The Science Sleuth Holding Fraudulent Research Accountable
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.
Introduction by Mary Inman, Whistleblower Attorney
For most people, when they see the word "whistleblower," the image that leaps to mind is a lone individual bravely stepping forward to shine a light on misconduct she has witnessed first-hand. Meryl Streep as Karen Silkwood exposing safety violations observed while working the line at the Kerr-McGee plutonium plant. Matt Damon as Mark Whitacre in The Informant!, capturing on his pocket recorder clandestine meetings between his employer and its competitors to fix the price of lysine. However, a new breed of whistleblower is emerging who isn't at the scene of the crime but instead figures it out after the fact through laborious review of publicly available information and expert analysis. Elisabeth Bik belongs to this new class of whistleblower.
"There's this delicate balance where on one hand we want to spread results really fast as scientists, but on the other hand, we know it's incomplete, it's rushed and it's not great."
Using her expertise as a microbiologist and her trained eye, Bik studies publicly available scientific papers to sniff out potential irregularities in the images that suggest research fraud, later seeking retraction of the offending paper from the journal's publisher. There's no smoking gun, no first-hand account of any kind. Just countless hours spent reviewing scores of scientific papers and Bik's skills and dedication as a science fraud sleuth.
While Bik's story may not as readily lend itself to the big screen, her work is nonetheless equally heroic. By tirelessly combing scientific papers to expose research fraud, Bik is playing a vital role in holding the scientific publishing process accountable and ensuring that misleading information does not spread unchecked. This is important work in any age, but particularly so in the time of COVID, where we can ill afford the setbacks and delays of scientists building on false science. In the present climate, where science is politicized and scientific principles are under attack, strong voices like Bik's must rise above the din to ensure the scientific information we receive, and our governments act upon, is accurate. Our health and wellbeing depend on it.
Whistleblower outsiders like Bik are challenging the traditional concept of what it means to be a whistleblower. Fortunately for us, the whistleblower community is a broad church. As with most ecosystems, we all benefit from a diversity of voices —whistleblower insiders and outsiders alike. What follows is an illuminating conversation between Bik, and Ivan Oransky, the co-founder of Retraction Watch, an influential blog that reports on retractions of scientific papers and related topics. (Conversation facilitated by LeapsMag Editor-in-Chief Kira Peikoff)
Elisabeth Bik and Ivan Oransky.
(Photo credits Michel & Co Photography, San Jose, CA and Elizabeth Solaka)
Ivan
I'd like to hear your thoughts, Elisabeth, on an L.A. Times story, which was picking up a preprint about mutations and the novel coronavirus, alleging that the virus is mutating to become more infectious – even though this conclusion wasn't actually warranted.
Elisabeth
A lot of the news around it is picking up on one particular side of the story that is maybe not that much exaggerated by the scientists. I don't think this paper really showed that the mutations were causing the virus to be more virulent. Some of these viruses continuously mutate and mutate and mutate, and that doesn't necessarily make a strain more virulent. I think in many cases, a lot of people want to read something in a paper that is not actually there.
Ivan
The tone level, everything that's being published now, it's problematic. It's being rushed, here it wasn't even peer-reviewed. But even when they are peer-reviewed, they're being peer-reviewed by people who often aren't really an expert in that particular area.
Elisabeth
That's right.
Ivan
To me, it's all problematic. At the same time, it's all really good that it's all getting out there. I think that five or 10 years ago, or if we weren't in a pandemic, maybe that paper wouldn't have appeared at all. It would have maybe been submitted to a top-ranked journal and not have been accepted, or maybe it would have been improved during peer review and bounced down the ladder a bit to a lower-level journal.
Yet, now, because it's about coronavirus, it's in a major newspaper and, in fact, it's getting critiqued immediately.
Maybe it's too Pollyanna-ish, but I actually think that quick uploading is a good thing. The fear people have about preprint servers is based on this idea that the peer-reviewed literature is perfect. Once it is in a peer-reviewed journal, they think it must have gone through this incredible process. You're laughing because-
Elisabeth
I am laughing.
Ivan
You know it's not true.
Elisabeth
Yes, we both know that. I agree and I think in this particular situation, a pandemic that is unlike something our generation has seen before, there is a great, great need for fast dissemination of science.
If you have new findings, it is great that there is a thing called a preprint server where scientists can quickly share their results, with, of course, the caveat that it's not peer-reviewed yet.
It's unlike the traditional way of publishing papers, which can take months or years. Preprint publishing is a very fast way of spreading your results in a good way so that is what the world needs right now.
On the other hand, of course, there's the caveat that these are brand new results and a good scientist usually thinks about their results to really interpret it well. You have to look at it from all sides and I think with the rushed publication of preprint papers, there is no such thing as carefully thinking about what results might mean.
So there's this delicate balance where on one hand we want to spread results really fast as scientists, but on the other hand, we know it's incomplete, it's rushed and it's not great. This might be hard for the general audience to understand.
Ivan
I still think the benefits of that dissemination are more positive than negative.
Elisabeth
Right. But there's also so many papers that come out now on preprint servers and most of them are not that great, but there are some really good studies in there. It's hard to find those nuggets of really great papers. There's just a lot of papers that come out now.
Ivan
Well, you've made more than a habit of finding problems in papers. These are mostly, of course, until now published papers that you examined, but what is this time like for you? How is it different?
Elisabeth
It's different because in the beginning I looked at several COVID-19-related papers that came out and wrote some critiques about it. I did experience a lot of backlash because of that. So I felt I had to take a break from social media and from writing about COVID-19.
I focused a little bit more on other work because I just felt that a lot of these papers on COVID-19 became so politically divisive that if you tried to be a scientist and think critically about a paper, you were actually assigned to a particular political party or to be against other political parties. It's hard for me to be sucked into the political discussion and to the way that our society now is so completely divided into two camps that seem to be not listening to each other.
Ivan
I was curious about that because I've followed your work for a number of years, as you know, and certainly you have had critics before. I'm thinking of the case in China that you uncovered, the leading figure in the Chinese Academy who was really a powerful political figure in addition to being a scientist.
Elisabeth
So that was a case in which I found a couple of papers at first from a particular group in China, and I was just posting on a website called PubPeer, where you can post comments, concerns about papers. And in this case, these were image duplication issues, which is my specialty.
I did not realize that the group I was looking at at that moment was led by one of the highest ranked scientists in China. If I had known that, I would probably not have posted that under my full name, but under a pseudonym. Since I had already posted, some people were starting to send me direct messages on Twitter like, "OMG, the guy you're posting about now is the top scientist in China so you're going to have a lot of backlash."
Then I decided I'll just continue doing this. I found a total of around 50 papers from this group and posted all of them on PubPeer. That story quickly became a very popular story in China: number two on Sina Weibo, a social media site in China.
I was surprised it wasn't suppressed by the Chinese government, it was actually allowed by journalists that were writing about it, and I didn't experience a lot of backlash because of that.
Actually the Chinese doctor wrote me an email saying that he appreciated my feedback and that he would look into these cases. He sent a very polite email so I sent him back that I appreciated that he would look into these cases and left it there.
Ivan
There are certain subjects that I know when we write about them in Retraction Watch, they have tended in the past to really draw a lot of ire. I'm thinking anything about vaccines and autism, anything about climate change, stem cell research.
For a while that last subject has sort of died down. But now it's become a highly politically charged atmosphere. Do you feel that this pandemic has raised the profile of people such as yourself who we refer to as scientific sleuths, people who look critically and analytically at new research?
Elisabeth
Yeah, some people. But I'm also worried that some people who are great scientists and have shown a lot of critical thinking are being attacked because of that. If you just look at what happened to Dr. Fauci, I think that's a prime example. Where somebody who actually is very knowledgeable and very cautious of new science has not been widely accepted as a great leader, in our country at least. It's sad to see that. I'm just worried how long he will be at his position, to be honest.
Ivan
We noticed a big uptick in our traffic in the last few days to Retraction Watch and it turns out it was because someone we wrote about a number of years ago has really hopped on the bandwagon to try and discredit and even try to have Dr. Fauci fired.
It's one of these reminders that the way people think about scientists has, in many cases, far more to do with their own history or their own perspective going in than with any reality or anything about the science. It's pretty disturbing, but it's not a new thing. This has been happening for a while.
You can go back and read sociologists of science from 50-60 years ago and see the same thing, but I just don't think that it's in the same way that it is now, maybe in part because of social media.
Elisabeth
I've been personally very critical about several studies, but this is the first time I've experienced being attacked by trolls and having some nasty websites written about me. It is very disturbing to read.
"I don't think that something that's been peer-reviewed is perfect and something that hasn't been peer reviewed, you should never bother reading it."
Ivan
It is. Yet you have been a fearless and vocal critic of some very high-profile papers, like the infamous French study about hydroxychloroquine.
Elisabeth
Right, the paper that came out was immediately tweeted by the President of the United States. At first I thought it was great that our President tweeted about science! I thought that was a major breakthrough. I took a look at this paper.
It had just come out that day, I believe. The first thing I noticed is that it was accepted within 24 hours of being submitted to the journal. It was actually published in a journal where one of the authors is the editor-in-chief, which is a huge conflict of interest, but it happens.
But in this particular case, there were also a lot of flaws with the study and that, I think, should have been caught during peer review. The paper was first published on a preprint server and then within 24 hours or so it was published in that paper, supposedly after peer review.
There were very few changes between the preprint version and the peer review paper. There were just a couple of extra lines, extra sentences added here and there, but it wasn't really, I think, critically looked at. Because there were a lot of things that I thought were flaws.
Just to go over a couple of them. This paper showed supposedly that people who were treated with hydroxychloroquine and azithromycin were doing much better by clearing their virus much faster than people who were not treated with these drugs.
But if you look carefully at the paper there were a couple of people who were left out of the study. So they were treated with hydroxychloroquine, but they were not shown in the end results of the paper. All six people who were treated with the drug combination were clearing the virus within six days, but there were a couple of others who were left out of the study. They also started the drug combination, but they stopped taking the drugs for several reasons and three of them were admitted to the intensive care, one died, one had some side effects and one apparently walked out of the hospital.
They were left out of the study but they were actually not doing very well with the drug combination. It's not very good science if you leave out people who don't do very well with your drug combination in your study. That was one of my biggest critiques of the paper.
Ivan
What struck us about that case was, in addition to what you, of course, mentioned, the fact that Trump tweeted it and was talking about hydroxychloroquine, was that it seemed to be a perfect example of, "well, it was in a peer review journal." Yeah, it was a preprint first, but, well, it's a peer review journal. And yet, as you point out, when you look at the history of the paper, it was accepted in 24 hours.
If you talk to most scientists, the actual act of a peer review, once you sit down to do it and can concentrate, a good one takes, again, these are averages, but four hours, a half a day is not unreasonable. So you had to find three people who could suddenly review this paper. As you pointed out, it was in a journal where one of the authors was editor.
Then some strange things also happened, right? The society that actually publishes the journal, they came out with a statement saying this wasn't up to our standards, which is odd. Then Elsevier came in, they're the ones who are actually contracted to publish the journal for the society. They said, basically, "Oh, we're going to look into this now too."
It just makes you wonder what happened before the paper was actually published. All the people who were supposed to have been involved in doing the peer review or checking on it are clearly very distraught about what actually happened. It's that scene from Casablanca, "I'm shocked, shocked there's gambling going on here." And then, "Your winnings, sir."
Elisabeth
Yes.
Ivan
And I don't actually blame the public, I don't blame reporters for getting a bit confused about what it all means and what they should trust. I don't think trust is a binary any more than anything else is a binary. I don't think that something that's been peer-reviewed is perfect and something that hasn't been peer reviewed, you should never bother reading it. I think everything is much more gray.
Yet we've turned things into a binary. Even if you go back before coronavirus, coffee is good for you, coffee is bad for you, red wine, chocolate, all the rest of it. A lot of that is because of this sort of binary construct of the world for journalists, frankly, for scientists that need to get their next grants. And certainly for the general public, they want answers.
On the one hand, if I had to choose what group of experts, or what field of human endeavor would I trust with finding the answer to a pandemic like this, or to any crisis, it would absolutely be scientists. Hands down. This is coming from someone who writes about scientific fraud.
But on the other hand, that means that if scientists aren't clear about what they don't know and about the nuances and about what the scientific method actually allows us to do and learn, that just sets them up for failure. It sets people like Dr. Fauci up for failure.
Elisabeth
Right.
Ivan
It sets up any public health official who has a discussion about models. There's a famous saying: "All models are wrong, but some are useful."
Just because the projections change, it's not proof of wrongness, it's not proof that the model is fatally flawed. In fact, I'd be really concerned if the projections didn't change based on new information. I would love it if this whole episode did lead to a better understanding of the scientific process and how scientific publishing fits into that — and doesn't fit into it.
Elisabeth
Yes, I'm with you. I'm very worried that the general audience's perspective is based on maybe watching too many movies where the scientist comes up with a conclusion one hour into the movie when everything is about to fail. Like that scene in Contagion where somebody injects, I think, eight monkeys, and one of the monkeys survives and boom we have the vaccine. That's not really how science works. Everything takes many, many years and many, many applications where usually your first ideas and your first hypothesis turn out to be completely wrong.
Then you go back to the drawing board, you develop another hypothesis and this is a very reiterative process that usually takes years. Most of the people who watch the movie might have a very wrong idea and wrong expectations about how science works. We're living in the movie Contagion and by September, we'll all be vaccinated and we can go on and live our lives. But that's not what is going to happen. It's going to take much, much longer and we're going to have to change the models every time and change our expectations. Just because we don't know all the numbers and all the facts yet.
Ivan
Generally it takes a fairly long time to change medical practice. A lot of times people see that as a bad thing. What I think that ignores, or at least doesn't take into as much account as I would, is that you don't want doctors and other health care professionals to turn on a dime and suddenly switch. Unless, of course, it turns out there was no evidence for what you were looking at.
It's a complicated situation.
Everybody wants scientists to be engineers, right?
Elisabeth
Right.
Ivan
I'm not saying engineering isn't scientific, nor am I saying that science is just completely whimsical, but there's a different process. It's a different way of looking at things and you can't just throw all the data into a big supercomputer, which is what I think a lot of people seem to want us to do, and then the obvious answer will come out on the other side.
Elisabeth
No. It's true and a lot of engineers suddenly feel their inherent need to solve this as a problem. They're not scientists and it's not building a bridge over a big river. But we're dealing with something that is very hard to solve because we don't understand the problem yet. I think scientists are usually first analyzing the problem and trying to understand what the problem actually is before you can even think about a solution.
Ivan
I think we're still at the understanding the problem phase.
Elisabeth
Exactly. And going back to the French group paper, that promised such a result and that was interpreted as such by a lot of people including presidents, but it's a very rare thing to find a medication that will have a 100% curation rate. That's something that I wish the people would understand better. We all want that to happen, but it's very unlikely and very unprecedented in the best of times.
Ivan
I would second that and also say that the world needs to better value the work that people like Elisabeth and others are doing. Because we're not going to get to a better answer if we're not rigorous about scrutinizing the literature and scrutinizing the methodology and scrutinizing the results.
"I quit my job to be able to do this work."
It's a relatively new phenomenon that you're able to do this at any scale at all, and even now it's at a very small scale. Elisabeth mentioned PubPeer and I'm a big fan — also full disclosure, I'm on their board of directors as a volunteer — it's a very powerful engine for readers and journal editors and other scientists to discuss issues.
And Elisabeth has used it really, really well. I think we need to start giving credit to people like that. And, also creating incentives for that kind of work in a way that science hasn't yet.
Elisabeth
Yeah. I quit my job to be able to do this work. It's really hard to combine it with a job either in academia or industry because we're looking for or criticizing papers and it's hard when you are still employed to do that.
I try to make it about the papers and do it in a polite way, but still it's a very hard job to do if you have a daytime job and a position and a career to worry about. Because if you're critical of other academics, that could actually mean the end of your career and that's sad. They should be more open to polite criticism.
Ivan
And for the general public, if you're reading a newspaper story or something online about a single study and it doesn't mention any other studies that have said the same thing or similar, or frankly, if it doesn't say anything about any studies that contradicted it, that's probably also telling you something.
Say you're looking at a huge painting of a shoreline, a beach, and a forest. Any single study is just a one-centimeter-by-one-centimeter square of any part of that canvas. If you just look at that, you would either think it was a painting of the sea, of a beach, or of the forest. It's actually all three of those things.
We just need to be patient, and that's very challenging to us as human beings, but we need to take the time to look at the whole picture.
DISCLAIMER: Neither Elisabeth Bik nor Ivan Oransky was compensated for participation in The Pandemic Issue. While the magazine's editors suggested broad topics for discussion, consistent with Bik's and Oransky's work, neither they nor the magazine's underwriters had any influence on their conversation.
[Editor's Note: This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]
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.
Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.
"I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads," Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.
A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.
Melanoma is the deadliest form of skin cancer. About 85,000 people are diagnosed with it each year in the U.S. and more than 8,000 die of the cancer when it spreads to other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
There are two peaks in diagnosis of melanoma; one is in younger women ages 30-40 and often is tied to past use of tanning beds; the second is older men 60+ and is related to outdoor activity from farming to sports. Light-skinned people have a twenty-times greater risk of melanoma than do people with dark skin.
"When I graduated from medical school, in 2005, melanoma was a death sentence" --Diwakar Davar.
Jamie had a follow up PET scan about six months after his surgery. A suspicious spot on his lung led to a biopsy that came back positive for melanoma. The cancer had spread. Treatment with a monoclonal antibody (nivolumab/Opdivo®) didn't prove effective and he was referred to the UPMC Hillman Cancer Center in Pittsburgh, a four-hour drive from his home in western Ohio.
An alternative monoclonal antibody treatment brought on such bad side effects, diarrhea as often as 15 times a day, that it took more than a week of hospitalization to stabilize his condition. The only options left were experimental approaches in clinical trials.
Early research
"When I graduated from medical school, in 2005, melanoma was a death sentence" with a cure rate in the single digits, says Diwakar Davar, 39, an oncologist at UPMC Hillman Cancer Center who specializes in skin cancer. That began to change in 2010 with introduction of the first immunotherapies, monoclonal antibodies, to treat cancer. The antibodies attach to PD-1, a receptor on the surface of T cells of the immune system and on cancer cells. Antibody treatment boosted the melanoma cure rate to about 30 percent. The search was on to understand why some people responded to these drugs and others did not.
At the same time, there was a growing understanding of the role that bacteria in the gut, the gut microbiome, plays in helping to train and maintain the function of the body's various immune cells. Perhaps the bacteria also plays a role in shaping the immune response to cancer therapy.
One clue came from genetically identical mice. Animals ordered from different suppliers sometimes responded differently to the experiments being performed. That difference was traced to different compositions of their gut microbiome; transferring the microbiome from one animal to another in a process known as fecal transplant (FMT) could change their responses to disease or treatment.
When researchers looked at humans, they found that the patients who responded well to immunotherapies had a gut microbiome that looked like healthy normal folks, but patients who didn't respond had missing or reduced strains of bacteria.
Davar and his team knew that FMT had a very successful cure rate in treating the gut dysbiosis of Clostridioides difficile, a persistant intestinal infection, and they wondered if a fecal transplant from a patient who had responded well to cancer immunotherapy treatment might improve the cure rate of patients who did not originally respond to immunotherapies for melanoma.
The ABCDE of melanoma detection
Adobe Stock
Clinical trial
"It was pretty weird, I was totally blasted away. Who had thought of this?" Jamie first thought when the hypothesis was explained to him. But Davar's explanation that the procedure might restore some of the beneficial bacterial his gut was lacking, convinced him to try. He quickly signed on in October 2018 to be the first person in the clinical trial.
Fecal donations go through the same safety procedures of screening for and inactivating diseases that are used in processing blood donations to make them safe for transfusion. The procedure itself uses a standard hollow colonoscope designed to screen for colon cancer and remove polyps. The transplant is inserted through the center of the flexible tube.
Most patients are sedated for procedures that use a colonoscope but Jamie doesn't respond to those drugs: "You can't knock me out. I was watching them on the TV going up my own butt. It was kind of unreal at that point," he says. "There were about twelve people in there watching because no one had seen this done before."
A test two weeks after the procedure showed that the FMT had engrafted and the once-missing bacteria were thriving in his gut. More importantly, his body was responding to another monoclonal antibody (pembrolizumab/Keytruda®) and signs of melanoma began to shrink. Every three months he made the four-hour drive from home to Pittsburgh for six rounds of treatment with the antibody drug.
"We were very, very lucky that the first patient had a great response," says Davar. "It allowed us to believe that even though we failed with the next six, we were on the right track. We just needed to tweak the [fecal] cocktail a little better" and enroll patients in the study who had less aggressive tumor growth and were likely to live long enough to complete the extensive rounds of therapy. Six of 15 patients responded positively in the pilot clinical trial that was published in the journal Science.
Davar believes they are beginning to understand the biological mechanisms of why some patients initially do not respond to immunotherapy but later can with a FMT. It is tied to the background level of inflammation produced by the interaction between the microbiome and the immune system. That paper is not yet published.
Surviving cancer
It has been almost a year since the last in his series of cancer treatments and Jamie has no measurable disease. He is cautiously optimistic that his cancer is not simply in remission but is gone for good. "I'm still scared every time I get my scans, because you don't know whether it is going to come back or not. And to realize that it is something that is totally out of my control."
"It was hard for me to regain trust" after being misdiagnosed and mistreated by several doctors he says. But his experience at Hillman helped to restore that trust "because they were interested in me, not just fixing the problem."
He is grateful for the support provided by family and friends over the last eight years. After a pause and a sigh, the ruggedly built 47-year-old says, "If everyone else was dead in my family, I probably wouldn't have been able to do it."
"I never hesitated to ask a question and I never hesitated to get a second opinion." But Jamie acknowledges the experience has made him more aware of the need for regular preventive medical care and a primary care physician. That person might have caught his melanoma at an earlier stage when it was easier to treat.
Davar continues to work on clinical studies to optimize this treatment approach. Perhaps down the road, screening the microbiome will be standard for melanoma and other cancers prior to using immunotherapies, and the FMT will be as simple as swallowing a handful of freeze-dried capsules off the shelf rather than through a colonoscopy. Earlier this year, the Food and Drug Administration approved the first oral fecal microbiota product for C. difficile, hopefully paving the way for more.
An older version of this hit article was first published on May 18, 2021
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.