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.
With a deadly pandemic sweeping the planet, many are questioning the comfort and security we have taken for granted in the modern world.
A century ago, when an influenza pandemic struck, we barely knew what viruses were.
More than a century after the germ theory, we are still at the mercy of a microbe we can neither treat, nor control, nor immunize against. Even more discouraging is that technology has in some ways exacerbated the problem: cars and air travel allow a new disease to quickly encompass the globe.
Some say we have grown complacent, that we falsely assume the triumphs of the past ensure a happy and prosperous future, that we are oblivious to the possibility of unpredictable "black swan" events that could cause our destruction. Some have begun to lose confidence in progress itself, and despair of the future.
But the new coronavirus should not defeat our spirit—if anything, it should spur us to redouble our efforts, both in the science and technology of medicine, and more broadly in the advance of industry. Because the best way to protect ourselves against future disasters is more progress, faster.
Science and technology have overall made us much better able to deal with disease. In the developed world, we have already tamed most categories of infectious disease. Most bacterial infections, such as tuberculosis or bacterial pneumonia, are cured with antibiotics. Waterborne diseases such as cholera are eliminated through sanitation; insect-borne ones such as malaria through pest control. Those that are not contagious until symptoms appear, such as SARS, can be handled through case isolation and contact tracing. For the rest, such as smallpox, polio, and measles, we develop vaccines, given enough time. COVID-19 could start a pandemic only because it fits a narrow category: a new, viral disease that is highly contagious via pre-symptomatic droplet/aerosol transmission, and that has a high mortality rate compared to seasonal influenza.
A century ago, when an influenza pandemic struck, we barely knew what viruses were; no one had ever seen one. Today we know what COVID-19 is down to its exact genome; in fact, we have sequenced thousands of COVID-19 genomes, and can track its history and its spread through their mutations. We can create vaccines faster today, too: where we once developed them in live animals, we now use cell cultures; where we once had to weaken or inactivate the virus itself, we can now produce vaccines based on the virus's proteins. And even though we don't yet have a treatment, the last century-plus of pharmaceutical research has given us a vast catalog of candidate drugs, already proven safe. Even now, over 50 candidate vaccines and almost 100 candidate treatments are in the research pipeline.
It's not just our knowledge that has advanced, but our methods. When smallpox raged in the 1700s, even the idea of calculating a case-fatality rate was an innovation. When the polio vaccine was trialled in the 1950s, the use of placebo-controlled trials was still controversial. The crucial measure of contagiousness, "R0", was not developed in epidemiology until the 1980s. And today, all of these methods are made orders of magnitude faster and more powerful by statistical and data visualization software.
If you're seeking to avoid COVID-19, the hand sanitizer gel you carry in a pocket or purse did not exist until the 1960s. If you start to show symptoms, the pulse oximeter that tests your blood oxygenation was not developed until the 1970s. If your case worsens, the mechanical ventilator that keeps you alive was invented in the 1950s—in fact, no form of artificial respiration was widely available until the "iron lung" used to treat polio patients in the 1930s. Even the modern emergency medical system did not exist until recently: if during the 1918 flu pandemic you became seriously ill, there was no 911 hotline to call, and any ambulance that showed up would likely have been a modified van or hearse, with no equipment or trained staff.
As many of us "shelter in place", we are far more able to communicate and collaborate, to maintain some semblance of normal life, than we ever would have been. To compare again to 1918: long-distance telephone service barely existed at that time, and only about a third of homes in the US even had electricity; now we can videoconference over Zoom and Skype. And the enormous selection and availability provided by online retail and food delivery have kept us stocked and fed, even when we don't want to venture out to the store.
Let the virus push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts.
"Black swan" calamities can strike without warning at any time. Indeed, humanity has always been subject to them—drought and frost, fire and flood, war and plague. But we are better equipped now to deal with them than ever before. And the more progress we make, the better prepared we'll be for the next one. The accumulation of knowledge, technology, industrial infrastructure, and surplus wealth is the best buffer against any shock—whether a viral pandemic, a nuclear war, or an asteroid impact. In fact, the more worried we are about future crises, the more energetically we should accelerate science, technology and industry.
In this sense, we have grown complacent. We take the modern world for granted, so much so that some question whether further progress is even still needed. The new virus proves how much we do need it, and how far we still have to go. Imagine how different things would be if we had broad-spectrum antiviral drugs, or a way to enhance the immune system to react faster to infection, or a way to detect infection even before symptoms appear. These technologies may seem to belong to a Star Trek future—but so, at one time, did cell phones.
The virus reminds us that nature is indifferent to us, leaving us to fend entirely for ourselves. As we go to war against it, let us not take the need for such a war as reason for despair. Instead, let it push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts. No matter the odds, applied intelligence is our best weapon against disaster.
With millions of people left feeling helpless as COVID-19 sweeps across the U.S. and the rest of the planet, there is one way in which absolutely anyone can help fight the pandemic -- all you need is a computer and an Internet connection.
"The more donors that participate, the more science we're able to do."
The Folding@home project allows members of the public to contribute a portion of their computing power to a gigantic virtual network which has mushroomed over the past month to become the most powerful supercomputer on the planet.
As of April 6, more than one million people across the globe have donated some of their home computing resources to the project. Combined, this gives Folding@home processing powers that dwarf even NASA and IBM's most powerful devices. To join, all you have to do is go to this website and click 'Download Now' to load the Folding@home software on your computer. This runs in the background, and only adds your unused computing power to the project, so it will not drain resources from tasks you're trying to do.
"It's totally crazy," said Vincent Voelz, associate professor of chemistry at Temple University, Philadelphia, and one of the scientists leading the project. "A month ago, we had around 30,000 to 40,000 participants. And then last week, it rose up 400,000 and now we've hit a million. But the more donors that participate, the more science we're able to do."
Voelz and the other scientists behind Folding@home are using these vast resources to model the ever-changing shapes of the coronavirus's proteins, in the hopes of identifying vulnerabilities or 'pockets' in its structure that can be targeted with new drugs.
One of the reasons it's difficult to find treatments for viruses like COVID-19 and Ebola is because the proteins, the innate building blocks of the viral structure, have notoriously smooth surfaces, making it hard for drugs to bind to them.
But viral proteins don't stay still. They are constantly evolving and changing shape as the atoms within push and pull against each other. Having a supercomputer enables scientists to simulate all these different shapes, revealing potential weaknesses which were not immediately visible. And the more powerful the supercomputer, the faster these simulations can happen.
"Simulating these protein motions also enables us to answer basic questions such as what makes this new coronavirus strain different from previous strains," said Voelz. "Is there something about the dynamics of these proteins that makes it more virulent?"
Finding a genuinely novel drug for COVID-19 is particularly critical.
Once they have identified suitable pockets within the proteins of COVID-19, the Folding@home scientists can then take the many compounds being identified by chemists around the world as potential drugs, and try to predict which ones will stand the best chance of binding to those pockets and inhibiting the virus's ability to invade and take over human cells.
"We have so much bandwidth now with Folding@home that we really think we can make a dent with screening these, and prioritizing which compounds are then going to get experimentally tested," said Voeltz.
The team are particularly hopeful they can succeed, having already used the supercomputer to identify a new vulnerability in the Ebola virus, which could go on to yield a new treatment for the disease.
Finding a genuinely novel drug for COVID-19 is particularly critical. While researchers are also looking at repurposing existing medications, like the antimalarials Hydroxychloroquine and Chloroquine (which have just been approved by the FDA for emergency use in coronavirus patients), concerns remain about the safety of these treatments. Researchers at the Mayo Clinic recently warned that the use of these drugs could have the side effect of inducing heart problems and run the risk of sudden cardiac arrest.
But with the death toll increasing by the day, speed is of the essence. Voelz explains that the scientific community has been left playing catch-up, because a drug was never actually developed for the original SARS outbreak in the early 2000s. The enormous computational power of the Folding@home project has the potential to allow scientists to quickly answer some of the key questions needed to get a new treatment into the pipeline.
"We don't have a SARS drug for whatever reason," said Voelz. "So the missing ingredient really, is the basic science to reveal possible drug targets and then the pharma can take that information and do the engineering work and optimizing and clinically testing drugs. But we now have a lot of basic science going on in response to this pandemic."