Aaron James now has one blue eye and one brown — the former his own, the latter from an unprecedented whole-eye transplant.Credit: Haley Ricciardi/NYU Langone Health
For Aaron James, it still hasn’t quite sunk in that he received the first successful whole-eye transplant in history. “It just blows my mind being a part of something this big,” says the 47-year-old father from Hot Springs, Arkansas.
In 2021, James was injured in an electrical accident while working as a high-voltage lineman. He lost his dominant left arm, left eye, chin and nose. For two years, he was unable to eat solid food, taste, smell or talk normally.
In May 2023, he received the first whole-eye and face transplant at New York University (NYU) Langone Health in New York City. More than a year after the surgery, his transplanted eye remains healthy — the retina can even respond to light — but James cannot see out of it.
“It is a technically brilliant operation,” says surgeon Bohdan Pomahač at Yale School of Medicine in New Haven, Connecticut, who in 2011 performed the first full facial transplant in the United States, but was not involved with James’s case. “The authors pushed the boundaries of innovation.” The surgery is described today in JAMA1.
Marathon surgery
A large medical team transplanted the whole left eye, the bony socket around it, the nose, a piece of chin bone and the associated muscles, nerves and blood vessels to James from a donor whose brain showed no functional activity. The surgery took about 21 hours.
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Doctors never expected James to regain sight in the transplanted eye, says Daniel Ceradini, a surgeon at NYU Langone Health and first author of the study.That’s because there was no evidence that the donor’s optic nerve could successfully reconnect to James’s brain. The optic nerve, which sends information from the retina to the brain, is part of the central nervous system, and how to regenerate that system is a mystery. But the operation does take researchers a step closer to an eye transplant that could one day restore vision, which, Ceradini says, has been “considered a holy grail”.
James needed a face transplant and was willing to take on the extra risk associated with an attempted eye transplant in return for helping future transplant recipients. “I was already going to be on immunosuppressants from the face transplant,” he says. “All we could do was gain something.”
Practice, practice
Surgical dissection of the eye is so complex that the team practiced at least 15 times on cadavers, says Ceradini.
Many scientific advances came together to make the surgery happen. The team “essentially developed a new operation based on existing principles”, says Pomahač. The blood supply to the eyes is from a different artery from that supplying the rest of the face. To ensure that the donated eye didn’t lose blood flow for too long, the surgeons connected the artery that supplied the donor’s eye to a branch of the donor’s external carotid artery, a large vessel that starts near the neck. The whole assembly was then transplanted into James, a procedure that has never been achieved in humans . “They figured out how to recover an eyeball so that it doesn’t damage the blood flow,” says Pomahač.
Another advance was the creation of a pair of 3D-printed surgical guides that allowed the surgeons to take precisely the right amount of donor bone needed to fit James’s face. The guides were based on computed tomography scans of the donor’s and James’s faces, and were fitted over their faces during surgery.“The donor piece fits right in there, like a snap-fit puzzle piece,” says Ceradini.
After all this, no one knew how the transplanted eyeball would behave, says Ceradini: “Does it shrink? Does the retina work?”
An itching sensation
When James awoke from surgery, the first thing he noticed was the smell. After two years with no sense of smell, he was grateful, even though the odour was “hospital”, he says, laughing.
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After about a week and a half, he saw his new face for the first time. Even now, when he passes a mirror, he will gaze, captivated. He no longer wears an eye patch and mask when he goes out, as he did before the transplant. He is thrilled to be able to grow a beard again.
The transplanted eye cannot move or see, but it hasnormal pressure and good blood flow, and the retina responds to light. James can feel a sensation of itching deep in the eye socket, and feeling around the eye has started to come back.The peripheral nerves around the eye regrow rather randomly, Ceradini says.
Restoring vision
It is unclear whether an eye transplant in which the recipient regains vision will one day be feasible. Ceradini thinks it is “an achievable goal in the near future”. Pomahač disagrees. Both do agree, however, that the key missing piece to achieving it is working out how to regenerate the optic nerve. Pomahač thinks that this is unlikely to be possible. “It may happen if we figure out brain or spinal-cord regeneration,” he says.
Nonetheless, James, his wife Meagan and their 19-year-old daughter Allie are in good spirits, which for them means teasing each other. Allie recently posted on TikTok, rating things her dad has done, Meaghan recalls. “100/10, made medical history,” Allie posted. “Still bald headed, tho.”
00:45 Why a ‘nuclear clock’ is now within researchers’ reach
Researchers have made a big step towards the creation of the long theorized nuclear clock, by getting the most accurate measurement of the frequency of light required to push thorium nuclei into a higher energy state. Such a timekeeper would differ from the best current clocks as their ‘tick’ corresponds to the energy transitions of protons and neutrons, rather than electrons. Nuclear clocks have the potential to be more robust and accurate than current systems, and could offer researchers new insights into fundamental forces present within atomic nuclei.
Research Article: Zhang et al.
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10:10 Research Highlights
The star that got partially shredded by a supermassive black hole, not just once, but twice, and how heatwaves could mangle bumblebees’ sense of smell.
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12:11 How engineered immune cells could help limit damage after spinal injury
By harnessing T cells to fine-tune the inflammation response, researchers have limited the damage caused by spinal injury in mice, an approach they hope might one day translate into a human therapy. Following injury to the central nervous system, immune cells rush to the scene, resulting in a complex array of effects, both good and bad. In this work researchers have identified the specific kind of T cells that amass at the site, and used them to create an immunotherapy that helps the mice recover more quickly from injuries by slowing damage to neurons.
Research article: Gao et al.
20:36 Briefing Chat
How unprecedented floods in Brazil have helped and hindered paleontologists, and the ‘AI scientist’ that does everything from literature review through to manuscript writing, to an extent.
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A transgender person receives a testosterone injection as part of their gender-affirming hormone therapy.Credit: Zuma Press/Alamy
When trans men receive testosterone therapy, their bodies begin to resemble those of cis men in many ways — including their immune systems. That’s according to a study published today in Nature1, one of the largest yet to examine how gender-affirming hormone therapy (GAHT) affects the immune system over time.
The results provide much-needed insight and could help to explain why men tend to be more susceptible to viral infections than women and women are often more susceptible to autoimmune conditions.
The study is important because physicians want GAHT “to be safe, of course”, says co-author Mats Holmberg, an endocrinologist at the Karolinska Institute in Stockholm, who provides gender-affirming care. It is a step towards being able to administer the best treatment possible, Holmberg says.
An immune balance point?
During their study, Holmberg and his colleagues collected blood samples from 23 trans men (who were assigned female at birth but sought masculinizing GAHT) at three time points: before they began GAHT, three months into treatment and one year into treatment. Over time, the researchers observed a shift in the participants’ immune response, from a type characterized by high levels of immune-signalling proteins called type I interferons, which specialize in fighting viral infections, to one featuring an abundance of an inflammatory protein called tumour necrosis factor (TNF), which is associated with muscle growth.
What’s new here is that sex hormones seem to cross-regulate immunological pathways, says study co-author Petter Brodin, a paediatric immunologist at the Karolinska Institute. As testosterone levels go up and oestrogen levels go down, it seems as if the immune system passes through a balance point, Brodin adds.
“This is a very interesting new finding that will trigger a lot of research,” says Marcus Altfeld, an immunologist at the University Medical Center Hamburg–Eppendorf in Germany. In particular, Altfeld wants to understand whether rising TNF levels reduce the amount of type I interferons directly, or whether testosterone mediates both of these effects independently.
Disease implications
The researchers point out that their molecular-level findings echo real-world susceptibility to infection and disease. For instance, during the early days of the COVID-19 pandemic, men infected with the coronavirus SARS-CoV-2 had about a 50% higher death rate than did women who were infected. This makes sense, Brodin says, because women typically have high levels of type I interferons, helping them to fight off infections.
Heed lessons from past studies involving transgender people: first, do no harm
On the flip side, women develop long COVID more frequently than do men — about 76% more often, according to one study2. This could be because long COVID bears a resemblance to autoimmune diseases, some of which are associated with overactivation of the type I interferon system.
Other research also points in this direction. A preprint posted ahead of peer review3 in March shows that low levels of testosterone are a predictor of whether women will develop long COVID. “The importance of sex hormones in both acute, severe COVID and long COVID is becoming more appreciated,” says preprint co-author Akiko Iwasaki, an immunologist at Yale University in New Haven, Connecticut.
But hormones are probably not the whole story when it comes to differences in susceptibility to COVID-19 or other diseases, researchers say. The X-chromosome — of which females typically have two copies, and males one — also deserves consideration, says Sabra Klein, an immunologist at Johns Hopkins University in Baltimore, Maryland. The X-chromosome is rich in genes related to the immune system so, for instance, attributing sex differences in COVID-19 outcomes to hormones alone is “probably simplifying something that’s more complex”, she says.
Autoimmune risk
Trans men need not be too concerned that testosterone therapy will raise their risk of viral infections. “Most of the normal infections, they are common in both sexes,” Altfeld says, and people get over them. Autoimmune disorders, by contrast, can be severe, and Holmberg is concerned that oestrogen therapy, which reduces testosterone, might increase the risk of developing these conditions.
The fraught quest to account for sex in biology research
But the study didn’t examine oestrogen therapy or safety directly. Klein thinks it’s too early to say whether the link between autoimmune diseases and GAHT warrants consideration. “These are small sample sizes,” she says — 23 people isn’t a lot. “This is pointing towards the need for more research.”
Some physicians already warn their patients about the link. Altfeld, who studies the effect of GAHT on the immune system, says he works with clinicians who inform trans women that oestrogen therapy comes with a risk of developing an autoimmune disease. The potential downside is “well known in the community”, he says.
But not everyone has such well-informed doctors. It’s “really hard” to find a medical provider who specializes in multiple disciplines, such as immunology and gender-affirming care, and can treat “intersectional needs”, says Jamie, a transmasculine person (assigned female at birth but identifying with masculinity) who has an autoimmune condition called Sjögren’s syndrome, and who asked to be identified by a pseudonym because not everyone in their life is aware of their gender identity.
Jamie decided to undergo testosterone therapy both for gender affirmation and to treat Sjögren’s syndrome — a course of action they undertook on the basis of their own reading of the scientific literature, rather than because of a physician’s advice. Since then, Jamie has traded testosterone therapy for an immunosuppressant called adalimumab (sold as Humira) in an effort to improve their health. Adalimumab inhibits TNF, which is elevated in people with Sjögren’s. Holmberg and Brodin’s work makes Jamie wonder whether returning to testosterone therapy would make the adalimumab they are taking less effective, given that their TNF levels could rise as a result. “My god, I wish there were studies on this so that we knew how the interactions worked instead of just having to guess,” they say.
Nature, Published online: 03 September 2024; doi:10.1038/d41586-024-02789-5
The human brain is usually considered to be beyond the reach of most immune cells. However, analysis of people who have brain tumours has revealed tumour-targeting T cells of the immune system in skull bones near the cancer site.
Nature, Published online: 28 August 2024; doi:10.1038/d41586-024-02436-z
After a heart attack, cardiac muscle cells at the border between injured and healthy tissue instigate an inflammatory response, which spreads to neighbouring cells and makes the heart wall vulnerable to tearing.
Nature, Published online: 28 August 2024; doi:10.1038/d41586-024-02657-2
The immune-signalling protein TNF has an essential role in inflammatory responses. Two people who were found to have no functional TNF are surprisingly healthy and able to fend off most infections, but are susceptible to tuberculosis.
Crohn’s disease, a form of inflammatory bowel disease, often affects the intestines (artist’s illustration).Credit: Sebastian Kaulitzki/Science Photo Library
When geneticist James Lee and his colleagues published a paper in June linking a gene to inflammatory bowel disease (IBD), he didn’t expect the public to take much notice. Things did not go as planned.
“I got inundated,” he says.
By the end, Lee did more than 25 interviews for radio and print outlets around the world and received hundreds of e-mails from people with IBD. “It’s a testament to how common inflammatory bowel disease is,” says Lee, who works at the Francis Crick Institute in London. “And also a testament to how desperate people are for better treatments.”
Lee’s paper, published in Nature1, is one of several recent reports offering hope that people with IBD could one day have better treatment options tailored to their disease. Lee and his colleagues found that changes in the activity of a gene that is important in the immune system could contribute to some cases of the disease. Another study found that some people with IBD make antibodies that disable a pivotal anti-inflammatory protein2 and a third study tracked how populations of gut bacteria adapt to an inflamed environment3.
The papers look at IBD from different angles, but together offer a glimpse into the ways that physicians might one day be able to better match people with IBD to appropriate treatments, says David Artis, an immunologist at Weill Cornell Medicine in New York City. “Not every inflammatory bowel disease patient who walks in the door is the same,” he says. “If we can map that difference to some extent, I think we’re going to be able to better treat those people.”
Life-altering diseases
IBD is a painful condition that causes chronic inflammation of the digestive tract. Two of the most common forms of IBD are ulcerative colitis and Crohn’s disease. Both can cause diarrhoea, anaemia and abdominal cramping.
Like many autoimmune disorders, IBD has an aetiology that is murky and complex, with contributions from both genetics and the environment. What is clear is that incidence of the disease is rising in many regions of the world4.
Over the past decade, researchers have amassed a lengthy list of genetic variations that are linked to IBD. But Lee and his colleagues decided to examine a region of the genome where few geneticists had bothered to look: a “gene desert”, says Lee, so named because it is devoid of any recognizable genes. “We didn’t know what we were going to find,” he says. “And we ended up finding a master regulator of inflammatory responses.”
Mucus-producing cells (pink; artificially coloured) stud the intestines of a person with ulcerative colitis, a common form of inflammatory bowel disease.Credit: Steve Gschmeissner/Science Photo Library
This master regulator is a stretch of DNA that controls the activity of a gene called ETS2, which is located far away from the gene desert. High levels of ETS2 activity, the team found, boost the ability of immune cells called macrophages to promote inflammation.
The finding also indicated that a class of cancer drugs called MEK inhibitors might prevent the activation of ETS2. The team found that these drugs could block the effects of the ETS2 protein, including the release of inflammation-promoting molecules, in cells grown in the laboratory. But MEK inhibitors can become toxic to other cells if given over the long term, says Lee, and so the team is developing ways to deliver the inhibitors only to macrophages before testing the approach in people with IBD.
Rogue antibodies
Another study has found a select group of people with IBD who might have a new therapeutic option in the near future. Paediatric immunologist Sophie Hambleton at Newcastle University in Newcastle upon Tyne, UK, and her colleagues analysed samples from two children with IBD. The scientists discovered that the children were producing antibodies that block the activity of a protein called IL-102. This protein has anti-inflammatory effects in the gut.
But the children’s antibodies meant that IL-10 was unable to dampen inflammation in their intestines, leading to IBD, the researchers reported in July in the New England Journal of Medicine. Once the link between IL-10 and their disease was identified, one of the children was treated with therapies to deplete the antibodies, easing their symptoms.
It’s unclear how many people with IBD make antibodies against their own IL-10, says Hambleton. But when the team looked at a sample of adults with IBD, they found “a clear minority” who also produced the antibodies. “We are very confident that this is going to be a contributory mechanism in more patients,” she says.
Microbiome reaction
In addition to genetics and immune cells, microorganisms are thought to play a part in IBD. In the third study, Christopher Smillie, who studies the human microbiome at Harvard Medical School in Boston, Massachusetts, and his colleagues, looked at how chronic inflammation shapes evolution of the microorganisms living in the digestive track3.
Gut feeling yields evidence of microbial involvement in autoimmunity
They identified 140,000 bacterial strains in stool samples from people with and without IBD. Hundreds of these strains were associated with IBD, and many appear to have adapted to living in inflamed tissue. Among those, several could be used to predict disease severity: for example, the abundance of some strains of Eggerthella lenta declined as the levels of a protein associated with inflammation rose. The results were published in Cell Host & Microbe in July.
Ultimately, Smillie hopes that characterization of these microorganisms will lead to ways to monitor disease progression, and to sort people with IBD into groups on the basis of how likely they are to respond to potential therapies.
Each of these studies could contribute to that goal, but the work is still preliminary, says Gabriel Nuñez, an immunologist at the University of Michigan Medical School in Ann Arbor. For example, the microbial study does not show that any of these organisms contribute to disease, he notes. And it is unclear what proportion of people with IBD have altered ETS2 activity or make autoantibodies against IL-10. “Perhaps these are rare patients, and only a handful in the world will benefit,” he says.
Nevertheless, if only a handful of people find relief because of these results, that will be progress, he adds. “Even if you cure only one patient, it’s important for that person and their family.”
The vagus nerve connects the brain region called the amygdala (red; artist’s illustration) to nerves for the Brunner’s glands in the gut.Credit: Sebastian Kaulitzki/Science Photo Library
Stress can make people feel sick, and bacteria in the gut might be to blame, according to a study1 in mice. The research suggests that a stressed brain directly shuts down specific glands in the gut, affecting gut bacteria and the body’s broader immune system.
The study “is a technical tour de force”, says neuroscientist John Cryan at University College Cork in Ireland, who reviewed the study. Most work on the gut–brain connection has focused on how bacteria affect the brain, so Cryan welcomes research into how psychological states can exert ‘top-down’ control of bacteria. “It’s a really cool part of the puzzle”, he says. The research was published on 8 August in Cell.
Gut–brain chitchat
Researchers have long known that the gut and brain ‘talk’ to each other. Under stress, the brain spurs the release of hormones that can trigger gut conditions such as inflammatory bowel disease. And certain bacteria in the gut can release chemical signals that affect the brain and behaviour.
Your brain could be controlling how sick you get — and how you recover
But the neural communication pathways are less understood. To find out more, neuroscientist Ivan de Araujo at the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, and his colleagues focused on small organs called Brunner’s glands that are found in the walls of the small intestine. Little is known about these glands, other than that they produce mucus and contain numerous neurons.
De Araujo’s team found that removing the Brunner’s glands of mice made the animals more susceptible to infection. It also raised markers of inflammation, a flood of immune chemicals and cells that can damage tissues. The team saw a similar effect in humans: people who’d had tumours removed from the part of the gut containing Brunner’s glands had higher levels of white blood cells — a marker of inflammation — than people who’d had tumours removed from other areas.
Housekeeping bacteria
Closer analysis showed that removing the Brunner’s glands from mice eliminates bacteria in the Lactobacillus genus, which live in the small intestine. In a healthy gastrointestinal tract, Lactobacilli stimulate production of proteins that act as grout between the cells lining the gut, keeping most of the gut’s contents inside while allowing certain nutrients to enter the bloodstream. But when Lactobacilli are gone, the gut becomes ‘leaky’ and “things that shouldn’t cross into the blood do so”, de Araujo says. The immune system attacks these foreign molecules, causing the inflammation and illness seen in mice without Brunner’s glands.
The researchers then examined the glands’ neurons. They found that the neurons connect to fibres in the vagus nerve, a communications pathway between the gut and the brain. These fibres run directly to the brain’s amygdala, which is involved in emotion and stress response.
Placing mice with intact Brunner’s glands under chronic stress had the same effect as removing the glands: Lactobacillus levels fell, and inflammation increased. This suggested that stress had shut down the Brunner’s glands.
Lines of communication
Asya Rolls, a neuroimmunologist at the Technion — Israel Institute of Technology in Haifa, is impressed by the direct line between the brain, Brunner’s glands, bacteria and immune system. “The specificity of the connection is amazing,” she says. But she cautions that the pathways in mice might not be identical to those in humans.
“This paper is pretty inspiring,” says Christoph Thaiss, a microbiologist and neuroscientist at the University of Pennsylvania in Philadelphia. Understanding the specific pathways that connect the brain and gut, he says, could help researchers to study questions such as why some people are more resilient to stress than others.
De Araujo says the study could have implications for treating stress-related disorders such as inflammatory bowel disease. His group is now studying whether chronic stress affects this pathway in infants, who receive their Lactobacillus through breast milk. “We are excited about the idea that these glands are important for normal development and immune function early in life,” de Araujo says.
