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.
Have you felt a bit like an armchair epidemiologist lately? Maybe you've been poring over coronavirus statistics on your county health department's website or on the pages of your local newspaper.
If the percentage of positive tests steadily stays under 8 percent, that's generally a good sign.
You're likely to find numbers and charts but little guidance about how to interpret them, let alone use them to make day-to-day decisions about pandemic safety precautions.
Enter the gurus. We asked several experts to provide guidance for laypeople about how to navigate the numbers. Here's a look at several common COVID-19 statistics along with tips about how to understand them.
Case Counts: Consider the Context
The number of confirmed COVID-19 cases in American counties is widely available. Local and state health departments should provide them online, or you can easily look them up at The New York Times' coronavirus database. However, you need to be cautious about interpreting them.
"Case counts are the obvious numbers to look at. But they're probably the hardest thing to sort out," said Dr. Jeff Martin, an epidemiologist at the University of California at San Francisco.
That's because case counts by themselves aren't a good window into how the coronavirus is affecting your community since they rely on testing. And testing itself varies widely from day to day and community to community.
"The more testing that's done, the more infections you'll pick up," explained Dr. F. Perry Wilson, a physician at Yale University. The numbers can also be thrown off when tests are limited to certain groups of people.
"If the tests are being mostly given to people with a high probability of having been infected -- for example, they have had symptoms or work in a high-risk setting -- then we expect lots of the tests to be positive. But that doesn't tell us what proportion of the general public is likely to have been infected," said Eleanor Murray, an epidemiologist at Boston University.
These Stats Are More Meaningful
According to Dr. Wilson, it's more useful to keep two other statistics in mind: the number of COVID tests that are being performed in your community and the percentage that turn up positive, showing that people have the disease. (These numbers may or may not be available locally. Check the websites of your community's health department and local news media outlets.)
If the number of people being tested is going up, but the percentage of positive tests is going down, Dr. Wilson said, that's a good sign. But if both numbers are going up – the number of people tested and the percentage of positive results – then "that's a sign that there are more infections burning in the community."
It's especially worrisome if the percentage of positive cases is growing compared to previous days or weeks, he said. According to him, that's a warning of a "high-risk situation."
Dr. George Rutherford, an epidemiologist at University of California at San Francisco, offered this tip: If the percentage of positive tests steadily stays under 8 percent, that's generally a good sign.
There's one more caveat about case counts. It takes an average of a week for someone to be infected with COVID-19, develop symptoms, and get tested, Dr. Rutherford said. It can take an additional several days for those test results to be reported to the county health department. This means that case numbers don't represent infections happening right now, but instead are a picture of the state of the pandemic more than a week ago.
Hospitalizations: Focus on Current Statistics
You should be able to find numbers about how many people in your community are currently hospitalized – or have been hospitalized – with diagnoses of COVID-19. But experts say these numbers aren't especially revealing unless you're able to see the number of new hospitalizations over time and track whether they're rising or falling. This number often isn't publicly available, however.
If new hospitalizations are increasing, "you may want to react by being more careful yourself."
And there's an important caveat: "The problem with hospitalizations is that they do lag," UC San Francisco's Dr. Martin said, since it takes time for someone to become ill enough to need to be hospitalized. "They tell you how much virus was being transmitted in your community 2 or 2.5 weeks ago."
Also, he said, people should be cautious about comparing new hospitalization rates between communities unless they're adjusted to account for the number of more-vulnerable older people.
Still, if new hospitalizations are increasing, he said, "you may want to react by being more careful yourself."
Deaths: They're an Even More Delayed Headline
Cable news networks obsessively track the number of coronavirus deaths nationwide, and death counts for every county in the country are available online. Local health departments and media websites may provide charts tracking the growth in deaths over time in your community.
But while death rates offer insight into the disease's horrific toll, they're not useful as an instant snapshot of the pandemic in your community because severely ill patients are typically sick for weeks. Instead, think of them as a delayed headline.
"These numbers don't tell you what's happening today. They tell you how much virus was being transmitted 3-4 weeks ago," Dr. Martin said.
'Reproduction Value': It May Be Revealing
You're not likely to find an available "reproduction value" for your community, but it is available for your state and may be useful.
A reproduction value, also known as R0 or R-naught, "tells us how many people on average we expect will be infected from a single case if we don't take any measures to intervene and if no one has been infected before," said Boston University's Murray.
As The New York Times explained, "R0 is messier than it might look. It is built on hard science, forensic investigation, complex mathematical models — and often a good deal of guesswork. It can vary radically from place to place and day to day, pushed up or down by local conditions and human behavior."
It may be impossible to find the R0 for your community. However, a website created by data specialists is providing updated estimates of a related number -- effective reproduction number, or Rt – for each state. (The R0 refers to how infectious the disease is in general and if precautions aren't taken. The Rt measures its infectiousness at a specific time – the "t" in Rt.) The site is at rt.live.
"The main thing to look at is whether the number is bigger than 1, meaning the outbreak is currently growing in your area, or smaller than 1, meaning the outbreak is currently decreasing in your area," Murray said. "It's also important to remember that this number depends on the prevention measures your community is taking. If the Rt is estimated to be 0.9 in your area and you are currently under lockdown, then to keep it below 1 you may need to remain under lockdown. Relaxing the lockdown could mean that Rt increases above 1 again."
"Whether they're on the upswing or downswing, no state is safe enough to ignore the precautions about mask wearing and social distancing."
Keep in mind that you can still become infected even if an outbreak in your community appears to be slowing. Low risk doesn't mean no risk.
Putting It All Together: Why the Numbers Matter
So you've reviewed COVID-19 statistics in your community. Now what?
Dr. Wilson suggests using the data to remind yourself that the coronavirus pandemic "is still out there. You need to take it seriously and continue precautions," he said. "Whether they're on the upswing or downswing, no state is safe enough to ignore the precautions about mask wearing and social distancing. 'My state is doing well, no one I know is sick, is it time to have a dinner party?' No."
He also recommends that laypeople avoid tracking COVID-19 statistics every day. "Check in once a week or twice a month to see how things are going," he suggested. "Don't stress too much. Just let it remind you to put that mask on before you get out of your car [and are around others]."
GOOD10: The Pandemic Issue explores big-picture ways that science innovation and communication can usher in a more equitable, more progress-oriented, and safer world.
This issue is a collaboration among GOOD, leapsmag, and the Aspen Institute Science & Society Program.
The GOOD10 format explores fundamental issues facing humanity through the lenses of ten forces pushing the needle toward progress: Places, Philanthropists, Celebrities, Whistleblowers, Companies, Media, Products, Politicians, Scientists, and Actions. Across these categories, we seek to present unexpected and encouraging paradigms emerging from this historic crisis.
This special issue is available as an e-reader version for both desktop and mobile. It is also available as a free downloadable PDF.
TABLE OF CONTENTS:
- PLACES:
55 Lessons Learned About Science Communication Around the World; Quarantining Our Way Into Outer Space - PLACES:
Quarantining Our Way Into Outer Space - PHILANTHROPISTS:
An Exclusive Interview with Wendy Schmidt about Science in the Pandemic Era - CELEBRITIES:
Neil deGrasse Tyson Wants Celebrities to Promote Scientists - WHISTLEBLOWERS:
The Science Sleuths Holding Fraudulent Research Accountable - COMPANIES:
The Biggest Challenge for a COVID-19 Vaccine: Making It Accessible and Affordable - MEDIA:
Isaac Asimov on the History of Infectious Disease—And How Humanity Learned To Fight Back - PRODUCTS:
Will COVID-19 Pave the Way For DIY Precision Medicine? - POLITICIANS:
Will the Pandemic Propel STEM Experts to Political Power? - SCIENTISTS:
Would a Broad-Spectrum Antiviral Drug Stop the Pandemic? - ACTIONS:
Pseudoscience is Rampant: How Not to Fall For It - ACTIONS:
How COVID-19 Could Usher In a New Age of Collective Drug Discovery
THE EVENT:
"The Pandemic Science Summit" focused on how science innovation is key to society's future stability as we emerge from the pandemic, featuring:
Christopher Bailey – Arts and Health Lead, World Health Organization
Elisabeth Bik, Ph.D. – Microbiologist and scientific integrity consultant
Margaret Hamburg, M.D. – Foreign Secretary, National Academy of Medicine; former Commissioner, U.S. Food and Drug Administration
Peggy Oti-Boateng, Ph.D. – Director, Division of Science Policy and Capacity- Building, UNESCO
George Yancopoulos, M.D., Ph.D. – President and Chief Scientific Officer, Regeneron Pharmaceuticals
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.