, it was just slightly below average (20/25) and stayed that way. In March 2023, Sabater performed the same procedure on his young patient’s other eye, and the vision in it has also steadily improved.
“I’ve seen the transformation in Antonio’s life,” said Sabater. “He’s always been a happy kid. Now he’s very happy. He can function pretty much normally. He can read, he can study, he can play video games.”
Looking ahead: The topical gene therapy isn’t a permanent fix — it doesn’t alter Antonio’s own genes, so he has to have the eye drops reapplied every month. Still, that’s far less invasive than having to undergo repeated surgeries.
Sabater is now working with Krystal Biotech to launch trials of the eye drops in other patients, and not just those with DEB. By changing the gene delivered by the therapy, he believes it could be used to treat other eye disorders that are far more common — Fuchs’ dystrophy, for example, affects the vision of an estimated 300 million people over the age of 30.
Antonio’s mother, Yunielkys “Yuni” Carvajal, meanwhile, has said that having her son be the first to receive the eye drops was “very scary,” but she’s hopeful others will take a chance on new gene therapies if given the opportunity.
“I would send this message to other families in similar situations, whether it’s DEB or another condition that can benefit from genetic therapy,” she said. “Don’t be afraid.”
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
A chatbot from the nonprofit National Eating Disorders Association aimed to provide 24/7 guidance on eating disorders. Several drawbacks point to the importance of therapist-tech collaboration in multiple areas of health.
Then everything went off the rails. Tessa told Maxwell an unequivocal yes, and that “it’s important to approach weight loss with a balanced and realistic mindset,” and recommended eating whole foods and lean proteins to create a 500-1000 calorie per day deficit that would lead to a loss of 1-2 pounds per week. To most people, the advice sounds anodyne, but alarm bells sounded in Maxwell’s head.
“This is actively going to feed eating disorders,” Maxwell says. “Having a chatbot be the direct response to someone reaching out for support for an eating disorder instead of the helpline seems careless.”
“The scripts that are being fed into the chatbot are only going to be as good as the person who’s feeding them.” -- Alexis Conason.
According to several decades of research, deliberate weight loss in the form of dieting is a serious risk for people with eating disorders. Maxwell says that following medical advice like what Tessa prescribed was what triggered her eating disorder as a child. And Maxwell wasn’t the only one who got such advice from the bot. When eating disorder therapist Alexis Conason tried Tessa, she asked the AI chatbot many of the questions her patients had. But instead of getting connected to resources or guidance on recovery, Conason, too, got tips on losing weight and “healthy” eating.
“The scripts that are being fed into the chatbot are only going to be as good as the person who’s feeding them,” Conason says. “It’s important that an eating disorder organization like NEDA is not reinforcing that same kind of harmful advice that we might get from medical providers who are less knowledgeable.”
Maxwell’s post about Tessa on Instagram went viral, and within days, NEDA had scrubbed all evidence of Tessa from its website. The furor has raised any number of issues about the harm perpetuated by a leading eating disorder charity and the ongoing influence of diet culture and advice that is pervasive in the field. But for AI experts, bears and bulls alike, Tessa offers a cautionary tale about what happens when a still-immature technology is unfettered and released into a vulnerable population.
Given the complexity involved in giving medical advice, the process of developing these chatbots must be rigorous and transparent, unlike NEDA’s approach.
“We don’t have a full understanding of what’s going on in these models. They’re a black box,” says Stephen Schueller, a clinical psychologist at the University of California, Irvine.
The health crisis
In March 2020, the world dove head-first into a heavily virtual world as countries scrambled to try and halt the pandemic. Even with lockdowns, hospitals were overwhelmed by the virus. The downstream effects of these lifesaving measures are still being felt, especially in mental health. Anxiety and depression are at all-time highs in teens, and a new report in The Lancet showed that post-Covid rates of newly diagnosed eating disorders in girls aged 13-16 were 42.4 percent higher than previous years.
And the crisis isn’t just in mental health.
“People are so desperate for health care advice that they'll actually go online and post pictures of [their intimate areas] and ask what kind of STD they have on public social media,” says John Ayers, an epidemiologist at the University of California, San Diego.
For many people, the choice isn’t chatbot vs. well-trained physician, but chatbot vs. nothing at all.
I know a bit about that desperation. Like Maxwell, I have struggled with a multi-decade eating disorder. I spent my 20s and 30s bouncing from crisis to crisis. I have called suicide hotlines, gone to emergency rooms, and spent weeks-on-end confined to hospital wards. Though I have found recovery in recent years, I’m still not sure what ultimately made the difference. A relapse isn't improbably, given my history. Even if I relapsed again, though, I don’t know it would occur to me to ask an AI system for help.
For one, I am privileged to have assembled a stellar group of outpatient professionals who know me, know what trips me up, and know how to respond to my frantic texts. Ditto for my close friends. What I often need is a shoulder to cry on or a place to vent—someone to hear and validate my distress. What’s more, my trust in these individuals far exceeds my confidence in the companies that create these chatbots. The Internet is full of health advice, much of it bad. Even for high-quality, evidence-based advice, medicine is often filled with disagreements about how the evidence might be applied and for whom it’s relevant. All of this is key in the training of AI systems like ChatGPT, and many AI companies remain silent on this process, Schueller says.
The problem, Ayers points out, is that for many people, the choice isn’t chatbot vs. well-trained physician, but chatbot vs. nothing at all. Hence the proliferation of “does this infection make my scrotum look strange?” questions. Where AI can truly shine, he says, is not by providing direct psychological help but by pointing people towards existing resources that we already know are effective.
“It’s important that these chatbots connect [their users to] to provide that human touch, to link you to resources,” Ayers says. “That’s where AI can actually save a life.”
Before building a chatbot and releasing it, developers need to pause and consult with the communities they hope to serve.
Unfortunately, many systems don’t do this. In a study published last month in the Journal of the American Medical Association, Ayers and colleagues found that although the chatbots did well at providing evidence-based answers, they often didn’t provide referrals to existing resources. Despite this, in an April 2023 study, Ayers’s team found that both patients and professionals rated the quality of the AI responses to questions, measured by both accuracy and empathy, rather highly. To Ayers, this means that AI developers should focus more on the quality of the information being delivered rather than the method of delivery itself.
Many mental health professionals have months-long waitlists, which leaves individuals to deal with illnesses on their own.
Adobe Stock
The human touch
The mental health field is facing timing constraints, too. Even before the pandemic, the U.S. suffered from a shortage of mental health providers. Since then, the rates of anxiety, depression, and eating disorders have spiked even higher, and many mental health professionals report waiting lists that are months long. Without support, individuals are left to try and cope on their own, which often means their condition deteriorates even further.
Nor do mental health crises happen during office hours. I struggled the most late at night, long after everyone else had gone to bed. I needed support during those times when I was most liable to hurt myself, not in the mornings and afternoons when I was at work.
In this sense, a 24/7 chatbot makes lots of sense. “I don't think we should stifle innovation in this space,” Schueller says. “Because if there was any system that needs to be innovated, it's mental health services, because they are sadly insufficient. They’re terrible.”
But before building a chatbot and releasing it, Tina Hernandez-Boussard, a data scientist at Stanford Medicine, says that developers need to pause and consult with the communities they hope to serve. It requires a deep understanding of what their needs are, the language they use to describe their concerns, existing resources, and what kinds of topics and suggestions aren’t helpful. Even asking a simple question at the beginning of a conversation such as “Do you want to talk to an AI or a human?” could allow those individuals to pick the type of interaction that suits their needs, Hernandez-Boussard says.
NEDA did none of these things before deploying Tessa. The researchers who developed the online body positivity self-help program upon which Tessa was initially based created a set of online question-and-answer exercises to improve body image. It didn’t involve generative AI that could write its own answers. The bot deployed by NEDA did use generative AI, something that no one in the eating disorder community was aware of before Tessa was brought online. Consulting those with lived experience would have flagged Tessa’s weight loss and “healthy eating” recommendations, Conason says.
The question for healthcare isn’t whether to use AI, but how.
NEDA did not comment on initial Tessa’s development and deployment, but a spokesperson told Leaps.org that “Tessa will be back online once we are confident that the program will be run with the rule-based approach as it was designed.”
The tech and therapist collaboration
The question for healthcare isn’t whether to use AI, but how. Already, AI can spot anomalies on medical images with greater precision than human eyes and can flag specific areas of an image for a radiologist to review in greater detail. Similarly, in mental health, AI should be an add-on for therapy, not a counselor-in-a-box, says Aniket Bera, an expert on AI and mental health at Purdue University.
“If [AIs] are going to be good helpers, then we need to understand humans better,” Bera says. That means understanding what patients and therapists alike need help with and respond to.
One of the biggest challenges of struggling with chronic illness is the dehumanization that happens. You become a patient number, a set of laboratory values and test scores. Treatment is often dictated by invisible algorithms and rules that you have no control over or access to. It’s frightening and maddening. But this doesn’t mean chatbots don’t have any place in medicine and mental health. An AI system could help provide appointment reminders and answer procedural questions about parking and whether someone should fast before a test or a procedure. They can help manage billing and even provide support between outpatient sessions by offering suggestions for what coping skills to use, the best ways to manage anxiety, and point to local resources. As the bots get better, they may eventually shoulder more and more of the burden of providing mental health care. But as Maxwell learned with Tessa, it’s still no replacement for human interaction.
“I'm not suggesting we should go in and start replacing therapists with technologies,” Schueller says. Instead, he advocates for a therapist-tech collaboration. “The technology side and the human component—these things need to come together.”