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.
Time to visit your TikTok doc? The good and bad of doctors on social media
Rakhi Patel has carved a hobby out of reviewing pizza — her favorite food — on Instagram. In a nod to her preferred topping, she calls herself thepepperoniqueen. Photos and videos show her savoring slices from scores of pizzerias. In some of them, she’s wearing scrubs — her attire as an inpatient neurology physician associate at Tufts Medical Center in Boston.
“Depending on how you dress your pizza, it can be more nutritious,” said Patel, who suggests a thin crust, sugarless tomato sauce and vegetables galore as healthier alternatives. “There are no boundaries for a health care professional to enjoy pizza.”
Beyond that, “pizza fuels my mental health and makes me happy, especially when loaded with pepperoni,” she said. “If I’m going to be a pizza connoisseur, then I also need to take care of my physical health by ensuring that I get at least three days of exercise per week and eat nutritiously when I’m not eating pizza.”
She’s among an increasing number of health care professionals, including doctors and nurses, who maintain an active persona on social media, according to bioethics researchers. They share their hobbies and interests with people inside and outside the world of medicine, helping patients and the public become acquainted with the humans behind the scrubs or white coats. Other health care experts limit their posts to medical topics, while some opt for a combination of personal and professional commentaries. Depending on the posts, ethical issues may come into play.
“Health care professionals are quite prevalent on social media,” said Mercer Gary, a postdoctoral researcher at The Hastings Center, an independent bioethics research institute in Garrison, New York. “They’ve been posting on #medTwitter for many years, mainly to communicate with one another, but, of course, anyone can see the threads. Most recently, doctors and nurses have become a presence on TikTok.”
On social media, many health care providers perceive themselves to be “humanizing” their profession by coming across as more approachable — “reminding patients that providers are people and workers, as well as repositories of medical expertise,” Gary said. As a result, she noted that patients who are often intimidated by clinicians may feel comfortable enough to overcome barriers to scheduling health care appointments. The use of TikTok in particular may help doctors and nurses connect with younger followers.
When health care providers post on social media, they must bear in mind that they have legal and ethical duties to their patients, profession and society, said Elizabeth Levy, founder and director of Physicians for Justice.
While enduring three years of pandemic conditions, many health care professionals have struggled with burnout, exhaustion and moral distress. “Much health care provider content on social media seeks to expose the difficulties of the work,” Gary added. “TikTok and Instagram reels have shown health care providers crying after losing a patient or exhausted after a night shift in the emergency department.”
A study conducted in Beijing, China and published last year found that TikTok is the world’s most rapidly growing video application, amassing 1.6 billion users in 2021. “More and more patients are searching for information on genitourinary cancers via TikTok,” the study’s authors wrote in Frontiers in Oncology, referring to cancers of the urinary tracts and male reproductive organs. Among the 61 sample videos examined by the researchers, health care practitioners contributed the content in 29, or 47 percent, of them. Yet, 22 posts, 36 percent, were misinformative, mostly due to outdated information.
More than half of the videos offered good content on disease symptoms and examinations. The authors concluded that “most videos on genitourinary cancers on TikTok are of poor to medium quality and reliability. However, videos posted by media agencies enjoyed great public attention and interaction. Medical practitioners could improve the video quality by cooperating with media agencies and avoiding unexplained terminologies.”
When health care providers post on social media, they must bear in mind that they have legal and ethical duties to their patients, profession and society, said Elizabeth Levy, founder and director of Physicians for Justice in Irvine, Calif., a nonprofit network of volunteer physicians partnering with public interest lawyers to address the social determinants of health.
“Providers are also responsible for understanding the mechanics of their posts,” such as who can see these messages and how long they stay up, Levy said. As a starting point for figuring what’s acceptable, providers could look at social media guidelines put out by their professional associations. Even beyond that, though, they must exercise prudent judgment. “As social media continues to evolve, providers will also need to stay updated with the changing risks and benefits of participation.”
Patients often research their providers online, so finding them on social media can help inform about values and approaches to care, said M. Sara Rosenthal, a professor and founding director of the program for bioethics and chair of the hospital ethics committee at the University of Kentucky College of Medicine.
Health care providers’ posts on social media also could promote patient education. They can advance informed consent and help patients navigate the risks and benefits of various treatments or preventive options. However, providers could violate ethical principles if they espouse “harmful, risky or questionable therapies or medical advice that is contrary to clinical practice guidelines or accepted standards of care,” Rosenthal said.
Inappropriate self-disclosure also can affect a provider’s reputation, said Kelly Michelson, a professor of pediatrics and director of the Center for Bioethics and Medical Humanities at Northwestern University’s Feinberg School of Medicine. A clinician’s obligations to professionalism extend beyond those moments when they are directly taking care of their patients, she said. “Many experts recommend against clinicians ‘friending’ patients or the families on social media because it blurs the patient-clinician boundary.”
Meanwhile, clinicians need to adhere closely to confidentiality. In sharing a patient’s case online for educational purposes, safeguarding identity becomes paramount. Removing names and changing minor details is insufficient, Michelson said.
“The patient-clinician relationship is sacred, and it can only be effective if patients have 100 percent confidence that all that happens with their clinician is kept in the strictest of confidence,” she said, adding that health care providers also should avoid obtaining information about their patients from social media because it can lead to bias and risk jeopardizing objectivity.
Academic clinicians can use social media as a recruitment tool to expand the pool of research participants for their studies, Michelson said. Because the majority of clinical research is conducted at academic medical centers, large segments of the population are excluded. “This affects the quality of the data and knowledge we gain from research,” she said.
Don S. Dizon, a professor of medicine and surgery at the Warren Alpert Medical School of Brown University in Providence, Rhode Island, uses LinkedIn and Doximity, as well as Twitter, Instagram, TikTok, Facebook, and most recently, YouTube and Post. He’s on Twitter nearly every day, where he interacts with the oncology community and his medical colleagues.
Also, he said, “I really like Instagram. It’s where you will see a hybrid of who I am professionally and personally. I’ve become comfortable sharing both up to a limit, but where else can I combine my appreciation of clothes with my professional life?” On that site, he’s seen sporting shirts with polka dots or stripes and an occasional bow-tie. He also posts photos of his cats.
Don S. Dizon, a professor of medicine and surgery at Brown, started using TikTok several years ago, telling medical stories in short-form videos.
Don S. Dizon
Dizon started using TikTok several years ago, telling medical stories in short-form videos. He may talk about an inspirational patient, his views on end-of-life care and death, or memories of people who have passed. But he is careful not to divulge any details that would identify anyone.
Recently, some people have become his patients after viewing his content on social media or on the Internet in general, which he clearly states isn’t a forum for medical advice. “In both situations, they are so much more relaxed when we meet, because it’s as if they have a sense of who I am as a person,” Dizon said. “I think that has helped so much in talking through a cancer diagnosis and a treatment plan, and yes, even discussions about prognosis.”
He also posts about equity and diversity. “I have found myself more likely to repost or react to issues that are inherently political, including racism, homophobia, transphobia and lack-of-access issues, because medicine is not isolated from society, and I truly believe that medicine is a social justice issue,” said Dizon, who is vice chair of diversity, equity, inclusion and professional integrity at the SWOG Cancer Research Network.
Through it all, Dizon likes “to break through the notion of doctor as infallible and all-knowing, the doctor as deity,” he said. “Humanizing what I do, especially in oncology, is something that challenges me on social media, and I appreciate the opportunities to do it on TikTok.”
Could this habit related to eating slow down rates of aging?
Last Thursday, scientists at Columbia University published a new study finding that cutting down on calories could lead to longer, healthier lives. In the phase 2 trial, 220 healthy people without obesity dropped their calories significantly and, at least according to one test, their rate of biological aging slowed by 2 to 3 percent in over a couple of years. Small though that may seem, the researchers estimate that it would translate into a decline of about 10 percent in the risk of death as people get older. That's basically the same as quitting smoking.
Previous research has shown that restricting calories results in longer lives for mice, worms and flies. This research is unique because it applies those findings to people. It was published in Nature Aging.
But what did the researchers actually show? Why did two other tests indicate that the biological age of the research participants didn't budge? Does the new paper point to anything people should be doing for more years of healthy living? Spoiler alert: Maybe, but don't try anything before talking with a medical expert about it. I had the chance to chat with someone with inside knowledge of the research -- Dr. Evan Hadley, director of the National Institute of Aging's Division of Geriatrics and Clinical Gerontology, which funded the study. Dr. Hadley describes how the research participants went about reducing their calories, as well as the risks and benefits involved. He also explains the "aging clock" used to measure the benefits.
Evan Hadley, Director of the Division of Geriatrics and Clinical Gerontology at the National Institute of Aging
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