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.
More than 20 percent of American adults suffer from chronic pain. And as many as one in four of those prescribed opioids to manage that pain go on to misuse – or abuse – them, often with devastating consequences. Patients afflicted by both chronic pain and opioid addiction are especially difficult to treat, according to Eric Garland, PhD, Director of the University of Utah’s Center on Mindfulness and Integrative Health Intervention Development, because opioid overuse increases pain sensitivity, and pain promotes relapse among those being treated for addiction.
A new study, however, shows that a mindfulness-based therapy can successfully tackle both problems at once, pointing to a tool that could potentially help in fighting the opioid crisis. “This is the first large-scale clinical trial to show that any psychological intervention can reduce opioid misuse and chronic pain for the long term,” says Garland, lead author of the study, published February 28th in JAMA Internal Medicine.
Garland’s study focused on 250 adults who had received opioid therapy for chronic pain for 90 days or longer, randomly assigning them to eight weeks of either a standard psychotherapy support group or Mindfulness-Oriented Recovery Enhancement (MORE) therapy, which combines mindfulness training, cognitive-behavioral therapy (CBT) and positive psychology. Nine months after getting these treatments in primary care settings, 45 percent of patients in the MORE group were no longer misusing opioids, compared to 24 percent of those in group therapy. In fact, about a third of the patients in the MORE group were able to cut their opioid dose in half or reduce it even further.
Patients treated with MORE also experienced more significant pain relief than those in support groups, according to Garland. Conventional approaches to treating opioid addiction include 12-step programs and medically-assisted treatment using drugs like methadone and Suboxone, sometimes coupled with support groups. But patients with Opioid Use Disorder (OUD) – the official diagnosis for opioid addiction – have high relapse rates following treatment, especially if they have chronic pain.
While medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in.
“For patients suffering from moderate pain and OUD, the relapse rate is three times higher than in patients without chronic pain; for those with severe chronic pain, the relapse rate is five times higher,” says Amy Wachholtz, PhD, Director of Clinical Health Psychology and associate professor at University of Colorado in Denver. “So if we don’t treat the chronic pain along with the OUD addiction simultaneously, we are setting patients up for failure.”
Unfortunately, notes Garland, the standard of care for patients with chronic pain who are misusing their prescribed painkillers is “woefully inadequate.” Many patients don’t meet the criteria for OUD, he says, but instead fall into a gray zone somewhere between legitimate opioid use and full-blown addiction. And while medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in. But behavioral therapies are often not available in primary care settings, and even when clinicians do refer patients to behavioral health providers, they often prescribe CBT. A large scale study last year showed that CBT – without the added components of mindfulness training and positive psychology – reduced pain but not opioid misuse.
Psychotherapist Eric Garland teaches mindfulness.
University of Utah
Reward Circuitry Rewired
Opioids are highly physiologically addictive. Repeated and high-dose drug use causes the brain to become hypersensitive to stress, pain, and drug-related cues, such as the sight of one’s pill bottle, says Garland, while at the same time becoming increasingly insensitive to natural pleasures. “As an individual becomes more and more dependent on the opioids just to feel okay, they feel less able to extract a healthy sense of joy, pleasure and meaning out of everyday life,” he explains. “This drives them to take higher and higher doses of the opioid to maintain a dwindling sense of well-being.”
The changes are not just psychological: Chronic opioid use actually causes changes in the brain’s reward circuitry. “You can see on brain imaging,” says Garland. “The brain’s reward circuitry becomes more responsive when a person is viewing opioid related images than when they are viewing images of smiling babies, lovers holding hands, or sunsets over the beach.” MORE, he says, teaches “savoring” – a tenet of positive psychology – as a means of restructuring the reward processes in the brain so the patient becomes sensitive to pleasure from natural, healthy rewards, decreasing cravings for drug-related rewards.
Mindfulness and Addiction
Mindfulness, a form of meditation that teaches people to observe their feelings and sensations without judgement, has been increasingly applied to the treatment of addiction. By observing their pain and cravings objectively, for example, patients gain increased awareness of their responses to pain and their habits of opioid use. “They learn how to be with discomfort, whether emotional or physical, in a more compassionate way,” says Sarah Bowen, PhD, associate professor of psychology at Pacific University in Oregon. “And if your mind gives you a message like ‘Oh, I can’t handle that,’ to recognize that that’s a thought that might not be true.”
Bowen’s research is focused on Mindfulness-Based Relapse Prevention, which addresses the cravings associated with addiction. She has patients practice what she calls “urge surfing”: riding out a craving or urge rather than relying on a substance for immediate relief. “Craving will happen, so rather than fighting it, we look at understanding it better,” she says.
MORE differs from other forms of mindfulness-based therapy in that it integrates reappraisal and savoring training. Reappraisal is a technique often used in CBT in which patients learn to change negative thought patterns in order to reduce their emotional impact, while savoring helps to restructure the reward processes in the brain.
Mindfulness training not only helps patients to understand and gain control over their behavior in response to cravings and triggers like pain, says Garland, but also provides a means of pain relief. “We use mindfulness to zoom into pain and break it down into its subcomponents – feelings of heat or tightness or tingling – which reduces the impact that negative emotions have on pain processing in the brain.”
Eric Garland examines brain waves.
University of Utah
Powerful interventions
As the dangers of opioid addiction have become increasingly evident, some scientists are developing less addictive, non-opioid painkillers, but more trials are needed. Meanwhile, behavioral approaches to chronic pain relief have continued to gain traction, and researchers like Garland are probing the possibilities of integrative treatments to treat the addiction itself. Given that the number of people suffering from chronic pain and OUD have reached new heights during the COVID-19 pandemic, says Wachholtz, new treatment alternatives for patients caught in the relentless cycle of chronic pain and opioid misuse are sorely needed. “We’re trying to refine the techniques,” she says, “but we’re starting to realize just how powerful some of these mind-body interventions can be.”
Exactly 67 years ago, in 1955, a group of scientists and reporters gathered at the University of Michigan and waited with bated breath for Dr. Thomas Francis Jr., director of the school’s Poliomyelitis Vaccine Evaluation Center, to approach the podium. The group had gathered to hear the news that seemingly everyone in the country had been anticipating for the past two years – whether the vaccine for poliomyelitis, developed by Francis’s former student Jonas Salk, was effective in preventing the disease.
Polio, at that point, had become a household name. As the highly contagious virus swept through the United States, cities closed their schools, movie theaters, swimming pools, and even churches to stop the spread. For most, polio presented as a mild illness, and was usually completely asymptomatic – but for an unlucky few, the virus took hold of the central nervous system and caused permanent paralysis of muscles in the legs, arms, and even people’s diaphragms, rendering the person unable to walk and breathe. It wasn’t uncommon to hear reports of people – mostly children – who fell sick with a flu-like virus and then, just days later, were relegated to spend the rest of their lives in an iron lung.
For two years, researchers had been testing a vaccine that would hopefully be able to stop the spread of the virus and prevent the 45,000 infections each year that were keeping the nation in a chokehold. At the podium, Francis greeted the crowd and then proceeded to change the course of human history: The vaccine, he reported, was “safe, effective, and potent.” Widespread vaccination could begin in just a few weeks. The nightmare was over.
The road to success
Jonas Salk, a medical researcher and virologist who developed the vaccine with his own research team, would rightfully go down in history as the man who eradicated polio. (Today, wild poliovirus circulates in just two countries, Afghanistan and Pakistan – with only 140 cases reported in 2020.) But many people today forget that the widespread vaccination campaign that effectively ended wild polio across the globe would have never been possible without the human clinical trials that preceded it.
As with the COVID-19 vaccine, skepticism and misinformation around the polio vaccine abounded. But even more pervasive than the skepticism was fear. The consequences of polio had arguably never been more visible.
The road to human clinical trials – and the resulting vaccine – was a long one. In 1938, President Franklin Delano Roosevelt launched the National Foundation for Infantile Paralysis in order to raise funding for research and development of a polio vaccine. (Today, we know this organization as the March of Dimes.) A polio survivor himself, Roosevelt elevated awareness and prevention into the national spotlight, even more so than it had been previously. Raising funds for a safe and effective polio vaccine became a cornerstone of his presidency – and the funds raked in by his foundation went primarily to Salk to fund his research.
The Trials Begin
Salk’s vaccine, which included an inactivated (killed) polio virus, was promising – but now the researchers needed test subjects to make global vaccination a possibility. Because the aim of the vaccine was to prevent paralytic polio, researchers decided that they had to test the vaccine in the population that was most vulnerable to paralysis – young children. And, because the rate of paralysis was so low even among children, the team required many children to collect enough data. Francis, who led the trial to evaluate Salk’s vaccine, began the process of recruiting more than one million school-aged children between the ages of six and nine in 272 counties that had the highest incidence of the disease. The participants were nicknamed the “Polio Pioneers.”
Double-blind, placebo-based trials were considered the “gold standard” of epidemiological research back in Francis's day - and they remain the best approach we have today. These rigorous scientific studies are designed with two participant groups in mind. One group, called the test group, receives the experimental treatment (such as a vaccine); the other group, called the control, receives an inactive treatment known as a placebo. The researchers then compare the effects of the active treatment against the effects of the placebo, and every researcher is “blinded” as to which participants receive what treatment. That way, the results aren’t tainted by any possible biases.
But the study was controversial in that only some of the individual field trials at the county and state levels had a placebo group. Researchers described this as a “calculated risk,” meaning that while there were risks involved in giving the vaccine to a large number of children, the bigger risk was the potential paralysis or death that could come with being infected by polio. In all, just 200,000 children across the US received a placebo treatment, while an additional 725,000 children acted as observational controls – in other words, researchers monitored them for signs of infection, but did not give them any treatment.
As with the COVID-19 vaccine, skepticism and misinformation around the polio vaccine abounded. But even more pervasive than the skepticism was fear. President Roosevelt, who had made many public and televised appearances in a wheelchair, served as a perpetual reminder of the consequences of polio, as an infection at age 39 had rendered him permanently unable to walk. The consequences of polio had arguably never been more visible, and parents signed up their children in droves to participate in the study and offer them protection.
The Polio Pioneer Legacy
In a little less than a year, roughly half a million children received a dose of Salk’s polio vaccine. While plenty of children were hesitant to get the shot, many former participants still remember the fear surrounding the disease. One former participant, a Polio Pioneer named Debbie LaCrosse, writes of her experience: “There was no discussion, no listing of pros and cons. No amount of concern over possible side effects or other unknowns associated with a new vaccine could compare to the terrifying threat of polio.” For their participation, each kid received a certificate – and sometimes a pin – with the words “Polio Pioneer” emblazoned across the front.
When Francis announced the results of the trial on April 12, 1955, people did more than just breathe a sigh of relief – they openly celebrated, ringing church bells and flooding into the streets to embrace. Salk, who had become the face of the vaccine at that point, was instantly hailed as a national hero – and teachers around the country had their students to write him ‘thank you’ notes for his years of diligent work.
But while Salk went on to win national acclaim – even accepting the Presidential Medal of Freedom for his work on the polio vaccine in 1977 – his success was due in no small part to the children (and their parents) who took a risk in order to advance medical science. And that risk paid off: By the early 1960s, the yearly cases of polio in the United States had gone down to just 910. Where before the vaccine polio had caused around 15,000 cases of paralysis each year, only ten cases of paralysis were recorded in the entire country throughout the 1970s. And in 1979, the virus that once shuttered entire towns was declared officially eradicated in this country. Thanks to the efforts of these brave pioneers, the nation – along with the majority of the world – remains free of polio even today.