If approved by the FDA, a new procedure for kidney transplants that doesn't require anti-rejection medication could soon become the standard of care.
Talaris is now moving into the final clinical trial, phase III, before submitting for FDA approval. Known as Freedom-1, this trial has 17 sites open throughout the U.S., and Talaris will enroll a total of 120 kidney transplant recipients. One day after receiving their donor’s kidney, 80 people will undergo the company’s therapy, involving the donor’s stem cells and other critical cells that are processed at their facility. Forty will have a regular kidney transplant and remain on immunosuppression to provide a control group.
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Robert Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
The procedure was pioneered decades ago by Suzanne Ildstad as a faculty member at the University of Pittsburgh before she became founding CEO of Talaris and then its Chief Scientific Officer. If approved by the FDA, the method could soon become the standard of care for patients in need of a kidney transplant.
“We are working to find a way to reprogram the immune system of transplant recipients so that it sees the donated organ as [belonging to one]self and doesn’t attack it,” explains Scott Requadt, CEO of Talaris. “That obviates the need for lifelong immunosuppression.”
Each year, there are roughly 20,000 kidney transplants, making kidneys the most transplanted organ. About 6,500 of those come from living donors, while deceased donors provide roughly 13,000.
One of the challenges, Requadt points out, is that kidney transplant recipients aren’t always aware of all the implications of immunosuppression. Typically, they will need to take about 20 anti-rejection drugs several times a day to provide immunosuppression as well as treat complications caused by the toxicities of immunosuppression medications. The side effects of chronic immunosuppression include weight gain, high blood pressure, and high cholesterol. These cardiovascular comorbidities, Requadt says, are “often more frequently the cause of death than failure of a transplanted organ.”
Patients who are chronically immunosuppressed generally have much higher rates of infections and cancers that have an immune component to them, such as skin cancers.
For the past couple of years, those patients have experienced heightened anxiety because of the COVID-19 pandemic. Immune-suppressing medicine used to protect their new organ also makes it hard for patients to build immunity to foreign invaders like COVID-19.
A study appearing in the Proceedings of the National Academy of Sciences found the probability of a pandemic with similar impact to COVID-19 is about 2 percent in any year, and estimated that the probability of novel disease outbreaks will grow three-fold in the next few decades. All the more reason to identify an FDA-approved alternative to harsh immunosuppressive drugs.
Of the 18 patients during the phase II research trial who received the Talaris therapy, didn’t take immunosuppression medication and were vaccinated, only two ended up with a COVID infection, according to a review of the data. Among patients who needed to continue taking immunosuppressants or those who didn’t have them but were unvaccinated, the rates of infection were between 40 and 60 percent.
In the earlier phase II study by Talaris with 37 patients, the combined transplantation approach allowed 70 percent of patients to get off all immunosuppression.
“We’ve followed that whole cohort for more than six and a half years and one of them for 12 years from transplant, and every single patient that we got off immunosuppression has been able to stay off,” Requadt says.
That one patient, Robert Waddell, 55, was especially thankful to be weaned off immunosuppressive drugs approximately one year after his transplant procedure. The Louisville resident had long watched his mother, sister and other family members with polycystic kidney disease, or PKD, suffer the effects of chronic immunosuppression. That became his greatest fear when he was diagnosed with end stage renal failure.
Waddell enrolled in the phase II research taking place in Louisville after learning about it in early 2006. He chose to remain in the study when it relocated its clinical headquarters to Northwestern University’s medical center in Chicago a couple years later.
Before surgery, he underwent an enervating regimen of chemotherapy and radiation. It’s required to clear out a patient’s bone marrow cells so that they can be replaced by the donor’s cells. Waddell says the result was worth it: he had his combined kidney and immune system stem cell transplant in May 2009, without any need for chronic immunosuppression.
“I call it ‘short-term pain, long-term gain,’ because it was difficult to go through the conditioning, but after that, it was great,” he says. “I’ve talked to so many kidney recipients who say, ‘I wish I would have done that,’ because most people don’t think about clinical trials, but I was very fortunate.”
Waddell has every reason to support the success of this research, especially given the genetic disorder, PKD, that has plagued his family. One of his four children has PKD. He is anxious for the procedure to become standard of care, if and when his son needs it.
The Talaris procedure was pioneered decades ago by Suzanne Ildstad, founding CEO of Talaris and the company's Chief Scientific Officer, pictured here with the current CEO, Scott Requadt.
Talaris
“The beauty of this procedure is that I don’t have to take all of the anti-rejection drugs,” says Waddell, a finance professional. “I forget that I ever had any kidney issues. That’s how impactful it is.”
Talaris will continue to follow Waddell and the rest of his cohort to track the effectiveness and safety of the procedure. According to Requadt, the average life of a transplanted kidney is 12 to 15 years, partly because the immunosuppressive drugs worsen the functioning of the organ each year.
“We were the first group to show that we could robustly and fairly reproducibly do this in a clinical setting in humans,” Requadt says. “Most important, we’ve been able to show that we can still get a good engraftment of the stem cells from the donor, even if there is a profound…mismatch between the donor and the recipient’s immune systems.”
In kidney transplantation, it’s important to match for human leukocyte antigens (HLA) because there is a better graft survival in HLA-identical kidney transplants compared with HLA mismatched transplants.
About three months after the transplant, Talaris researchers look for evidence that the donated immune cells and stem cells have engrafted, while making a donor immune system for the patient. If more than 50 percent of the T cells contain the donor’s DNA after six months, patients can start taking fewer immunosuppressants.
“We know from phase II that in our patients who were able to tolerize [accept the organ without rejection] to their donated organ, we saw completely preserved and in fact slightly increased kidney function,” Requadt says. “So, it stands to reason that if you eliminate the drugs that are associated with declining kidney function that you would preserve kidney function, so hopefully the patient will have that one kidney for life.”
Matthew Cooper, director of kidney and pancreas transplantation for MedStar Georgetown Transplant Institute in Washington, DC, states that, “Right now, the Achilles’ heel is we have such a long waiting list and few donors that people die every day waiting for a kidney transplant. Eventually, we will eliminate the organ shortage so that people won’t die from organ failure.”
Cooper, a nationally recognized clinical transplant surgeon for 20 years, says when he started his career, finding a way for patients to forgo immunosuppression was considered “the Holy Grail” of modern transplant medicine.
“Now that we’ve got the protocols in place and some personal examples of how that can happen, it’s pretty exciting to see that all coming together,” he adds.
Some researchers argue that active, playful engagement with a "robot nanny" for a few hours a day is better than several hours in front of a TV or with an iPad.
A 2017 study led by Google executive James Manyika suggested that skills like creativity, emotional intelligence, and communication will always be needed in the classroom and that robots aren’t likely to provide them at the same level that humans naturally do. But robot teachers do bring advantages, such as a depth of subject knowledge that teachers can’t match, and they’re great for student engagement.
The teacher and robot can complement each other in new ways, with the teacher facilitating interactions between robots and students. So far, this is the case with teaching “assistants” being adopted now in China, Japan, the U.S., and Europe. In this scenario, the robot (usually the SoftBank child-size robot NAO) is a tool for teaching mainly science, technology, engineering, and math (the STEM subjects), but the teacher is very involved in planning, overseeing, and evaluating progress. The students get an entertaining and enriched learning experience, and some of the teaching load is taken off the teacher. At least, that’s what researchers have been able to observe so far.
To be sure, there are some powerful arguments for having robots in the classroom. A not-to-be-underestimated one is that robots “speak the language” of today’s children, who have been steeped in technology since birth. These children are adept at navigating a media-rich environment that is highly visual and interactive. They are plugged into the Internet 24-7. They consume music, games, and huge numbers of videos on a weekly basis. They expect to be dazzled because they are used to being dazzled by more and more spectacular displays of digital artistry. Education has to compete with social media and the entertainment vehicles of students’ everyday lives.
Another compelling argument for teaching robots is that they help prepare students for the technological realities they will encounter in the real world when robots will be ubiquitous. From childhood on, they will be interacting and collaborating with robots in every sphere of their lives from the jobs they do to dealing with retail robots and helper robots in the home. Including robots in the classroom is one way of making sure that children of all socioeconomic backgrounds will be better prepared for a highly automated age, when successfully using robots will be as essential as reading and writing. We’ve already crossed this threshold with computers and smartphones.
Students need multimedia entertainment with their teaching. This is something robots can provide through their ability to connect to the Internet and act as a centralized host to videos, music, and games. Children also need interaction, something robots can deliver up to a point, but which humans can surpass. The education of a child is not just intended to make them technologically functional in a wired world, it’s to help them grow in intellectual, creative, social, and emotional ways. When considered through this perspective, it opens the door to questions concerning just how far robots should go. Robots don’t just teach and engage children; they’re designed to tug at their heartstrings.
It’s no coincidence that many toy makers and manufacturers are designing cute robots that look and behave like real children or animals, says Turkle. “When they make eye contact and gesture toward us, they predispose us to view them as thinking and caring,” she has written in The Washington Post. “They are designed to be cute, to provide a nurturing response” from the child. As mentioned previously, this nurturing experience is a powerful vehicle for drawing children in and promoting strong attachment. But should children really love their robots?
ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold (January 9, 2024).
St. Martin’s Publishing Group
The problem, once again, is that a child can be lulled into thinking that she’s in an actual relationship, when a robot can’t possibly love her back. If adults have these vulnerabilities, what might such asymmetrical relationships do to the emotional development of a small child? Turkle notes that while we tend to ascribe a mind and emotions to a socially interactive robot, “simulated thinking may be thinking, but simulated feeling is never feeling, and simulated love is never love.”
Always a consideration is the fact that in the first few years of life, a child’s brain is undergoing rapid growth and development that will form the foundation of their lifelong emotional health. These formative experiences are literally shaping the child’s brain, their expectations, and their view of the world and their place in it. In Alone Together, Turkle asks: What are we saying to children about their importance to us when we’re willing to outsource their care to a robot? A child might be superficially entertained by the robot while his self-esteem is systematically undermined.
Research has emerged showing that there are clear downsides to child-robot relationships.
Still, in the case of robot nannies in the home, is active, playful engagement with a robot for a few hours a day any more harmful than several hours in front of a TV or with an iPad? Some, like Xiong, regard interacting with a robot as better than mere passive entertainment. iPal’s manufacturers say that their robot can’t replace parents or teachers and is best used by three- to eight-year-olds after school, while they wait for their parents to get off work. But as robots become ever-more sophisticated, they’re expected to perform more of the tasks of day-to-day care and to be much more emotionally advanced. There is no question children will form deep attachments to some of them. And research has emerged showing that there are clear downsides to child-robot relationships.
Some studies, performed by Turkle and fellow MIT colleague Cynthia Breazeal, have revealed a darker side to the child-robot bond. Turkle has reported extensively on these studies in The Washington Post and in her book Alone Together. Most children love robots, but some act out their inner bully on the hapless machines, hitting and kicking them and otherwise trying to hurt them. The trouble is that the robot can’t fight back, teaching children that they can bully and abuse without consequences. As in any other robot relationship, such harmful behavior could carry over into the child’s human relationships.
And, ironically, it turns out that communicative machines don’t actually teach kids good communication skills. It’s well known that parent-child communication in the first three years of life sets the stage for a very young child’s intellectual and academic success. Verbal back-and-forth with parents and care-givers is like fuel for a child’s growing brain. One article that examined several types of play and their effect on children’s communication skills, published in JAMA Pediatrics in 2015, showed that babies who played with electronic toys—like the popular robot dog Aibo—show a decrease in both the quantity and quality of their language skills.
Anna V. Sosa of the Child Speech and Language Lab at Northern Arizona University studied twenty-six ten- to sixteen- month-old infants to compare the growth of their language skills after they played with three types of toys: electronic toys like a baby laptop and talking farm; traditional toys like wooden puzzles and building blocks; and books read aloud by their parents. The play that produced the most growth in verbal ability was having books read to them by a caregiver, followed by play with traditional toys. Language gains after playing with electronic toys came dead last. This form of play involved the least use of adult words, the least conversational turntaking, and the least verbalizations from the children. While the study sample was small, it’s not hard to extrapolate that no electronic toy or even more abled robot could supply the intimate responsiveness of a parent reading stories to a child, explaining new words, answering the child’s questions, and modeling the kind of back- and-forth interaction that promotes empathy and reciprocity in relationships.
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Most experts acknowledge that robots can be valuable educational tools. But they can’t make a child feel truly loved, validated, and valued. That’s the job of parents, and when parents abdicate this responsibility, it’s not only the child who misses out on one of life’s most profound experiences.
We really don’t know how the tech-savvy children of today will ultimately process their attachments to robots and whether they will be excessively predisposed to choosing robot companionship over that of humans. It’s possible their techno literacy will draw for them a bold line between real life and a quasi-imaginary history with a robot. But it will be decades before we see long-term studies culminating in sufficient data to help scientists, and the rest of us, to parse out the effects of a lifetime spent with robots.
This is an excerpt from ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold. The book will be published on January 9, 2024.
Stem cells from a fetus can travel to the heart and regenerate the muscle, essentially saving a mother’s life.
If there is a silver lining to peripartum cardiomyopathy, it’s that it is perhaps the most survivable form of heart failure. A remarkable 50% of women recover spontaneously. And there’s an even more remarkable explanation for that glowing statistic: The fetus‘ stem cells migrate to the heart and regenerate the beleaguered muscle. In essence, the developing or recently born child saves its mother’s life.
Saving mama
While this process has not been observed directly in humans, it has been witnessed in mice. In a 2015 study, researchers tracked stem cells from fetal mice as they traveled to mothers’ damaged cardiac cells and integrated themselves into hearts.
Evolutionarily, this function makes sense: It is in the fetus’ best interest that its mother remains healthy.
Scientists also have spotted cells from the fetus within the hearts of human mothers, as well as countless other places inside the body, including the skin, spleen, liver, brain, lung, kidney, thyroid, lymph nodes, salivary glands, gallbladder, and intestine. These cells essentially get everywhere. While most are eliminated by the immune system during pregnancy, some can persist for an incredibly long time — up to three decades after childbirth.
This integration of the fetus’ cells into the mother’s body has been given a name: fetal microchimerism. The process appears to start between the fourth and sixth week of gestation in humans. Scientists are actively trying to suss out its purpose. Fetal stem cells, which can differentiate into all sorts of specialized cells, appear to target areas of injury. So their role in healing seems apparent. Evolutionarily, this function makes sense: It is in the fetus’ best interest that its mother remains healthy.
Sending cells into the mother’s body may also prime her immune system to grow more tolerant of the developing fetus. Successful pregnancy requires that the immune system not see the fetus as an interloper and thus dispatch cells to attack it.
Fetal microchimerism
But fetal microchimerism might not be entirely beneficial. Greater concentrations of the cells have been associated with various autoimmune diseases such as lupus, Sjogren’s syndrome, and even multiple sclerosis. After all, they are foreign cells living in the mother’s body, so it’s possible that they might trigger subtle, yet constant inflammation. Fetal cells also have been linked to cancer, although it isn’t clear whether they abet or hinder the disease.
A team of Spanish scientists summarized the apparent give and take of fetal microchimerism in a 2022 review article. “On the one hand, fetal microchimerism could be a source of progenitor cells with a beneficial effect on the mother’s health by intervening in tissue repair, angiogenesis, or neurogenesis. On the other hand, fetal microchimerism might have a detrimental function by activating the immune response and contributing to autoimmune diseases,” they wrote.
Regardless of a fetus’ cells net effect, their existence alone is intriguing. In a paper published earlier this year, University of London biologist Francisco Úbeda and University of Western Ontario mathematical biologist Geoff Wild noted that these cells might very well persist within mothers for life.
“Therefore, throughout their reproductive lives, mothers accumulate fetal cells from each of their past pregnancies including those resulting in miscarriages. Furthermore, mothers inherit, from their own mothers, a pool of cells contributed by all fetuses carried by their mothers, often referred to as grandmaternal microchimerism.”
So every mother may carry within her literal pieces of her ancestors.
