A new approach to kidney transplants would reprogram the immune system
Talaris Therapeutics, Inc., a biotech company based in Louisville, Ky., is edging closer to eradicating the need for immunosuppressive drugs for kidney transplant patients.
In a series of research trials, Talaris is infusing patients with immune system stem cells from their kidney donor to create a donor-derived immune system that accepts the organ without the need for anti-rejection medications. That newly generated system does not attack other parts of the recipient’s body and also fights off infections and diseases as a healthy immune system would.
Talaris is now moving into the final clinical trial, phase III, before submitting for FDA approval. Known as Freedom-1, this trial has 17 sites open throughout the U.S., and Talaris will enroll a total of 120 kidney transplant recipients. One day after receiving their donor’s kidney, 80 people will undergo the company’s therapy, involving the donor’s stem cells and other critical cells that are processed at their facility. Forty will have a regular kidney transplant and remain on immunosuppression to provide a control group.
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Robert Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
The procedure was pioneered decades ago by Suzanne Ildstad as a faculty member at the University of Pittsburgh before she became founding CEO of Talaris and then its Chief Scientific Officer. If approved by the FDA, the method could soon become the standard of care for patients in need of a kidney transplant.
“We are working to find a way to reprogram the immune system of transplant recipients so that it sees the donated organ as [belonging to one]self and doesn’t attack it,” explains Scott Requadt, CEO of Talaris. “That obviates the need for lifelong immunosuppression.”
Each year, there are roughly 20,000 kidney transplants, making kidneys the most transplanted organ. About 6,500 of those come from living donors, while deceased donors provide roughly 13,000.
One of the challenges, Requadt points out, is that kidney transplant recipients aren’t always aware of all the implications of immunosuppression. Typically, they will need to take about 20 anti-rejection drugs several times a day to provide immunosuppression as well as treat complications caused by the toxicities of immunosuppression medications. The side effects of chronic immunosuppression include weight gain, high blood pressure, and high cholesterol. These cardiovascular comorbidities, Requadt says, are “often more frequently the cause of death than failure of a transplanted organ.”
Patients who are chronically immunosuppressed generally have much higher rates of infections and cancers that have an immune component to them, such as skin cancers.
For the past couple of years, those patients have experienced heightened anxiety because of the COVID-19 pandemic. Immune-suppressing medicine used to protect their new organ also makes it hard for patients to build immunity to foreign invaders like COVID-19.
A study appearing in the Proceedings of the National Academy of Sciences found the probability of a pandemic with similar impact to COVID-19 is about 2 percent in any year, and estimated that the probability of novel disease outbreaks will grow three-fold in the next few decades. All the more reason to identify an FDA-approved alternative to harsh immunosuppressive drugs.
Of the 18 patients during the phase II research trial who received the Talaris therapy, didn’t take immunosuppression medication and were vaccinated, only two ended up with a COVID infection, according to a review of the data. Among patients who needed to continue taking immunosuppressants or those who didn’t have them but were unvaccinated, the rates of infection were between 40 and 60 percent.
In the earlier phase II study by Talaris with 37 patients, the combined transplantation approach allowed 70 percent of patients to get off all immunosuppression.
“We’ve followed that whole cohort for more than six and a half years and one of them for 12 years from transplant, and every single patient that we got off immunosuppression has been able to stay off,” Requadt says.
That one patient, Robert Waddell, 55, was especially thankful to be weaned off immunosuppressive drugs approximately one year after his transplant procedure. The Louisville resident had long watched his mother, sister and other family members with polycystic kidney disease, or PKD, suffer the effects of chronic immunosuppression. That became his greatest fear when he was diagnosed with end stage renal failure.
Waddell enrolled in the phase II research taking place in Louisville after learning about it in early 2006. He chose to remain in the study when it relocated its clinical headquarters to Northwestern University’s medical center in Chicago a couple years later.
Before surgery, he underwent an enervating regimen of chemotherapy and radiation. It’s required to clear out a patient’s bone marrow cells so that they can be replaced by the donor’s cells. Waddell says the result was worth it: he had his combined kidney and immune system stem cell transplant in May 2009, without any need for chronic immunosuppression.
“I call it ‘short-term pain, long-term gain,’ because it was difficult to go through the conditioning, but after that, it was great,” he says. “I’ve talked to so many kidney recipients who say, ‘I wish I would have done that,’ because most people don’t think about clinical trials, but I was very fortunate.”
Waddell has every reason to support the success of this research, especially given the genetic disorder, PKD, that has plagued his family. One of his four children has PKD. He is anxious for the procedure to become standard of care, if and when his son needs it.
The Talaris procedure was pioneered decades ago by Suzanne Ildstad, founding CEO of Talaris and the company's Chief Scientific Officer, pictured here with the current CEO, Scott Requadt.
Talaris
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
Talaris will continue to follow Waddell and the rest of his cohort to track the effectiveness and safety of the procedure. According to Requadt, the average life of a transplanted kidney is 12 to 15 years, partly because the immunosuppressive drugs worsen the functioning of the organ each year.
“We were the first group to show that we could robustly and fairly reproducibly do this in a clinical setting in humans,” Requadt says. “Most important, we’ve been able to show that we can still get a good engraftment of the stem cells from the donor, even if there is a profound…mismatch between the donor and the recipient’s immune systems.”
In kidney transplantation, it’s important to match for human leukocyte antigens (HLA) because there is a better graft survival in HLA-identical kidney transplants compared with HLA mismatched transplants.
About three months after the transplant, Talaris researchers look for evidence that the donated immune cells and stem cells have engrafted, while making a donor immune system for the patient. If more than 50 percent of the T cells contain the donor’s DNA after six months, patients can start taking fewer immunosuppressants.
“We know from phase II that in our patients who were able to tolerize [accept the organ without rejection] to their donated organ, we saw completely preserved and in fact slightly increased kidney function,” Requadt says. “So, it stands to reason that if you eliminate the drugs that are associated with declining kidney function that you would preserve kidney function, so hopefully the patient will have that one kidney for life.”
Matthew Cooper, director of kidney and pancreas transplantation for MedStar Georgetown Transplant Institute in Washington, DC, states that, “Right now, the Achilles’ heel is we have such a long waiting list and few donors that people die every day waiting for a kidney transplant. Eventually, we will eliminate the organ shortage so that people won’t die from organ failure.”
Cooper, a nationally recognized clinical transplant surgeon for 20 years, says when he started his career, finding a way for patients to forgo immunosuppression was considered “the Holy Grail” of modern transplant medicine.
“Now that we’ve got the protocols in place and some personal examples of how that can happen, it’s pretty exciting to see that all coming together,” he adds.
Can tech help prevent the insect apocalypse?
This article originally appeared in One Health/One Planet, a single-issue magazine that explores how climate change and other environmental shifts are making us more vulnerable to infectious diseases by land and by sea - and how scientists are working on solutions.
On a warm summer day, forests, meadows, and riverbanks should be abuzz with insects—from butterflies to beetles and bees. But bugs aren’t as abundant as they used to be, and that’s not a plus for people and the planet, scientists say. The declining numbers of insects, coupled with climate change, can have devastating effects for people in more ways than one. “Insects have been around for a very long time and can live well without humans, but humans cannot live without insects and the many services they provide to us,” says Philipp Lehmann, a researcher in the Department of Zoology at Stockholm University in Sweden. Their decline is not just bad, Lehmann adds. “It’s devastating news for humans.
”Insects and other invertebrates are the most diverse organisms on the planet. They fill most niches in terrestrial and aquatic environments and drive ecosystem functions. Many insects are also economically vital because they pollinate crops that humans depend on for food, including cereals, vegetables, fruits, and nuts. A paper published in PNAS notes that insects alone are worth more than $70 billion a year to the U.S. economy. In places where pollinators like honeybees are in decline, farmers now buy them from rearing facilities at steep prices rather than relying on “Mother Nature.”
And because many insects serve as food for other species—bats, birds and freshwater fish—they’re an integral part of the ecosystem’s food chain. “If you like to eat good food, you should thank an insect,” says Scott Hoffman Black, an ecologist and executive director of the Xerces Society for Invertebrate Conservation in Portland, Oregon. “And if you like birds in your trees and fish in your streams, you should be concerned with insect conservation.”
Deforestation, urbanization, and agricultural spread have eaten away at large swaths of insect habitat. The increasingly poorly controlled use of insecticides, which harms unintended species, and the proliferation of invasive insect species that disrupt native ecosystems compound the problem.
“There is not a single reason why insects are in decline,” says Jessica L. Ware, associate curator in the Division of Invertebrate Zoology at the American Museum of Natural History in New York, and president of the Entomological Society of America. “There are over one million described insect species, occupying different niches and responding to environmental stressors in different ways.”
Jessica Ware, an entomologist at the American Museum of Natural History, is using DNA methods to monitor insects.
Credit:D.Finnin/AMNH
In addition to habitat loss fueling the decline in insect populations, the other “major drivers” Ware identified are invasive species, climate change, pollution, and fluctuating levels of nitrogen, which play a major role in the lifecycle of plants, some of which serve as insect habitants and others as their food. “The causes of world insect population declines are, unfortunately, very easy to link to human activities,” Lehmann says.
Climate change will undoubtedly make the problem worse. “As temperatures start to rise, it can essentially make it too hot for some insects to survive,” says Emily McDermott, an assistant professor in the Department of Entomology and Plant Pathology at the University of Arkansas. “Conversely in other areas, it could potentially also allow other insects to expand their ranges.”
Without Pollinators Humans Will Starve
We may not think much of our planet’s getting warmer by only one degree Celsius, but it can spell catastrophe for many insects, plants, and animals, because it’s often accompanied by less rainfall. “Changes in precipitation patterns will have cascading consequences across the tree of life,” says David Wagner, a professor of ecology and evolutionary biology at the University of Connecticut. Insects, in particular, are “very vulnerable” because “they’re small and susceptible to drying.”
For instance, droughts have put the monarch butterfly at risk of being unable to find nectar to “recharge its engine” as it migrates from Canada and New England to Mexico for winter, where it enters a hibernation state until it journeys back in the spring. “The monarch is an iconic and a much-loved insect,” whose migration “is imperiled by climate change,” Wagner says.
Warming and drying trends in the Western United States are perhaps having an even more severe impact on insects than in the eastern region. As a result, “we are seeing fewer individual butterflies per year,” says Matt Forister, a professor of insect ecology at the University of Nevada, Reno.
There are hundreds of butterfly species in the United States and thousands in the world. They are pollinators and can serve as good indicators of other species’ health. “Although butterflies are only one group among many important pollinators, in general we assume that what’s bad for butterflies is probably bad for other insects,” says Forister, whose research focuses on butterflies. Climate change and habitat destruction are wreaking havoc on butterflies as well as plants, leading to a further indirect effect on caterpillars and butterflies.
Different insect species have different levels of sensitivity to environmental changes. For example, one-half of the bumblebee species in the United States are showing declines, whereas the other half are not, says Christina Grozinger, a professor of entomology at the Pennsylvania State University. Some species of bumble bees are even increasing in their range, seemingly resilient to environmental changes. But other pollinators are dwindling to the point that farmers have to buy from the rearing facilities, which is the case for the California almond industry. “This is a massive cost to the farmer, which could be provided for free, in case the local habitats supported these pollinators,” Lehmann says.
For bees and other insects, climate change can harm the plants they depend on for survival or have a negative impact on the insects directly. Overly rainy and hot conditions may limit flowering in plants or reduce the ability of a pollinator to forage and feed, which then decreases their reproductive success, resulting in dwindling populations, Grozinger explains.
“Nutritional deprivation can also make pollinators more sensitive to viruses and parasites and therefore cause disease spread,” she says. “There are many ways that climate change can reduce our pollinator populations and make it more difficult to grow the many fruit, vegetable and nut crops that depend on pollinators.”
Disease-Causing Insects Can Bring More Outbreaks
While some much-needed insects are declining, certain disease-causing species may be spreading and proliferating, which is another reason for human concern. Many mosquito types spread malaria, Zika virus, West Nile virus, and a brain infection called equine encephalitis, along with other diseases as well as heartworms in dogs, says Michael Sabourin, president of the Vermont Entomological Society. An animal health specialist for the state, Sabourin conducts vector surveys that identify ticks and mosquitoes.
Scientists refer to disease-carrying insects as vector species and, while there’s a limited number of them, many of these infections can be deadly. Fleas were a well-known vector for the bubonic plague, while kissing bugs are a vector for Chagas disease, a potentially life-threatening parasitic illness in humans, dogs, and other mammals, Sabourin says.
As the planet heats up, some of the creepy crawlers are able to survive milder winters or move up north. Warmer temperatures and a shorter snow season have spawned an increasing abundance of ticks in Maine, including the blacklegged tick (Ixodes scapularis), known to transmit Lyme disease, says Sean Birkel, an assistant professor in the Climate Change Institute and Cooperative Extension at the University of Maine.
Coupled with more frequent and heavier precipitation, rising temperatures bring a longer warm season that can also lead to a longer period of mosquito activity. “While other factors may be at play, climate change affects important underlying conditions that can, in turn, facilitate the spread of vector-borne disease,” Birkel says.
For example, if mosquitoes are finding fewer of their preferred food sources, they may bite humans more. Both male and female mosquitoes feed on sugar as part of their normal behavior, but if they aren’t eating their fill, they may become more bloodthirsty. One recent paper found that sugar-deprived Anopheles gambiae females go for larger blood meals to stay in good health and lay eggs. “More blood meals equals more chances to pick up and transmit a pathogen,” McDermott says, He adds that climate change could reduce the number of available plants to feed on. And while most mosquitoes are “generalist sugar-feeders” meaning that they will likely find alternatives, losing their favorite plants can make them hungrier for blood.
Similar to the effect of losing plants, mosquitoes may get turned onto people if they lose their favorite animal species. For example, some studies found that Culex pipiens mosquitoes that transmit the West Nile virus feed primarily on birds in summer. But that changes in the fall, at least in some places. Because there are fewer birds around, C. pipiens switch to mammals, including humans. And if some disease-carrying insect species proliferate or increase their ranges, that increases chances for human infection, says McDermott. “A larger concern is that climate change could increase vector population sizes, making it more likely that people or animals would be bitten by an infected insect.”
Science Can Help Bring Back the Buzz
To help friendly insects thrive and keep the foes in check, scientists need better ways of trapping, counting, and monitoring insects. It’s not an easy job, but artificial intelligence and molecular methods can help. Ware’s lab uses various environmental DNA methods to monitor freshwater habitats. Molecular technologies hold much promise. The so-called DNA barcodes, in which species are identified using a short string of their genes, can now be used to identify birds, bees, moths and other creatures, and should be used on a larger scale, says Wagner, the University of Connecticut professor. “One day, something akin to Star Trek’s tricorder will soon be on sale down at the local science store.”
Scientists are also deploying artificial intelligence, or AI, to identify insects in agricultural systems and north latitudes where there are fewer bugs, Wagner says. For instance, some automated traps already use the wingbeat frequencies of mosquitoes to distinguish the harmless ones from the disease-carriers. But new technology and software are needed to further expand detection based on vision, sound, and odors.
“Because of their ubiquity, enormity of numbers, and seemingly boundless diversity, we desperately need to develop molecular and AI technologies that will allow us to automate sampling and identification,” says Wagner. “That would accelerate our ability to track insect populations, alert us to the presence of new disease vectors, exotic pest introductions, and unexpected declines.”
Your surgery could harm yourself and the planet. Here's what some doctors are doing about it.
This is part 1 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 2 here and part 3 here.
Susanne Koch, an anesthesiologist and neurologist, reached a pivot point when she was up to her neck in water, almost literally. The basement of her house in Berlin had flooded in the summer of 2018, when Berlin was pummeled by unusually strong rains. After she drained the house, “I wanted to dig into facts, to understand how exactly these extreme weather events are related to climate change,” she says.
Studying the scientific literature, she realized how urgent the climate crisis is, but the biggest shock was to learn that her profession contributed substantially to the problem: Inhalation gases used during medical procedures are among the most damaging greenhouse gases. Some inhalation gases are 3,000 times more damaging for the climate than CO2, Koch discovered. “Spending seven hours in the surgery room is the equivalent of driving a car for four days nonstop,” she says. Her job of helping people at Europe’s largest university hospital, the Charité in Berlin, was inadvertently damaging both the people and the planet.
“Nobody had ever even mentioned a word about that during my training,” Koch says.
On the whole, the medical sector is responsible for a disproportionally large percentage of greenhouse gas emissions, with the U.S. as the biggest culprit. According to a key paper published in 2020 in Health Affairs, the health industry “is among the most carbon-intensive service sectors in the industrialized world,” accounting for between 4.4 percent and 4.6 percent of greenhouse gas emissions. “It’s not just anesthesia but health care that has a problem,” says Jodi Sherman, anesthesiology professor and Medical Director of the Program on Healthcare Environmental Sustainability at Yale University as well as co-director of the Lancet Planetary Health Commission on Sustainable Healthcare. In the U.S., health care greenhouse gas emissions make up about 8.5 percent of domestic greenhouse gas emissions. They rose 6 percent from 2010 to 2018, to nearly 1,700 kilograms per person, more than in any other nation.
Of course, patients worry primarily about safety, not sustainability. Yet, Koch emphasizes that “as doctors, we have the responsibility to do no harm, and this includes making sure that we use resources as sustainably as possible.” Studies show that 2018 greenhouse gas and toxic air pollutant emissions resulted in the loss of 388,000 disability-adjusted life years in the U.S. alone. “Disease burden from health care pollution is of the same order of magnitude as deaths from preventable medical errors, and should be taken just as seriously,” Sherman cautions.
When Koch, the anesthesiologist, started discussing sustainable options with colleagues, the topic was immediately met with plenty of interest. Her experience is consistent with the latest representative poll of the nonprofit Foundation Health in Germany. Nine out of ten doctors were interested in urgently finding sustainable solutions for medical services but lacked knowhow and resources. For teaching purposes, Sherman and her team have developed the Yale Gassing Greener app that allows anesthesiologists to compare how much pollution they can avoid through choosing different anesthesia methods. Sherman also published professional guidelines intended to help her colleagues better understand how various methods affect carbon emissions.
Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
A solution espoused by both Sherman and Koch is comparatively simple: They stopped using desflurane, which is by far the most damaging of all inhalation gases to the climate. Its greenhouse effect is 2,590 times stronger than carbon dioxide. The Yale New Haven Hospital already stopped using desflurane in 2013, becoming the first known healthcare organization to eliminate a drug based on environmental grounds. Sherman points out that this resulted in saving more than $1.2 million in costs and 1,600 tons of CO2 equivalents, about the same as the exhaust from 360 passenger vehicles per year.
At the Charité, Koch claims that switching to other anesthesiology choices, such as propofol, has eliminated 90 percent of the climate gas emissions in the anesthesiology department since 2016. Young anesthesiologists are still taught to use desflurane as the standard because desflurane is absorbed less into the patients’ bodies, and they wake up faster. However, Koch who has worked as an anesthesiologist since 2006, says that with a little bit of experience, you can learn when to stop giving the propofol so it's timed just as well with a person’s wake-up process. In addition, “patients are less likely to feel nauseous after being given propofol,” Koch says. Intravenous drugs might require more skill, she adds, "but there is nothing unique to the drug desflurane that cannot be accomplished with other medications.”
Desflurane isn’t the only gas to be concerned about. Nitrous oxide is the second most damaging because it’s extremely long-lived in the environment, and it depletes the ozone layer. Climate-conscious anesthesiologists are phasing out this gas, too, or have implemented measures to decrease leaks.
Internationally, 192 governments agreed in the Kyoto protocol of 2005 to reduce halogenated hydrocarbons – resulting from inhalation gases, including desflurane and nitrous oxide – because of their immense climate-warming potential, and in 2016, they pledged to eliminate them by 2035. However, the use of inhalation anesthetics continues to increase worldwide, not least because more people access healthcare in developing countries, and because people in industrialized countries live longer and therefore need more surgeries. Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
Certain companies are now pushing new technology to capture inhalation gases before they are released into the atmosphere, but both Sherman and Koch believe marketing claims of 99 percent efficiency amount to greenwashing. After investigating the technology first-hand and visiting the company that is producing such filters in Germany, Koch concluded that such technology only reduces emissions by 25 percent. And Sherman believes such initiatives are akin to the fallacy of recycling plastic. In addition to questioning their efficiency, Sherman fears such technology “gives the illusion there is a magical solution that means I don’t need to change my behavior, reduce my waste and choose less harmful options.”
Financial interests are at play, too. “Desflurane is the most expensive inhalation gas, and some think, the most expensive must be the best,” Koch says. Both Koch and Sherman lament that efforts to increase sustainability in the medical sector are entirely voluntary in their countries and led by a few dedicated individual professionals while industry-wide standards and transparency are needed, a notion expressed in the American Hospital Association’s Sustainability Roadmap.
Susanne Koch, an anesthesiologist in Berlin, wants her colleagues to stop using a gas called desflurane, which is by far the most damaging of all inhalation gases to the climate.
Adobe Stock
Other countries have done more. The European Union recommends reducing inhalation gases and even contemplated a ban of desflurane, except in medical emergencies. In 2008, the National Health Service (NHS) created a Sustainable Development Unit, which measures CO2 emissions in the U.K. health sector. NHS is the first national health service that pledged to reach net zero carbon by 2040. The carbon footprint of the NHS fell by 26 percent from 1990 to 2019, mostly due to reduced use of certain inhalers and the switch to renewable energy for heat and power. “The evidence that the climate emergency is a health emergency is overwhelming,” said Nick Watts, the NHS Chief Sustainability Officer, in a press release, “with health professionals already needing to manage its symptoms.”
Sherman is a leading voice in demanding action in the U.S. To her, comprehensive solutions start with the mandatory, transparent measurement of emissions in the health sector to tackle the biggest sources of pollution. While the Biden administration highlighted its efforts to reduce these kinds of emissions during the United Nations Climate Conference (COP27) in November 2022 and U.S. delegates announced that more than 100 health care organizations signed the voluntary Health Sector Climate Pledge, with the aim to reduce emissions by 50 percent in the next eight years, Sherman is convinced that voluntary pledges are not enough. “Voluntary measures are insufficient,” she testified in congress. “The vast majority of U.S. health care organizations remain uncommitted to timely action. Those that are committed lack policies and knowledge to support necessary changes; even worse, existing policies drive inappropriate consumption of resources and pollution.”
Both Sherman and Koch look at the larger picture. “Health care organizations have an obligation to their communities to protect public health,” Sherman says. “We must lead by example. That includes setting ambitious, science-based carbon reduction targets to achieve net zero emissions before 2050. We must quantify current emissions and their sources, particularly throughout the health care supply chains.”