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.
This Startup Uses Dust to Fight Sweatshops
"Dust thou art, and unto dust shalt thou return." Whoever wrote that famous line probably didn't realize that dust actually contains a secret weapon.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain."
Far from being a collection of mere inanimate particles, dust is now recognized as a powerful tool filled with living sensors. Studying those sensors can reveal an object's location history, which can help brands fight unethical manufacturing.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain," explains Jessica Green, the CEO of Phylagen, a San-Francisco-based company that she co-founded in 2014.
So how does the technology work?
Dust gathers everywhere—on our bodies, on objects—and that dust contains microbes like bacteria and viruses. Just as we humans have our own unique microbiomes, research has shown that physical locations have their own identifiable patterns of microbes as well. Visiting a place means you may pick up its microbial fingerprint in the dust that settles on you. The DNA of those microbes can later be sequenced in a lab and matched back to the place of origin.
"Your environment is constantly imprinted on you and vice versa," says Justin Gallivan, the director of the Biotechnology Office at DARPA, the research and defense arm of the Pentagon, which is funding Phylagen. "If we have a microbial map of the world," he posits, "can we infer an object's transit history?"
So far, Phylagen has shown that it's possible to identify where a ship came from based on the unique microbial populations it picked up at different naval ports. In another experiment, the sampling technology allowed researchers to determine where a person had walked within 1 kilometer in San Francisco, because of the microbes picked up by their shoes.
Data scientist Roxana Hickey, left, and CEO Jessica Green of Phylagen.
One application of this technology is to help companies that make products abroad. Such companies are very interested in determining exactly where their products are coming from, especially if foreign subcontractors are involved.
"In retail and apparel, often the facilities performing the subcontracting are not up to the same code that the brands require their suppliers to be, so there could be poor working conditions," says Roxana Hickey, a data scientist at Phylagen. "A supplier might use a subcontractor to save on the bottom line, but unethical practices are very damaging to the brand."
Before this technology was developed, brands sometimes faced a challenge figuring out what was going on in their supply chain. But now a product can be tested upon arrival in the States; its microbial signature can theoretically be analyzed and matched against a reference database to help determine if its DNA pattern matches that of the place where the product was purported to have been made.
Phylagen declined to elaborate further about how their process works, such as how they are building a database of reference samples, and how consistent a microbial population remains across a given location.
As the technology grows more robust, though, one could imagine numerous other applications, like in police work and forensics. But today, Phylagen is solely focused on helping commercial entities bring greater transparency to their operations so they can root out unauthorized subcontracting.
Then those unethical suppliers can – shall we say – bite the dust.
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.
Surfing for Science: A Fin Sensor Is Making Waves
For David Walden, a Southern Californian, surfing is a lifestyle, not a hobby. The 38-year-old works nights at a seafood restaurant to leave his mornings free for surfing.
While the surfers are doing what they love, they are also collecting information that is helping scientists better understand the ocean.
"Once you fall in love with the ocean, you need it like a daily cleanse or refresher," he says. "The positive mental and physical effects of the ocean, the endorphins and dopamine, keep you addicted in a good way."
Given his dedication to surfing, Walden was delighted when he became one of more than 200 surfers last year to test Smartfin, a 5-1/2-inch surfboard fin that contains a circuit board, a rechargeable battery, a GPS device, a sensor that captures temperature to one-hundredth of a degree, and a motion sensor that tracks the movement of the waves. While Walden and his fellow surfers are doing what they love, they are also collecting information that is helping scientists better understand the health of the near-shore ocean and how its chemistry is shifting due to climate change.
"I'm excited to be a part of it," Walden says. "I like to tell people I surf for science."
Back on shore, the surfers download the Smartfin data via a smartphone app so they can be accessed by scientists and other interested parties. (You can see where Smartfin surfers go at this interactive map.)
By putting sensors directly onto surfboards, oceanographers can collect data to help them better understand the global-warming related changes occurring in coastal oceans in temperature, salinity, and pH, all properties that have huge implications for the species that live in near-shore ecosystems.
There is much unknown about coastal waters because it's so difficult to obtain meaningful measurements. Traditional methods to monitor the close shore, such as bottle samples and buoys, are time consuming and expensive and tend to get damaged by the surf.
The Smartfin is the brainchild of Dr. Andy Stern, a retired neurologist. He and his brother-in-law, sculptor and filmmaker Todd McGrain, run The Lost Bird Project, a nonprofit devoted to raising awareness about climate change and other environmental issues. Stern brought his super fin idea to engineer Benjamin Thompson, who spent several years creating a prototype in his garage workshop. Smartfin was further developed by scientists at the Scripps Institution of Oceanography at the University of California at San Diego.
"The big challenge was to make a sensor small enough to fit in the fin but still produce good measurements," says Andreas Andersson, an associate professor of geoscience research at Scripps.
The Surfrider Foundation, a surfer-led nonprofit environmental organization, came aboard two years ago to distribute the Smartfin to its San Diego members.
Smartfin has also made a splash with scientists at the University of the Sunshine Coast in Queensland on the eastern coast of Australia. They are using the fin's temperature sensor to better understand how climate change is affecting the movement and distribution of marine life. And at the Plymouth Marine Laboratory in Plymouth, United Kingdom, the Smartfin's precise temperature readings of the near-shore ocean's surface are being used to improve the accuracy of satellites that monitor the ocean from hundreds of miles away.
"It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin."
"The hope is that Smartfin will improve the satellite measurements, which could improve the retrieval of temperature data around the world," says Dr. Phil Bresnahan, Smartfin's lead engineer at Scripps. In the future, the fin will include sensors to measure pH, chlorophyll (algae), dissolved oxygen, and turbidity (water clarity).
Stern envisions a time when thousands of surfers, paddle boarders, and other water enthusiasts worldwide will have Smartfins and be downloading data for scientists and environmentalists. Right now, there are approximately 70 surfers in the San Diego area using Smartfin and an additional 30 globally.
Scientists have plenty of evidence that global warming is largely caused by humans. Now they are trying to figure out what the long-term effects of climate change may be. For example, scientists are trying to predict which sections of coral reef, which house 25 percent of marine species, are most vulnerable so interventions can be developed to save them. Because of its small size, Smartfin is ideal to measure temperature changes in coral reefs.
Smartfin was also intended to be an educational tool. "It's a great way to start a different conversation about climate change," says Stern. "It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin. People want to hear more."
Turning surfers into citizen scientists makes perfect sense, says David Pasquini, 35, a longtime surfer who works for the British Consulate General's office in Oceanside, Calif. "Anyone who spends a lot of time in the ocean is aware of the changes happening in the ecosystem, the climate," says Pasquini. "Everyone asks, 'What can I do?'" Surfing with Smartfin, Pasquini feels like he is giving back.
"I know the data will be analyzed and eventually used to make a policy that helps with climate change. That's a great feeling--just by surfing, doing something you love, you're contributing."