Scientists want the salamander's secret: how they regenerate tissue
All organisms have the capacity to repair or regenerate tissue damage. None can do it better than salamanders or newts, which can regenerate an entire severed limb.
That feat has amazed and delighted man from the dawn of time and led to endless attempts to understand how it happens – and whether we can control it for our own purposes. An exciting new clue toward that understanding has come from a surprising source: research on the decline of cells, called cellular senescence.
Senescence is the last stage in the life of a cell. Whereas some cells simply break up or wither and die off, others transition into a zombie-like state where they can no longer divide. In this liminal phase, the cell still pumps out many different molecules that can affect its neighbors and cause low grade inflammation. Senescence is associated with many of the declining biological functions that characterize aging, such as inflammation and genomic instability.
Oddly enough, newts are one of the few species that do not accumulate senescent cells as they age, according to research over several years by Maximina Yun. A research group leader at the Center for Regenerative Therapies Dresden and the Max Planck Institute of Molecular and Cell Biology and Genetics, in Dresden, Germany, Yun discovered that senescent cells were induced at some stages of regeneration of the salamander limb, “and then, as the regeneration progresses, they disappeared, they were eliminated by the immune system,” she says. “They were present at particular times and then they disappeared.”
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states.
Previous research on senescence in aging had suggested, logically enough, that applying those cells to the stump of a newly severed salamander limb would slow or even stop its regeneration. But Yun stood that idea on its head. She theorized that senescent cells might also play a role in newt limb regeneration, and she tested it by both adding and removing senescent cells from her animals. It turned out she was right, as the newt limbs grew back faster than normal when more senescent cells were included.
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states, which could then be turned into progenitors, a cell type in between stem cells and specialized cells, needed to regrow the muscle tissue of the missing limb. “We think that this ability to dedifferentiate is intrinsically a big part of why salamanders can regenerate all these very complex structures, which other organisms cannot,” she explains.
Yun sees regeneration as a two part problem. First, the cells must be able to sense that their neighbors from the lost limb are not there anymore. Second, they need to be able to produce the intermediary progenitors for regeneration, , to form what is missing. “Molecularly, that must be encoded like a 3D map,” she says, otherwise the new tissue might grow back as a blob, or liver, or fin instead of a limb.
Wound healing
Another recent study, this time at the Mayo Clinic, provides evidence supporting the role of senescent cells in regeneration. Looking closely at molecules that send information between cells in the wound of a mouse, the researchers found that senescent cells appeared near the start of the healing process and then disappeared as healing progressed. In contrast, persistent senescent cells were the hallmark of a chronic wound that did not heal properly. The function and significance of senescence cells depended on both the timing and the context of their environment.
The paper suggests that senescent cells are not all the same. That has become clearer as researchers have been able to identify protein markers on the surface of some senescent cells. The patterns of these proteins differ for some senescent cells compared to others. In biology, such physical differences suggest functional differences, so it is becoming increasingly likely there are subsets of senescent cells with differing functions that have not yet been identified.
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes.
Scientists initially thought that senescent cells couldn’t play a role in regeneration because they could no longer reproduce, says Anthony Atala, a practicing surgeon and bioengineer who leads the Wake Forest Institute for Regenerative Medicine in North Carolina. But Yun’s study points in the other direction. “What this paper shows clearly is that these cells have the potential to be involved in tissue regeneration [in newts]. The question becomes, will these cells be able to do the same in humans.”
As our knowledge of senescent cells increases, Atala thinks we need to embrace a new analogy to help understand them: humans in retirement. They “have acquired a lot of wisdom throughout their whole life and they can help younger people and mentor them to grow to their full potential. We're seeing the same thing with these cells,” he says. They are no longer putting energy into their own reproduction, but the signaling molecules they secrete “can help other cells around them to regenerate.”
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes. If so, it seems that our genes are unable to express this ability, perhaps as part of a tradeoff in acquiring other traits. It is a fertile area of research.
Dedifferentiation is likely to become an important process in the field of regenerative medicine. One extreme example: a lab has been able to turn back the clock and reprogram adult male skin cells into female eggs, a potential milestone in reproductive health. It will be more difficult to control just how far back one wishes to go in the cell's dedifferentiation – part way or all the way back into a stem cell – and then direct it down a different developmental pathway. Yun is optimistic we can learn these tricks from newts.
Senolytics
A growing field of research is using drugs called senolytics to remove senescent cells and slow or even reverse disease of aging.
“Senolytics are great, but senolytics target different types of senescence,” Yun says. “If senescent cells have positive effects in the context of regeneration, of wound healing, then maybe at the beginning of the regeneration process, you may not want to take them out for a little while.”
“If you look at pretty much all biological systems, too little or too much of something can be bad, you have to be in that central zone” and at the proper time, says Atala. “That's true for proteins, sugars, and the drugs that you take. I think the same thing is true for these cells. Why would they be different?”
Our growing understanding that senescence is not a single thing but a variety of things likely means that effective senolytic drugs will not resemble a single sledge hammer but more a carefully manipulated scalpel where some types of senescent cells are removed while others are added. Combinations and timing could be crucial, meaning the difference between regenerating healthy tissue, a scar, or worse.
Will religious people reject organ transplants from pigs?
The first successful recipient of a human heart transplant lived 18 days. The first artificial heart recipient lived just over 100.
Their brief post-transplant lives paved the way toward vastly greater successes. Former Vice President Dick Cheney relied on an artificial heart for nearly two years before receiving a human heart transplant. It still beats in his chest more than a decade later.
Organ transplantation recently reached its next phase with David Bennett. He survived for two months after becoming the first recipient of a pig’s heart genetically modified to function in a human body in February. Known as a xenotransplant, the procedure could pave the way for greatly expanding the use of transplanted vital organs to extend human lives.
Clinical trials would have to be held in the U.S. before xenotransplants become widespread; Bennett’s surgery was authorized under a special Food and Drug Administration program that addresses patients with life-threatening medical conditions.
German researchers plan to perform eight pig-to-human heart transplants as part of a clinical trial beginning in 2024. According to an email sent to Leaps.org by three scholars working on the German project, these procedures will focus on one of the reasons David Bennett did not survive longer: A porcine infection from his new heart.
The transplant team will conduct more sensitive testing of the donor organs, “which in all likelihood will be able to detect even low levels of virus in the xenograft,” note the scientists, Katharina Ebner, Jochen Ostheimer and Jochen Sautermeister. They are confident that the risk of infection with a porcine virus in the future will be significantly lower.
Moreover, hearts are not the only genetically modified organs that are being xenotransplanted. A team of surgeons at the University of Alabama at Birmingham successfully transplanted genetically modified pig kidneys into a brain-dead human recipient in September. The kidneys functioned normally for more than three days before the experiment ended. The UAB team is now moving forward with clinical trials focusing on transplanting pig kidneys into human patients.
Some experts believe the momentum for xenotransplantation is building, particularly given the recent successes. “I think there is a strong likelihood this will go mainstream,” says Brendan Parent of NYU Langone Health.
Douglas Anderson, a surgeon who is part of that kidney xenotransplant team, observes that, “organ shortages have been the major issue facing transplantation since its inception” and that xenotransplantation is a potential solution to that quandary. “It can’t be understated the number of people waiting for a kidney on dialysis, which has a significant mortality rate,” he says. According to the advocacy group Donate Life America, more than 100,000 people in the U.S. alone are waiting for a donated organ, and 85 percent of them need a kidney.
Other experts believe the momentum for xenotransplantation is building, particularly given the recent successes. “I think there is a strong likelihood this will go mainstream,” says Brendan Parent, director of transplant ethics and policy at NYU Langone Health, a New York City-based hospital system. Like the UAB team, surgeons at NYU Langone have had success coaxing modified pig kidneys to work in deceased humans.
“There is a genuinely good chance that within a generation, (xenotransplantation) might become very common in reasonably wealthy countries,” says Michael Reiss, professor of science education at University College in London. In addition to his academic position, Reiss sits on the Nuffield Council on Bioethics, a nonprofit that is one of Britain’s most prominent watchdogs regarding medical and scientific issues. Reiss is also an Anglican priest and has studied xenotransplantation from both a scientific and religious point of view.
Moreover, genetic modifications could one day lead to organs being specifically optimized for their recipients. That could ensure issues like donor rejection and the calculated risk of artificially suppressing recipient immune systems become concerns of the past.
Major bioethical, religious concerns
Despite the promise of xenotransplantation, numerous bioethical issues swirl around the procedure. They could be magnified if xenotransplantation evolves from one-off experiments to a routine medical procedure.
One of the biggest is the millennia-long prohibitions Islam and Judaism have had regarding the consumption of pork. Will followers of these religions assume such rules extend to those taboo materials being inserted into a human body?
“Initially, one’s instinctual reaction is that, oh, crumbs! – how are Jews and Muslims going to react to that?” Reiss says. But in a world where science and secularism are accepted on an everyday basis, he notes it is not a significant issue. Reiss points out that valves from pig hearts have been used in human patients for decades without any issues. He adds that both Islam and Judaism waive religious dietary restrictions if a human life is at risk.
“While nobody's saying an individual patient is to be forced to have these, the very high proportion of people who identify as Jews or Muslims when given this option are content with it,” he says.
Concurring with Reiss is Michael Gusamano, professor of health policy at Lehigh University and director of its Center for Ethics. He is currently performing research on the ethics of xenotransplantation for the National Institutes of Health.
“Leaders from all major religions have commented on this and have indicated that this is not inconsistent with religious doctrine,” Gusamano says in written remarks to Leaps.org. “Having said that, it is plausible to believe that some people will assume that this is inconsistent with the teaching of their religion and may object to…receiving a xenotransplant as part of routine medical care.”
A history of clashes
Despite those assurances, science has long clashed with theology. Although Galileo proved the planets revolved around the sun, the Catholic Church found him guilty of heresy and rewarded his discovery with house arrest for the last decade of his life. A revolt occurred in mid-19th century India after native-born soldiers believed the ammunition supplied by their British occupiers had been lubricated with pork and beef tallow. Given they had to use their mouths to tear open ammunition pouches, this violated both the tenets of Islam and Hinduism. And one of the conspiracy theories hatched as a result of COVID-19 was that the vaccines developed to fight the disease were the “mark of the beast” – a sign of impending Armageddon under evangelical Christian theology.
The German xenotransplant research team has encountered such potential concerns when the procedure is regarded through a religious lens. “The pastors in our research suspected that many recipients might feel disgust and revulsion,” they write. “Even beyond these special religious reservations, cultural scripts about pigs as inferior living beings are also generally widespread and effective in the western world, so that here too possible disgust reactions cannot be ruled out.”
The German researchers add that “Jewish and Muslim hospital pastoral workers believe possible considerable problems in this respect, which must be dealt with psychosocially, religiously, and pastorally prior to a possible transplantation in order to strengthen the acceptance of the received organ by the patients and their relatives.”
Parent, the director at NYU Langone, shares a concern that xenotransplantation could move “too fast,” although much of his worry is focused on zoonotic disease transmission – pig viruses jumping into humans as a result of such procedures.
Another ethical issue
Moreover, the way pigs and other animals are raised for transplants could pose future ethical dilemmas.
Reiss notes that pigs raised for medical procedures have to be grown and kept in what are known as a designated pathogen-free facility, or DPF. Such facilities are kept painstakingly antiseptic so as to minimize the risk of zoonotic transmissions. But given pigs are fond of outdoor activities such as wallowing in mud and sleeping on hay, they lead “stunningly boring lives” that they probably do not enjoy, Reiss observes.
Ethical concerns with using pigs may push transplantation medicine into its next logical phase: Growing functional organs for transplant in a laboratory setting.
“There’s no doubt that these research pigs have gotten much better veterinary care, et cetera, (compared to farmed pigs). But it’s not a great life,” Reiss says. “And although it hasn’t so far dominated the discussion, I think as the years go by, rather as we’ve seen with the use of apes and now monkeys in medical research, more and more theologians will get uncomfortable about us just assuming we can do this with…pigs.”
The German research team raises the same concerns, but has taken a fairly sanguine view on the topic. “The impairments of the species-typical behavior will certainly provoke criticism and perhaps also public protest. But the number of animals affected is very small in relation to slaughter cattle,” the German researchers note. “Moreover, the conditions there and also in several animal experiments are far worse.”
Observers say that may push transplantation medicine into its next logical phase: Growing functional organs for transplant in a laboratory setting. Anderson, the UAB transplant surgeon, believes such an accomplishment remains decades away.
But other experts believe there is a moral imperative that xenotransplantation remain a temporary solution. “I think we have a duty to go in that direction,” Parent says. “We have to go that way, with the xenotransplantation process (as) a steppingstone and research path that will be useful for bioengineered organs.”
The Friday Five: Scientists treated this girl's disease before she was born
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Kids treated for diseases before they're born
- How to lift weights in half the time
- Electric shocks help people regain the ability to walk
- Meditation just as good as medication?
- These foods could pump up your motivation