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.
What's the case-fatality rate?
Currently, the official rate is 3.4%. But this is likely way too high. China was hit particularly hard, and their healthcare system was overwhelmed. The best data we have is from South Korea. The Koreans tested 210,000 people and detected the virus in 7,478 patients. So far, the death toll is 53, which is a case-fatality rate of 0.7%. This is seven times worse than the seasonal flu (which has a case-fatality rate of 0.1%).
What's the best way to clean your hands? Soap and water? Hand sanitizer?
Soap and water is always best. Be sure to wash your hands thoroughly. (The CDC recommends 20 seconds.) If soap and water are not available, the CDC says to use hand sanitizer that is at least 60% alcohol. The problem with hand sanitizer, however, is that people neither use enough nor spread it over their hands properly. Also, the sanitizer should be covering your hands for 10-15 seconds, not evaporating before that.
How often should I wash my hands?
You should wash your hands after being in a public place, before you eat, and before you touch your face. It's a good idea to wash your hands after handling money and your cell phone, too.
How long can coronavirus live on surfaces?
It depends on the surface. According to the New York Times, "[C]old and flu viruses survive longer on inanimate surfaces that are nonporous, like metal, plastic and wood, and less on porous surfaces, like clothing, paper and tissue." According to the Journal of Hospital Infection, human coronaviruses "can persist on inanimate surfaces like metal, glass or plastic for up to 9 days, but can be efficiently inactivated by surface disinfection procedures with 62–71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute." (Note: Sodium hypochlorite is bleach.)
Can Lysol wipes kill it?
Maybe not. It depends on the active ingredient. Many Lysol products use benzalkonium chloride, which the aforementioned Journal of Hospital Infection paper said was "less effective." The EPA has released a list of disinfectants recommended for use against coronavirus.
Should you wear a mask in public?
The CDC does not recommend that healthy people wear a mask in public. The benefit is likely small. However, if you are sick, then you should wear a mask to help catch respiratory droplets as you exhale.
Will pets give it to you?
That can't be ruled out. There is a documented case of human-to-canine transmission. However, an article in LiveScience explains that canine-to-human is unlikely.
Are there any "normal" things we are doing that make things worse?
Yes! Not washing your hands!!
What does it mean that previously cleared people are getting sick again? Is it the virus within or have they caught it via contamination?
It's not entirely clear. It could be that the virus was never cleared to begin with. Or it could be that the person was simply infected again. That could happen if the antibodies generated don't last long.
Will the virus go away with the weather/summer?
Quite likely, yes. Cold and flu viruses don't do well outside in summer weather. (For influenza, the warm weather causes the viral envelope to become a liquid, and it can no longer protect the virus.) That's why cold and flu season is always during the late fall and winter. However, some experts think that it is a "false hope" that the coronavirus will disappear during the summer. We'll have to wait and see.
And will it come back in the fall/winter?
That's a likely outcome. Again, we'll have to wait and see. Some epidemiologists think that COVID-19 will become seasonal like influenza.
Does dry or humid air make a difference?
Flu viruses prefer cold, dry weather. That could be true of coronaviruses, too.
What is the incubation period?
According to the World Health Organization, it's about 5 days. But it could be anywhere from 1 to 14 days.
Should you worry about sitting next to asymptomatic people on a plane or train?
It's not possible to tell if an asymptomatic person is infected or not. That's what makes asymptomatic people tricky. Just be cautious. If you're worried, treat everyone like they might be infected. Don't let them get too close or cough in your face. Be sure to wash your hands.
Should you cancel air travel planned in the next 1-2 months in the U.S.?
There are no hard and fast rules. Use common sense. Avoid hotspots of infection. If you have a trip planned to Wuhan, you might want to wait on that one. If you have a trip planned to Seattle and you're over the age of 60 and/or have an underlying health condition, you may want to hold off on that, too. If you do fly on a plane, former FDA commissioner Dr. Scott Gottlieb recommends cleaning the back of your seat and other close contact areas with antiseptic wipes. He also refuses to take anything handed out by flight attendants, since he says the biggest route of transmission comes from touching contaminated surfaces (and then touching your face).
There have been reports of an escalation of hate crimes towards Asian Americans. Can the microbiologist help illuminate that this disease has impacted all racial groups?
People might be racist, but COVID-19 is not. It can infect anyone. Older people (i.e., 60 years and older) and those with underlying health conditions are most at risk. Interestingly, young people (aged 9 and under) are minimally impacted.
To what extent/if any should toddlers -- who put everything in mouth -- avoid group classes like Gymboree?
If they get infected, toddlers will probably experience only a mild illness. The problem is if the toddler then infects somebody at higher risk, like grandpa or grandma.
Should I avoid events like concerts or theater performances if I live in a place where there is known coronavirus?
It's not an unreasonable thing to do.
Any special advice or concerns for pregnant women?
There isn't good data on this. Previous evidence, reported by the CDC, suggests that pregnant women may be more susceptible to respiratory viruses.
Advice for residents of long-term care facilities/nursing homes?
Remind the nurse or aide to constantly wash their hands.
Can we eat at Chinese restaurants? Does eating onions kill viruses? Can I take an Uber and be safe from infection?
Yes. No. Does the Uber driver or previous passengers have coronavirus? It's not possible to tell. So, treat an Uber like a public space and behave accordingly.
What public spaces should we avoid?
That's hard to say. Some people avoid large gatherings, others avoid leaving the house. Ultimately, it's going to depend on who you are and what sort of risk you're willing to take. (For example, are you young and healthy or old and sick?) I would be willing to do things that I would advise older people avoid, like going to a sporting event.
What are the differences between the L strain and the S strain?
That's not entirely clear, and it's not even clear that they are separate strains. There are some genetic differences between them. However, just because RNA viruses mutate doesn't necessarily mean that the virus will mutate to something more dangerous or unrecognizable by our immune system. The measles virus mutates, but it more or less remains the same, which is why a single vaccine could eradicate it – if enough people actually were willing to get a measles shot.
Should I wear disposable gloves while traveling?
No. If you touch something that's contaminated, the virus will be on your glove instead of your hand. If you then touch your face, you still might get sick.
The Best Coronavirus Experts to Follow on Twitter
As the coronavirus tears across the globe, the world's anxiety is at a fever-pitch, and we're all craving information to stay on top of the crisis.
But turning to the Internet for credible updates isn't as simple as it sounds, since we have an invisible foe spreading as quickly as the virus itself: misinformation. From wild conspiracy theories to baseless rumors, an infodemic is in full swing.
For the latest official information, you should follow the CDC, WHO, and FDA, in addition to your local public health department. But it's also helpful to pay attention to the scientists, doctors, public health experts and journalists who are sharing their perspectives in real time as new developments unfold. Here's a handy guide to get you started:
VIROLOGY
Dr. Trevor Bedford/@trvrb: Scientist at the Fred Hutchinson Cancer Research Center studying viruses, evolution and immunity.
Dr. Benhur Lee/@VirusWhisperer: Professor of microbiology at the Icahn School of Medicine at Mount Sinai
Dr. Angela Rasmussen/@angie_rasmussen: Virologist and associate research scientist at Columbia University
Dr. Florian Krammer/@florian_krammer: Professor of Microbiology at the Icahn School of Medicine at Mount Sinai
EPIDEMIOLOGY:
Dr. Alice Sim/@alicesim: Infectious disease epidemiologist and consultant at the World Health Organization
Dr. Tara C. Smith/@aetiology: Infectious disease specialist and professor at Kent State University
Dr. Caitlin Rivers/@cmyeaton: Epidemiologist and assistant professor at the Johns Hopkins Bloomberg School of Public Health
Dr. Michael Mina/@michaelmina_lab: Physician and Assistant Professor of Epidemiology & Immunology at the Harvard TH Chan School of Public Health
INFECTIOUS DISEASE:
Dr. Nahid Bhadelia/@BhadeliaMD: Infectious diseases physician and the medical director of Special Pathogens Unit at Boston University School of Medicine
Dr. Paul Sax/@PaulSaxMD: Clinical Director of the Division of Infectious Diseases at Brigham and Women's Hospital
Dr. Priya Sampathkumar/@PsampathkumarMD: Infectious Disease Specialist at the Mayo Clinic
Dr. Krutika Kuppalli/@KrutikaKuppalli: Medical doctor and Infectious Disease Specialist based in Palo Alto, CA
PANDEMIC PREP:
Dr. Syra Madad/@syramadad: Senior Director, System-wide Special Pathogens Program at New York City Health + Hospitals
Dr Sylvie Briand/@SCBriand: Director of Pandemic and Epidemic Diseases Department at the World Health Organization
Jeremy Konyndyk/@JeremyKonyndyk: Senior Policy Fellow at the Center for Global Development
Amesh Adalja/@AmeshAA: Senior Scholar at the Johns Hopkins University Center for Health Security
PUBLIC HEALTH:
Scott Becker/@scottjbecker: CEO of the Association of Public Health Laboratories
Dr. Scott Gottlieb/@ScottGottliebMD: Physician, former commissioner of the Food and Drug Administration
APHA Public Health Nursing/@APHAPHN: Public Health Nursing Section of the American Public Health Association
Dr. Tom Inglesby/@T_Inglesby: Director of the Johns Hopkins SPH Center for Health Security
Dr. Nancy Messonnier/@DrNancyM_CDC: Director of the Center for the National Center for Immunization and Respiratory Diseases (NCIRD)
Dr. Arthur Caplan/@ArthurCaplan: Professor of Bioethics at New York University Langone Medical Center
SCIENCE JOURNALISTS:
Laura Helmuth/@laurahelmuth: Incoming Editor in Chief of Scientific American
Helen Branswell/@HelenBranswell: Infectious disease and public health reporter at STAT
Sharon Begley/@sxbegle: Senior writer at STAT
Carolyn Johnson/@carolynyjohnson: Science reporter at the Washington Post
Amy Maxmen/@amymaxmen: Science writer and senior reporter at Nature
Laurie Garrett/@Laurie_Garrett: Pulitzer-prize winning science journalist, author of The Coming Plague, former senior fellow for global health at the Council on Foreign Relations
Soumya Karlamangla/@skarlamangla: Health writer at the Los Angeles Times
André Picard/@picardonhealth: Health Columnist, The Globe and Mail
Caroline Chen/@CarolineYLChen: Healthcare reporter at ProPublica
Andrew Jacobs/@AndrewJacobsNYT: Science reporter at the New York Times
Meg Tirrell/@megtirrell: Biotech and pharma reporter for CNBC
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.