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.
Scientists Just Created Liquid Solar Power That Can Be Stored for 18 Years
Look no further than this week's climate strikes for evidence that millions of people are passionate about curbing global warming.
Unlike relatively limited solar panel energy storage, norbornadiene can potentially maintain its potency for years.
But even potential solutions, like alternative meats, have their own challenges. Some scientists are putting their focus on the sun to help balance out our energy consumption.
In fact, they are gathering solar power so pure that, until recently, capturing it was an impossibility.
The Lowdown
A group of Swedish scientists has created a liquid called norbornadiene. This liquid sunshine can capture up to 30 percent of raw solar power. To put it in perspective, the best publicly available solar panels can harness 21 percent. Norbornadiene would bring in about 50 percent more power – a significant difference in energy efficiency.
Most notably, unlike relatively limited solar panel energy storage, norbornadiene can potentially maintain its potency for years. We could have the ability to collect and store premium solar power, making it easier for current and future generations to use fossil and nuclear fuel alternatives.
"The norbornadiene molecules that we have made have very good properties, in terms of solar energy capture efficiency, storage time and energy density," says team lead Dr. Kasper Moth-Poulson of the Chamlers University of Technology. "They can store energy without the need for insulation materials for 18 or more years."
Next Up
Swedish scientist Moth-Poulsen and his team have been testing the norbornadiene on the physics building roof at the Chalmers University of Technology. Once activated, it heats up to just below boiling and provides enough power to be useful.
The energy density is 250 watt-hours per kilogram, twice the strength of Tesla's popular Powerall battery.
It requires potentially toxic solvents, like a cobalt-based activator, to transform into its full potential. The team is currently trying to find less-hazardous catalysts to help transform the norbornadiene to its active form, quadricyclane. Exposing it to sunlight is the main way to reactivate the norbornadiene's power. Over time, scientists will likely make it more efficient with less toxic agents.
The energy density is 250 watt-hours per kilogram, twice the strength of Tesla's popular Powerall battery.
Open Questions
The biggest question is safety, perceived or otherwise: Are you ready to drive around with 250 kWh of pure solar in your Hyundai? Norbornadiene may be stable in a hermetically sealed lab, but sculpting it for everyday use requires another level of security.
The half-life of the sunshine power is also an estimate, too. The challenge with new scientific substances is you don't know how the matter will evolve over time. It is easy to be overly optimistic about this one discovery being the key to our energy needs. For the time being, it is wiser to look at norbornadiene as a progressive step rather than a revolutionary one.
Even at its least effective, norbornadiene and its related material is a step toward us utilizing the one natural resource that won't run out for generations. In the short-term, a stable form of it could offset our fossil and nuclear fuel use and even help lower the carbon footprint made by long-distance transportation. It will be fascinating to see what future aircraft builders, home designers and even car manufacturers do as the solar technology conversation heats up.
Moth-Poulsen wants norbornadiene to be a definitive part of the climate change puzzle.
"I hope that in five years, we will see the first products based on our molecules and could help mitigate the daily variations in temperature," he says. "This will lead to increased thermal comfort and reduced energy consumption for heating and cooling."
Virtual Reality is Making Medical Care for Kids Less Scary and Painful
A blood draw is not normally a fun experience, but these days, virtual reality technology is changing that.
Instead of watching a needle go into his arm, a child wearing a VR headset at Children's Hospital Los Angeles can play a game throwing balls at cartoon bears. In Seattle, at the University of Washington, a burn patient can immerse herself in a soothing snow scene. And at the University of Miami Hospital, a five-minute skin biopsy can become an exciting ride at an amusement park.
VR is transforming once-frightening medical encounters for kids, from blood draws to biopsies to pre-surgical prep, into tolerable ones.
It's literally a game changer, says pediatric neurosurgeon Kurtis Auguste, who uses the tool to help explain pending operations to his young patients and their families. The virtual reality 3-D portrait of their brain is recreated from an MRI, originally to help plan the surgery. The image of normally bland tissue is painted with false colors to better see the boundaries and anomalies of each component. It can be rotated, viewed from every possible angle, zoomed in and out; incisions can be made and likely results anticipated. Auguste has extended its use to patients and families.
"The moment you put these headsets on the kids, we immediately have a link, because honestly, this is how they communicate with each other," says Auguste. "We're all sitting around the table playing games. It's really bridged the distance between me, the pediatric specialist, and my patients" at the Benioff Children's Hospital Oakland, now affiliated with the University of California San Francisco School of Medicine.
The VR experience engages people where they are, immersing them in the environment rather than lecturing them. And it seems to work in all environments, across age and cultural differences, leading to a better grasp of what will be undertaken. That understanding is crucial to meaningful informed consent for surgery. It is particularly relevant for safety-net hospitals, which includes most children's hospitals, because often members of the families were born elsewhere and may have limited understanding of English, not to mention advanced medicine.
Targeting pain
"We're trying to target ways that we can decrease pain, anxiety, fear – what people usually experience as a function of a needle," says Jeffrey Gold, a pioneer in adapting VR at Children's Hospital Los Angeles. He ran the pain clinic there and in 2004 initially focused on phlebotomy, simple blood draws. Many of their kids require frequent blood draws to monitor serious chronic conditions such as diabetes, HIV infection, sickle cell disease, and other conditions that affect the heart, liver, kidneys and other organs.
The scientific explanation of how VR works for pain relief draws upon two basic principles of brain function. The first is "top down inhibition," Gold explains. "We all have the inherent capacity to turn down signals once we determine that signal is no longer harmful, dangerous, hurtful, etc. That's how our brain operates on purpose. It's not just a distraction, it's actually your brain stopping the pain signal at the spinal cord before it can fire all the way up to the frontal lobe."
Second is the analgesic effect from endorphins. "If you're in a gaming environment, and you're having fun and you're laughing and giggling, you are actually releasing endorphins...a neurochemical reaction at the synaptic level of the brain," he says.
Part of what makes VR effective is "what's called a cognitive load, where you have to actually learn something and do something," says Gold. He has worked with developers on a game call Bear Blast, which has proven to be effective in a clinical trial for mitigating pain. But he emphasizes, it is not a one-size-fits all; the programs and patients need to be evaluated to understand what works best for each case.
Gold was a bit surprised to find that VR "actually facilitates quicker blood draws," because the staff doesn't have to manage the kids' anxiety, so "they require fewer needle sticks." The kids, parents, and staff were all having a good time, "and that's a big win when everybody is benefiting." About two years ago the hospital made VR an option that patients can request in the phlebotomy lab, and about half of kids age 4 and older choose to do so.
The technology "gets the kids engaged and performing the activity the way we want them to" to maximize recovery.
VR reduces or eliminates the need to use sedation or anesthesia, which carries a small but real risk of an adverse reaction. And important to parents, it eliminates the recovery time from using sedation, which shortens the visit and time missed from school and work.
A more intriguing question is whether reducing fear and anxiety in early-life experiences with the healthcare system through activities like VR will have a long-term affect on kids' attitudes toward medicine as they grow older. "If you're a screaming meemie when you come get your blood draw when you're five or seven, you're still that anxious adolescent or adult who is all quivering and sweating and avoiding healthcare," Gold says. "That's a longitudinal health outcome I'd love to get my hands on in 10-15 years from now."
Broader applications
Dermatologist Hadar Lev-Tov read about the use of VR to treat pain and decided to try it in his practice at the University of Miami Hospital. He thought, "OK, this is low risk, it's easy to do. So we got some equipment and got it done." It was so affordable he paid for it out of his own pocket, rather than wait to go through administrative channels. The results were so interesting that he decided to publish it as a series of case studies with a wide variety of patients and types of procedures.
Some of them, such as freezing off warts, are not particularly painful. "But there can be a lot of anxiety, especially for kids, which can be worse than pain and can disrupt the procedure." It can trigger a non-rational, primal fight or flight response in the limbic region of the brain.
Adults understand the need for a biopsy of a skin growth and tolerate what might be a momentary flick of pain. "But for a kid you think twice about a biopsy, both because it's a hassle and because it could be a traumatic event for a child," says Lev-Tov. VR has helped to allay such fears and improve medical care.
Integrating VR into practice has been relatively easy, primarily focusing on simple training for staff and ensuring that standard infection control practices are used in handling equipment that is used by different patients. More mundane issues are ensuring that the play back and wi-fi equipment are functioning properly. He has had a few complaints from kids when the procedure is competed and the VR is turned off prematurely, which is why he favors programs like a roller coaster ride that lasts about five minutes, ample time to take a biopsy or two.
The future is today
The pediatric neurosurgeon Auguste is collaborating with colleagues at Oakland Children's to expand use of VR into different areas of care. Cancer specialists often use a port, a bubble installed under the skin in the chest of the child, to administer chemotherapy. But the young patient's curiosity often draws their attention downward to the port and their chin can potentially contaminate or obstruct it, interfering with the procedure. So the team developed a VR game involving birds that requires players to move their heads upward, away from the port, improving administration of the drugs and reducing the risk of infection.
Innovative use of VR just may be one tool that actually makes kids eager to visit the doctor.
Other games are being developed for rehabilitation that require the use of specific nerve and muscle combinations. The technology "gets the kids engaged and performing the activity the way we want them to" to maximize recovery, Auguste explains. "We can monitor their progress by the score on the game, and if it plateaus, maybe switch to another game."
Another project is trying to ease the anxiety and confusion of the patient and family experience within the hospital itself. Hospital staff are creating a personalized VR introductory walking tour that leads from the parking garage through the maze of structures and corridors in the hospital complex to Dr. Auguste's office, phlebotomy, the MRI site, and other locations they might visit. The goal is to make them familiar with key landmarks before they even set foot in the facility. "So when they come the day of the visit they have already taken that exact same path, hopefully more than once."
"They don't miss their MRI appointment and therefore they don't miss their clinical appointment with me," says Auguste. It reduces patient anxiety about the encounter and from the hospital's perspective, it will reduce costs of missed and rescheduled visits simply because patients did not go to the right place at the right time.
The VR visit will be emailed to patients ahead of time and they can watch it on a smartphone installed in a disposable cardboard viewer. Oakland Children's hopes to have the system in place by early next year. Auguste says their goal in using VR, like other health care providers across the country, is "to streamline the entire patient experience."
Innovative use of VR just may be one tool that actually makes kids eager to visit the doctor. That would be a boon to kids, parents, and the health of America.