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.
CandyCodes could provide sweet justice against fake pills
When we swallow a pill, we hope it will work without side effects. Few of us know to worry about a growing issue facing the pharmaceutical industry: counterfeit medications. These pills, patches, and other medical products might look just like the real thing. But they’re often stuffed with fillers that dilute the medication’s potency or they’re simply substituted for lookalikes that contain none of the prescribed medication at all.
Now, bioengineer William Grover at the University of California, Riverside, may have a solution. Inspired by the tiny, multi-colored sprinkles called nonpareils that decorate baked goods and candies, Grover created CandyCodes pill coatings to prevent counterfeits.
The idea was borne out of pandemic boredom. Confined to his home, Grover was struck by the patterns of nonpareils he saw on candies, and found himself counting the number of little balls on each one. “It’s random, how they’re applied,” he says. “I wondered if it ever repeats itself or if each of these candies is unique in the entire world.” He suspected the latter, and some quick math proved his hypothesis: Given dozens of nonpareils per candy in a handful of different colors, it’s highly unlikely that the sprinklings on any two candies would be identical.
He quickly realized his finding could have practical applications: pills or capsules could be coated with similar “sprinkles,” with the manufacturer photographing each pill or capsule before selling its products. Consumers looking to weed out fakes could potentially take a photo with their cell phones and go online to compare images of their own pills to the manufacturer’s database, with the help of an algorithm that would determine their authenticity. Or, a computer could generate another type of unique identifier, such as a text-based code, tracking to the color and location of the sprinkles. This would allow for a speedier validation than a photo-based comparison, Grover says. “It could be done very quickly, in a fraction of a second.”
Researchers and manufacturers have already developed some anti-counterfeit tools, including built-in identifiers like edible papers with scannable QR codes. But such methods, while functional, can be costly to implement, Grover says.
It wouldn’t be paranoid to take such precautions. Counterfeits are a growing problem, according to Young Kim, a biomedical engineer at Purdue University who was not involved in the CandyCodes study. “There are approximately 40,000 online pharmacies that one can access via the Internet,” he says. “Only three to four percent of them are operated legally.” Purchases from online pharmacies rose dramatically during the pandemic, and Kim expects a boom in counterfeit medical products alongside it.
The FDA warns that U.S. consumers can be exposed to counterfeits through online purchases, in particular. The problem is magnified in low- to middle-income nations, where one in 10 medical products are counterfeit, according to a World Health Organization estimate. Cost doesn’t seem to be a factor, either; antimalarials and antibiotics are most often reported as counterfeits or fakes, and generic medications are swapped as often as brand-name drugs, according to the same WHO report.
Counterfeits weren’t tracked globally until 2013; since then, there have been 1,500 reports to the WHO, with actual incidences of counterfeiting likely much higher. Fake medicines have been estimated to result in costs of $200 billion each year, and are blamed for more than 72,000 pneumonia- and 116,000 malaria-related deaths.
Researchers and manufacturers have already developed some anti-counterfeit tools, including built-in identifiers like edible papers with scannable QR codes or barcodes that are stamped onto or otherwise incorporated into pills and other medical products. But such methods, while functional, can be costly to implement, Grover says.
CandyCodes could provide unique identifiers for at least 41 million pills for every person on the planet.
William Grover
“Putting universal codes on each pill and each dosage is attractive,” he says. “The challenge is, how can we do it in a way that requires as little modification to the existing manufacturing process as possible? That's where I hope CandyCodes have an edge. It's not zero modification, but I hope it is as minor a modification of the manufacturing process as possible.”
Kim calls the concept “a clever idea to introduce entropy for high-level security” even if it may not be as close to market as other emerging technologies, including some edible watermarks he’s helped develop. He points out that CandyCodes still needs to be tested for reproducibility and readability.
The possibilities are already intriguing, though. Grover’s recent research, published in Scientific Reports, predicts that unique codes could be used for at least 41 million pills for every person on the planet.
Sadly, CandyCodes’ multicolored bits probably won’t taste like candy. They must be made of non-caloric ingredients to meet the international regulatory standards that govern food dyes and colorants. But Grover hopes CandyCodes represent a simple, accessible solution to a heart-wrenching issue. “This feels like trying to track down and go after bad guys,” he says. “Someone who would pass off a medicine intended for a child or a sick person and pass it off as something effective, I can't imagine anything much more evil than that. It's fun and, and a little fulfilling to try to develop technologies that chip away at that.”
Waste smothering our oceans is worth billions – here’s what we can do with all that sh$t
There’s hardly a person out there who hasn’t heard of the Great Pacific Garbage Patch. That type of pollution is impossible to miss. It stares you in the face from pictures and videos of sea turtles with drinking straws up their noses and acres of plastic swirling in the sea.
It demands you to solve the problem—and it works. The campaign to raise awareness about plastic pollution in the oceans has resulted in new policies, including bans on microplastics in personal care products, technology to clean up the plastic, and even new plastic-like materials that are better for the environment.
But there’s a different type of pollution smothering the ocean as you read this. Unfortunately, this one is almost invisible, but no less damaging. In fact, it’s even more serious than plastic and most people have no idea it even exists. It is literally under our noses, destroying our oceans, lakes, and rivers – and yet we are missing it completely while contributing to it daily. In fact, we exacerbate it multiple times a day—every time we use the bathroom.
It is the way we do our sewage.
Most of us don’t think much about what happens after we flush the toilet. Most of us probably assume that the substances we flush go “somewhere” and are dealt with safely. But we typically don’t think about it beyond that.
Most of us also probably don’t think about what’s in the ocean or lakes we swim in. Since others are swimming, jumping in is just fine. But our waterways are far from clean. In fact, at times they are incredibly filthy. In the US, we are dumping 1.2 trillion of gallons of untreated sewage into the environment every year. Just New York City alone discharges 27 billion gallons into the Hudson River basin annually.
How does this happen? Part of it is the unfortunate side effect of our sewage system design that dates back to over a century ago when cities were smaller and fewer people were living so close together.
Back then, engineers designed the so-called “combine sewer overflow systems,” or CSOs, in which the storm water pipes are connected to the sanitary sewer pipes. In normal conditions, the sewage effluent from homes flows to the treatment plants where it gets cleaned and released into the waterways. But when it rains, the pipe system becomes so overwhelmed with water that the treatment plant can’t process it fast enough. So the treatment plant has to release the excess water through its discharge pipes—directly, without treatment, into streams, rivers and the ocean.
The 1.2 trillion gallons of CSO releases isn’t even the full picture. There are also discharges from poorly maintained septic systems, cesspools and busted pipes of the aging wastewater infrastructure. The state of Hawaii alone has 88,000 cesspools that need replacing and are currently leaking 53 million gallons of raw sewage daily into their coastal waters. You may think twice about swimming on your Hawaii vacations.
Overall, the US is facing a $271 billion backlog in wastewater infrastructure projects to update these aging systems. Across the Western world, countries are facing similar challenges with their aging sewage systems, especially the UK and European Union.
That’s not to say that other parts of the planet are in better shape. Out of the 7+ billion people populating our earth, 4.2 billion don’t have access to safe sanitation. Included in this insane number are roughly 2 billion people who have no toilet at all. Whether washed by rains or dumped directly into the waterways, a lot of this sludge pollutes the environment, the drinking water, and ultimately the ocean.
Pipes pour water onto a rocky shore in Jakarta, Indonesia.
Tom Fisk
What complicates this from an ocean health perspective is that it’s not just poop and pee that gets dumped into nearby waterways. It is all the things we put in and on our bodies and flush down our drains. That vicious mix of chemicals includes caffeine, antibiotics, antidepressants, painkillers, hormones, microplastics, cocaine, cooking oils, paint thinners, and PFAS—the forever chemicals present in everything from breathable clothing to fire retardant fabrics of our living room couches. Recent reports have found all of the above substances in fish—and then some.
Why do we allow so much untreated sewage spill into the sea? Frankly speaking, for decades scientists and engineers thought that the ocean could handle it. The mantra back then was “dilution is the solution to pollution,” which might’ve worked when there were much fewer people living on earth—but not now. Today science is telling us that this old approach doesn’t hold. That marine habitats are much more sensitive than we had expected and can’t handle the amount of wastewater we are discharging into them.
The excess nitrogen and phosphorus that the sewage (and agricultural runoff) dumps into the water causes harmful algal blooms, more commonly known as red or brown tides. The water column is overtaken by tiny algae that sucks up all the oxygen from the water, creating dead zones like the big fish kills in the Gulf of Mexico. These algae also cause public health issues by releasing gases toxic to people and animals, including dementia, neurological damage, and respiratory illness. Marshes and mangroves end up with weakened root systems and start dying off. In a wastewater modeling study I published last year, we found that 31 percent of salt marshes globally were heavily polluted with human sewage. Coral reefs get riddled with disease and overgrown by seaweed.
We could convert sewage into high-value goods. It can be used to generate electricity, fertilizer, and drinking water. The technologies not only exist but are getting better and more efficient all the time.
Moreover, by way of our sewage, we managed to transmit a human pathogen—Serratia marcescens, which causes urinary, respiratory and other infections in people—to corals! Recent reports from the Florida Keys are showing white pox disease popping up in elk horn corals caused by S.marcescens, which somehow managed to jump species. Many recent studies have documented just how common this type of pollution is across the globe.
Yet, there is some good news in that abysmal sewage flow. Just like with plastic pollution, realizing that there’s a problem is the first step, so awareness is key. That’s exactly why I co-founded Ocean Sewage Alliance last year—a nonprofit that aims to “re-potty train the world” by breaking taboos in talking about the poop and pee problem, as well as uniting experts from various key sectors to work together to end sewage pollution in coastal areas.
To end this pollution, we have to change the ways we handle our sewage. Even more exciting is that by solving the sewage problem we can create all sorts of economic benefits. In 2015, human poop was valued at $9.5 billion a year globally, which today would be $11.5 billion per year.
What would one do with that sh$t?
We could convert it into high-value goods. Sewage can be used to generate electricity, fertilizer, and drinking water. The technologies not only exist but are getting better and more efficient all the time. Some exciting examples include biodigesters and urine diversion (or peecycling) systems that can produce fertilizer and biogas, essentially natural gas. The United Nations estimates that the biogas produced from poop could provide electricity for 138 million homes. And the recovered and cleaned water can be used for irrigation, laundry and flushing toilets. It can even be refined to the point that it is safe for drinking water – just ask the folks in Orange County, CA who have been doing so for the last few decades.
How do we deal with all the human-made pollutants in our sewage? There is technology for that too. Called pyrolysis, it heats up sludge to high temperatures in the absence of oxygen, which causes most of the substances to degrade and fall apart.
There are solutions to the problems—as long as we acknowledge that the problems exist. The fact that you are reading this means that you are part of the solution already. The next time you flush your toilet, think about where this output may flow. Does your septic system work properly? Does your local treatment plant discharge raw sewage on rainy days? Can that plant implement newer technologies that can upcycle waste? These questions are part of re-potty training the world, one household at a time. And together, these households are the force that can turn back the toxic sewage tide. And keep our oceans blue.