New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.
This month, Kira Peikoff passes the torch to me as editor-in-chief of Leaps.org. I’m excited to assume leadership of this important platform.
Leaps.org caught my eye back in 2018. I was in my late 30s and just starting to wake up to the reality that the people I care most about were getting older and more vulnerable to health problems. At the same time, three critical shifts were becoming impossible to ignore. First, the average age in the U.S. is getting older, a trend known as the “gray tsunami.” Second, healthcare expenses are escalating and becoming unsustainable. And third, our sedentary, stress-filled lifestyles are leading to devastating consequences.
These trends pointed to a future filled with disease, suffering and economic collapse. But whenever I visited Leaps.org, my outlook turned from gloomy to solution-oriented. I became just as fascinated in a fourth trend, one that stands to revolutionize our world: rapid, mind-bending innovations in health and medicine.
Brain atlases, genome sequencing and editing, AI, protein mapping, synthetic biology, 3-D printing—these technologies are yielding new opportunities for health, longevity and human thriving. COVID-19 has caused many setbacks, but it has accelerated scientific breakthroughs. History suggests we will see even more innovation—in digital health and virtual first care, for example—after the pandemic.
In 2020, I began covering these developments with articles for Leaps.org about clocks that measure biological aging, gene therapies for cystic fibrosis, and other seemingly futuristic concepts that are transforming the present. I wrote about them partly because I think most people aren’t aware of them—and meaningful progress can’t happen without public engagement. A broader set of stakeholders and society at large, not just the experts, must inform these changes to ensure that they reflect our values and ethics. Everyone should get the chance to participate in the conversation—and they must have the opportunity to benefit equally from the innovations we decide to move forward with. By highlighting cutting-edge advances, Leaps.org is helping to realize this important goal.
Meanwhile, as I wrote freelance pieces on health and wellness for outlets such as the Washington Post and Time Magazine, I kept seeing an intersect between the breakthroughs in research labs and our expanding knowledge about the science of well-being. Take, for example, emerging technologies designed to stop illnesses in their tracks and new research on the benefits of taking in natural daylight. These two areas, lab innovations and healthy lifestyles, both shift the focus from disease treatment to disease prevention and optimal health. It’s the only sensible, financially feasible way forward.
When Kira suggested that I consider a leadership role with Leaps.org, it struck me how much the platform’s ideals have informed my own perspectives. The frontpage gore of mainstream media outlets can feel like a daily dose of pessimism, with cynicism sometimes dressed up as wisdom. Leaps.org’s world view is rooted in something very different: rational optimism about the present moment and the possibility of human flourishing.
That’s why I’m proud to lead this platform, including our podcast, Making Sense of Science, and hope you’ll keep coming to Leaps.org to learn and join the conversation about scientific gamechangers through our sponsored events, our popular Instagram account and other social channels. Think critically about the breakthroughs and their ethical challenges. Help usher in the health and prosperity that could be ours if we stay open-minded to it.
Yours truly,
Matt Fuchs
Editor-in-Chief
Podcast: Trusting Science with Dr. Sudip Parikh, CEO of AAAS
The "Making Sense of Science" podcast features interviews with leading experts about health innovations and the big ethical and social questions they raise. The podcast is hosted by Matt Fuchs, editor of the award-winning science outlet Leaps.org.
As Pew research showed last month, many Americans have less confidence in science these days - our collective trust has declined to levels below when the pandemic began. But leaders like Dr. Sudip Parikh are taking important steps to more fully engage people in scientific progress, including breakthroughs that could benefit health and prevent disease. In January 2020, Sudip became the 19th Chief Executive Officer of the American Association for the Advancement of Science (AAAS), an international nonprofit that seeks to advance science, engineering and innovation throughout the world, with 120,000 members in 91 countries. He is the executive publisher of Science, one of the top academic journals in the world, and the Science family of journals.
Listen to the episode
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In this episode, Sudip and I talk about:
- Reasons to be excited about health innovations that could come to fruition in the next several years.
- Sudip's thoughts about areas of health innovation where we should be especially cautious.
- Strategies for scientists and journalists to instill greater trust in science.
- How to tap into and nurture kids' passion for STEM subjects.
- The best roles for experts to play in society and the challenges they face.
And we pack several other fascinating topics into our 35 minutes. Here are links to check out and learn more about Sudip Parikh and AAAS:
- Sudip Parikh's official bio - https://www.aaas.org/person/sudip-parikh
- Sudip Parikh, Why We Must Rebuild Trust in Science, Trend Magazine, Feb. 9, 2021 - https://www.pewtrusts.org/en/trend/archive/winter-...
- Follow Sudip on Twitter - https://twitter.com/sudipsparikh
- AAAS website - https://www.aaas.org/
- AAAS podcast - https://www.science.org/podcasts
- The latest issue of Science - https://www.science.org/
- Science Journals homepage - https://www.science.org/journals
- AAAS Mentor Resources - https://www.aaas.org/stemmentoring
- AAAS Science Journalism Awards - https://sjawards.aaas.org/enter
- Pew Research Center Report, Americans' Trust in Scientists, Other Groups Declines, Feb. 15, 2022 https://www.pewresearch.org/science/2022/02/15/ame...