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.
Coronavirus Misinformation: How You Can Fight Back
When it comes to fighting the new coronavirus threat, the truth is one of the few things more crucial than a gallon of hand sanitizer. But these days, both can be hard to find if you don't know where to look.
"Humans are wired to respond to emotional triggers and share misinformation if it reinforces existing beliefs and prejudices."
While it's only been around for a few months, COVID-19 has already produced an ever-expanding universe of conspiracy theories about its origins, its spread, and the danger it poses. Meanwhile, fraudulent cures and myths about treatments threaten to upend public health efforts to contain the epidemic.
But ordinary citizens aren't helpless. Research offers insight into why we're susceptible to misinformation, and armies of fact-checkers can tell us what's real and what isn't. Meanwhile, experts are offering tips about how we can effectively promote facts whether we're chatting with a stranger at the post office or challenging a cousin on Facebook.
Here a four-part strategy to help you fight back against the Coronavirus Misinformation Industrial Complex:
Understand How Bogus Beliefs Work
That crank on the Internet may be your neighbor. Or maybe even you.
According to a 2014 study published in JAMA Internal Medicine, nearly half of American surveyed said they believed in at least one grand medical conspiracy theory. Twenty percent agreed, for example, that cell phones cause cancer but officials won't do anything because of corporate pressure, and 37 percent believed an elaborate conspiracy theory about the suppression of natural cancer cures. "Although it is common to disparage adherents of conspiracy theories as a delusional fringe of paranoid cranks, our data suggest that medical conspiracy theories are widely known, broadly endorsed, and highly predictive of many common health behaviors," the study authors write.
In an interview with leapsmag, study lead author Eric Oliver said we're drawn to "conspiracy theories that correspond with our intuitions."
"In the case of medicine, I think there are three big factors: Fears of Big Pharma -- a large percentage of Americans have a distorted sense of what pharmaceutical companies are capable of -- fears of government, and fears of contagion," said Oliver, a political scientist at the University of Chicago.
Why does it matter if people believe in conspiracy theories about coronavirus? As Oliver's study notes, conspiracy theorists are less likely to rely on traditional medicine, get flu shots, or go to annual check-ups. They could be especially susceptible to disease and inappropriate treatment.
Joseph Uscinski, a professor of political science at the University of Miami who studies conspiracies, elaborated on how this works. "You could have people who think coronavirus is fake and say, 'I'm not going to wash my hand or take preventive action. This is the media making something up, or this is just a plot for the pharmaceutical companies to sell a vaccine.' If you have a lot of people acting that way, that increases the ability of the virus to spread."
Get the Facts from the Experts
How can you avoid being a misinformation source? Educate yourself to make sure you're not spouting fake facts yourself with the instant ease that the Internet allows. "Humans are wired to respond to emotional triggers and share misinformation if it reinforces existing beliefs and prejudices," writes misinformation scholar Claire Wardle in a 2019 Scientific American commentary. That means you too.
For coronavirus facts, experts recommend looking to the websites of government agencies (such as the CDC, World Health Organization and National Institutes of Health) and top-tier medical organizations (Mayo Clinic, Infectious Disease Society of America).
Respected mainstream news outlets such as The New York Times and National Public Radio offer extensive original reporting on the coronavirus threat. While some news outlets still require users to pay to get full access to stories, others have dropped their paywalls and made coronavirus content free to all. These include the Seattle Times, Bloomberg News and the medical news site Stat.
Locally, look to your region's public health department, news outlets, and medical organizations such as hospitals and health plans.
The Poynter Institute, a journalism watchdog outfit, offers a helpful guide to evaluating what you read about coronavirus. And a paid service called NewsGuard offers a browser plug-in that provides a "trust rating" for popular news sites. "Our goal is to teach news literacy–and we hope all websites will earn green ratings and be generally reliable to consumers," the NewsGuard site says.
"As we combat misinformation, we also need to be mindful of the fact that we're dealing with a lot of uncertainty."
Remember, however, that scientists and physicians are learning more about the coronavirus each day. Assumptions about the virus will change as more information comes in, and there are still many questions about crucial topics like its fatality rate and the ways the virus spreads. You should expect that reliable sources – and experts – may provide conflicting information.
"As we combat misinformation, we also need to be mindful of the fact that we're dealing with a lot of uncertainty," says Boston cardiologist and author Dr. Haider Warraich of Brigham and Women's Hospital.
Double-Check Suspicious Information
No, the coronavirus wasn't created in a Winnipeg laboratory. You can't kill it by drinking bleach or frolicking in snow. And, as the French Health Ministry helpfully advised on Twitter, "Non, La cocaïne NE protège PAS contre le #COVID19" – "No, cocaine does NOT prevent Covid-19."
Facebook, YouTube and Twitter are all trying to remove fake or misleading coronavirus content, The New York Times reported, and "all said they were making efforts to point people back to reliable sources of medical information." Still, as the Times reports, bogus cures and conspiracy theories are rampant across social media and beyond.
Fortunately, there are many fact-checking resources. Turn to them for ammunition before you amplify – or challenge -- a coronavirus claim that seems suspicious.
Helpful myth-busting resources include:
** The venerable fact-checking site Snopes.com, which has checked multiple coronavirus claims. (Example: No, garlic water won't cure coronavirus.)
** The World Health Organization. (Example: No, mosquito bites can't transmit coronavirus)
** FactCheck.org. (Example: No, a disgraced Harvard scientist wasn't arrested for creating the coronavirus.)
** PolitiFact.org. (Example: No, the coronavirus is not just "the common cold.")
** The International Fact-Checking Network, accessible via the social-media hashtags #CoronaVirusFacts and #DatosCoronaVirus.
Correct Others With Caution
On social media, anger and sarcasm make up a kind of common tongue. But sick burns won't force misinformed people see the light. Instead, try a gentler approach.
"The most important thing would be to first acknowledge their anxieties rather than first trying to rationalize away their misbeliefs," said the University of Chicago's Oliver. "People embrace misinformation and conspiracy theories because they are afraid and trying to make sense of the world. Their beliefs serve a strong emotional function and will be defended as such. Trying to rationalize with them or argue with them may be counterproductive if one can't first put them at some ease."
Turn yourself into a source of coronavirus facts and a bulwark against the fake, misleading, and fraudulent.
So what can you do? "There will never be a magic bullet," the University of Miami's Uscinski said, but one approach is to highlight reliable information from sources that the person trusts, such as news outlets (think MSNBC or Fox News) or politicians.
However, don't waste your time. "If you have people who are believing in the craziest thing, they're probably not going to offer a rational conversation," he said. And, he added, there's an alternative to correcting others: Turn yourself into a source of coronavirus facts and a bulwark against the fake, misleading, and fraudulent. "We can be preventive and inoculate people against these beliefs," he said, "by flooding the information environment with proper information as much as possible."
What's the case-fatality rate?
Currently, the official rate is 3.4%. But this is likely way too high. China was hit particularly hard, and their healthcare system was overwhelmed. The best data we have is from South Korea. The Koreans tested 210,000 people and detected the virus in 7,478 patients. So far, the death toll is 53, which is a case-fatality rate of 0.7%. This is seven times worse than the seasonal flu (which has a case-fatality rate of 0.1%).
What's the best way to clean your hands? Soap and water? Hand sanitizer?
Soap and water is always best. Be sure to wash your hands thoroughly. (The CDC recommends 20 seconds.) If soap and water are not available, the CDC says to use hand sanitizer that is at least 60% alcohol. The problem with hand sanitizer, however, is that people neither use enough nor spread it over their hands properly. Also, the sanitizer should be covering your hands for 10-15 seconds, not evaporating before that.
How often should I wash my hands?
You should wash your hands after being in a public place, before you eat, and before you touch your face. It's a good idea to wash your hands after handling money and your cell phone, too.
How long can coronavirus live on surfaces?
It depends on the surface. According to the New York Times, "[C]old and flu viruses survive longer on inanimate surfaces that are nonporous, like metal, plastic and wood, and less on porous surfaces, like clothing, paper and tissue." According to the Journal of Hospital Infection, human coronaviruses "can persist on inanimate surfaces like metal, glass or plastic for up to 9 days, but can be efficiently inactivated by surface disinfection procedures with 62–71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute." (Note: Sodium hypochlorite is bleach.)
Can Lysol wipes kill it?
Maybe not. It depends on the active ingredient. Many Lysol products use benzalkonium chloride, which the aforementioned Journal of Hospital Infection paper said was "less effective." The EPA has released a list of disinfectants recommended for use against coronavirus.
Should you wear a mask in public?
The CDC does not recommend that healthy people wear a mask in public. The benefit is likely small. However, if you are sick, then you should wear a mask to help catch respiratory droplets as you exhale.
Will pets give it to you?
That can't be ruled out. There is a documented case of human-to-canine transmission. However, an article in LiveScience explains that canine-to-human is unlikely.
Are there any "normal" things we are doing that make things worse?
Yes! Not washing your hands!!
What does it mean that previously cleared people are getting sick again? Is it the virus within or have they caught it via contamination?
It's not entirely clear. It could be that the virus was never cleared to begin with. Or it could be that the person was simply infected again. That could happen if the antibodies generated don't last long.
Will the virus go away with the weather/summer?
Quite likely, yes. Cold and flu viruses don't do well outside in summer weather. (For influenza, the warm weather causes the viral envelope to become a liquid, and it can no longer protect the virus.) That's why cold and flu season is always during the late fall and winter. However, some experts think that it is a "false hope" that the coronavirus will disappear during the summer. We'll have to wait and see.
And will it come back in the fall/winter?
That's a likely outcome. Again, we'll have to wait and see. Some epidemiologists think that COVID-19 will become seasonal like influenza.
Does dry or humid air make a difference?
Flu viruses prefer cold, dry weather. That could be true of coronaviruses, too.
What is the incubation period?
According to the World Health Organization, it's about 5 days. But it could be anywhere from 1 to 14 days.
Should you worry about sitting next to asymptomatic people on a plane or train?
It's not possible to tell if an asymptomatic person is infected or not. That's what makes asymptomatic people tricky. Just be cautious. If you're worried, treat everyone like they might be infected. Don't let them get too close or cough in your face. Be sure to wash your hands.
Should you cancel air travel planned in the next 1-2 months in the U.S.?
There are no hard and fast rules. Use common sense. Avoid hotspots of infection. If you have a trip planned to Wuhan, you might want to wait on that one. If you have a trip planned to Seattle and you're over the age of 60 and/or have an underlying health condition, you may want to hold off on that, too. If you do fly on a plane, former FDA commissioner Dr. Scott Gottlieb recommends cleaning the back of your seat and other close contact areas with antiseptic wipes. He also refuses to take anything handed out by flight attendants, since he says the biggest route of transmission comes from touching contaminated surfaces (and then touching your face).
There have been reports of an escalation of hate crimes towards Asian Americans. Can the microbiologist help illuminate that this disease has impacted all racial groups?
People might be racist, but COVID-19 is not. It can infect anyone. Older people (i.e., 60 years and older) and those with underlying health conditions are most at risk. Interestingly, young people (aged 9 and under) are minimally impacted.
To what extent/if any should toddlers -- who put everything in mouth -- avoid group classes like Gymboree?
If they get infected, toddlers will probably experience only a mild illness. The problem is if the toddler then infects somebody at higher risk, like grandpa or grandma.
Should I avoid events like concerts or theater performances if I live in a place where there is known coronavirus?
It's not an unreasonable thing to do.
Any special advice or concerns for pregnant women?
There isn't good data on this. Previous evidence, reported by the CDC, suggests that pregnant women may be more susceptible to respiratory viruses.
Advice for residents of long-term care facilities/nursing homes?
Remind the nurse or aide to constantly wash their hands.
Can we eat at Chinese restaurants? Does eating onions kill viruses? Can I take an Uber and be safe from infection?
Yes. No. Does the Uber driver or previous passengers have coronavirus? It's not possible to tell. So, treat an Uber like a public space and behave accordingly.
What public spaces should we avoid?
That's hard to say. Some people avoid large gatherings, others avoid leaving the house. Ultimately, it's going to depend on who you are and what sort of risk you're willing to take. (For example, are you young and healthy or old and sick?) I would be willing to do things that I would advise older people avoid, like going to a sporting event.
What are the differences between the L strain and the S strain?
That's not entirely clear, and it's not even clear that they are separate strains. There are some genetic differences between them. However, just because RNA viruses mutate doesn't necessarily mean that the virus will mutate to something more dangerous or unrecognizable by our immune system. The measles virus mutates, but it more or less remains the same, which is why a single vaccine could eradicate it – if enough people actually were willing to get a measles shot.
Should I wear disposable gloves while traveling?
No. If you touch something that's contaminated, the virus will be on your glove instead of your hand. If you then touch your face, you still might get sick.