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.
3 Futuristic Biotech Programs the U.S. Government Is Funding Right Now
Last month, at a conference celebrating DARPA, the research arm of the Defense Department, FBI Special Agent Edward You declared, "The 21st century will be the revolution of the life sciences."
Biomedical engineer Kevin Zhao has a sensor in his arm and chest that monitors his oxygen level in real time.
Indeed, four years ago, the agency dedicated a new office solely to advancing biotechnology. Its primary goal is to combat bioterrorism, protect U.S. forces, and promote warfighter readiness. But its research could also carry over to improve health care for the general public.
With an annual budget of about $3 billion, DARPA's employees oversee about 250 research and development programs, working with contractors from corporations, universities, and government labs to bring new technologies to life.
Check out these three current programs:
1) IMPLANTABLE SENSORS TO MEASURE OXYGEN, LACTATE, AND GLUCOSE LEVELS IN REAL TIME
Biomedical engineer Kevin Zhao has a sensor in his arm and his chest that monitors his oxygen level in those tissues in real time. With funding from DARPA for the program "In Vivo Nanoplatforms," he developed soft, flexible hydrogels that are injected just beneath the skin to perform the monitoring and that sync to a smartphone app to give the user immediate health insights.
A first-in-man trial for the glucose sensor is now underway in Europe for monitoring diabetics, according to Zhao. Volunteers eat sugary food to spike their glucose levels and prompt the monitor to register the changes.
"If this pans out, with approval from FDA, then consumers could get the sensors implanted in their core to measure their levels of glucose, oxygen, and lactate," Zhao said.
Lactate, especially, interests DARPA because it's a first responder molecule to the onset of trauma, sepsis, and potentially infection.
"The sensor could potentially detect rise of these [body chemistry numbers] and alert the user to prevent onset of dangerous illness."
2) NEAR INSTANTANEOUS VACCINE PROTECTION DURING A PANDEMIC
Traditional vaccines can take months or years to develop, then weeks to become effective once you get it. But when an unknown virus emerges, there's no time to waste.
This program, called P3, envisions a much more ambitious approach to stop a pandemic in its tracks.
"We want to confer near instantaneous protection by doing it a different way – enlist the body as a bioreactor to produce therapeutics," said Col. Matthew Hepburn, the program manager.
So how would it work?
To fight a pandemic, we will need 20,000 doses of a vaccine in 60 days.
If you have antibodies against a certain infection, you'll be protected against that infection. This idea is to discover the genetic code for the antibody to a specific pathogen, manufacture those pieces of DNA and RNA, and then inject the code into a person's arm so the muscle cells will begin producing the required antibodies.
"The amazing thing is that it actually works, at least in animal models," said Hepburn. "The mouse muscles made enough protective antibodies so that the mice were protected."
The next step is to test the approach in humans, which the program will do over the next two years.
But the hard part is actually not discovering the genetic code for highly potent antibodies, according to Hepburn. In fact, researchers already have been able to do so in two to four weeks' time.
"The hard part is once I have an antibody, a large pharma company will say in 2 years, I can make 100-200 doses. Give us 4 years to get to 20,000 doses. That's not good enough," Hepburn said.
To fight a pandemic, we will need 20,000 doses of a vaccine in 60 days.
"We have to fundamentally change the idea that it takes a billion dollars and ten years to make a drug," he concluded. "We're going to do something radically different."
3) RAPID DIAGNOSING OF PATHOGEN EXPOSURE THROUGH EPIGENETICS
Imagine that you come down with a mysterious illness. It could be caused by a virus, bacteria, or in the most extreme catastrophe, a biological agent from a weapon of mass destruction.
What if a portable device existed that could identify--within 30 minutes—which pathogen you have been exposed to and when? It would be pretty remarkable for soldiers in the field, but also for civilians seeking medical treatment.
This is the lofty ambition of a DARPA program called Epigenetic Characterization and Observation, or ECHO.
Its success depends on a biological phenomenon known as the epigenome. While your DNA is relatively immutable, your environment can modify how your DNA is expressed, leaving marks of exposure that register within seconds to minutes; these marks can persist for decades. It's thanks to the epigenome that identical twins – who share identical DNA – can differ in health, temperament, and appearance.
These three mice are genetically identical. Epigenetic differences, however, result in vastly different observed characteristics.
Reading your epigenetic marks could theoretically reveal a time-stamped history of your body's environmental exposures.
Researchers in the ECHO program plan to create a database of signatures for exposure events, so that their envisioned device will be able to quickly scan someone's epigenome and refer to the database to sort out a diagnosis.
"One difficult part is to put a timestamp on this result, in addition to the sign of which exposure it was -- to tell us when this exposure happened," says Thomas Thomou, a contract scientist who is providing technical assistance to the ECHO program manager.
Other questions that remain up in the air for now: Do all humans have the same epigenetic response to the same exposure events? Is it possible to distinguish viral from bacterial exposures? Does dose and duration of exposure affect the signature of epigenome modification?
The program will kick off in January 2019 and is planned to last four years, as long as certain milestones of development are reached along the way. The desired prototype would be a simple device that any untrained person could operate by taking a swab or a fingerprick.
"In an outbreak," says Dr. Thomou, "it will help everyone on the ground immediately to have a rapidly deployable machine that will give you very quick answers to issues that could have far-reaching ramifications for public health safety."
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.
Your Online Therapist Will Message You Now
For years, Jenna Sauber took advantage of traditional therapy, setting an appointment with a mental health professional to help her through various life and relationship issues.
"The traditional model of therapy suffers from access barriers that keep enormous numbers of people from getting the care they need."
But when Sauber, 33, needed help extricating herself from a friendship that was becoming toxic, she tried another route of therapy. Life was getting busy for the communications professional from Washington D.C., and Sauber decided it was time to try something new – signing up for an online therapy smartphone app.
She isn't the only one trying therapy on-the-go. The online mental health industry has been booming in recent years, and technology companies – even giants such as Apple and Google – are sensing an opportunity to serve a market that wants to tend to their mental health wherever they are. Some are even tapping virtual reality used with a smartphone to help fight alcohol and nicotine addiction.
For those seeking a sympathetic ear – or text – companies such as Woebot offer a mental health chatbot to help patients relieve their anxiety or depression. Other companies, like Better Help and Talkspace, provide licensed mental health professionals who are available to connect with a patient throughout the day.
Recently, Olympic swimmer Michael Phelps became a brand ambassador for Talkspace after he disclosed his own struggle with depression.
Since Talkspace launched in 2012 by two psychologists, the company says it has worked with more than one million people seeking help.
How It Works
Potential clients fill out a questionnaire, detailing their mental health needs, and are connected with a professional whose specialties align with those needs. Basic text messaging packages are often offered by online therapy companies, as well as live-conversation packages and couples therapy. The average cost of these packages can vary and is usually billed weekly, with the ability to discontinue at any time.
Dr. Neil Lieberman, the Chief Medical Officer of Talkspace, is a board-certified psychiatrist. His background includes the oversight of inmates with severe psychological issues. One of the biggest advantages of online therapy, he says, is its accessibility. More than 70 percent of Talkspace users have never before been in therapy.
"It's a promising, but largely untested way to receive care."
"The traditional model of therapy – brick-and-mortar, 45-minute sessions – suffers from access barriers that keep enormous numbers of people from getting the care they need," Dr. Lieberman says. "Talkspace makes it possible for people to enjoy all the benefits of traditional therapy for a fraction of the cost, and without the need to schedule an appointment, travel to an office or get time off work."
Is It Effective?
This industry, while fast-growing, is still young. Psychiatric professionals are still trying to gauge its success, and whether it's providing the support its clients seek.
Dr. Vaile Wright, a licensed psychologist and the director of research and special projects with the American Psychological Association, says there isn't a lot of research available regarding online therapy.
"It's a promising, but largely untested way to receive care," says Wright.
She describes a spectrum of online therapy-type products available to consumers, ranging from meditation apps to videoconferencing services with a live therapist.
"There may be someone who doesn't necessarily need a mental health diagnosis but could use the mindfulness app to really feel more centered. What we generally see and what we think is probably effective is the use of these apps in conjunction or as an adjunct to a face-to-face ongoing relationship."
The APA offers a set of guidelines for professionals and for consumers that highlight issues that potential patients should consider before choosing online therapy, along with research material and other sources for help, depending on the condition.
There are still a lot of unknowns about online therapy, including potential security, confidentiality, privacy laws, and emergency situations, Wright says. "Consumers do need to be aware of that."
Lieberman says that the Talkspace app and website is encrypted to protect information. The company has also been certified as HIPAA compliant, meaning that the company must have a system in place to protect patient information.
"We take privacy, security, and confidentiality very seriously," he says.
For Sauber and her problematic friendship, online therapy was ultimately a let-down.
"She was very nice," Sauber says of her app therapist. "She would check in twice a day, once during the day and then at night. I'd type out what was going on and she would chime in that night or the next morning. It wasn't truly real-time unless you happened to be online with her window. I found that I was typing in huge paragraphs of what was happening and then me waiting for her to respond." Eventually, Sauber left the friendship on her own and quit the app.
When she decided to get help for sleeping issues last fall, she found her way back to a traditional therapist. And although her schedule was still tight, she was able to schedule FaceTime sessions with the therapist, which helped. The sleep issues, she felt, required a relationship with a live therapist who could notice how her body was responding to stressors.
Wright says that the live aspect of traditional therapy can be instructive in guiding a patient's care.
"Being face-to-face allows a therapist to pick up on body language. Maybe a person looks away when they're talking about a particular topic, or somebody's affect doesn't match up with the content of what they're talking about. For example, they're talking about something that's traumatic and yet they're smiling. That kind of nuance can be lost in texts or even e-mails."
Still, Sauber said she could see the benefits of the apps for different types of personalities and situations.
"I can see it being helpful for people who may not be comfortable being in person with someone because they're shy or just uncomfortable about their body language or may be just better communicating behind a screen," she said.
As far as the future of this kind of therapy, Lieberman says that Talkspace is hard at work expanding its network of clinicians and investing in research and science. The company is also working to develop partnerships with employers and health plans to offer the service to more people.
"Our intention to is to make therapy – a profession we think can lead to meaningful change in anybody's life – as common as going to the dentist or hitting the gym."
"These technology-based approaches can supplement the face-to-face work that you do."
[Correction: An earlier version of this article mistakenly implied that the company Woebot offers licensed mental health professionals to speak with patients. Woebot offers a chatbot service, a fully automated conversational agent, to help patients with anxiety and depression.]