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.
23andMe Is Using Customers’ Genetic Data to Develop Drugs. Is This Brilliant or Dubious?
Leading direct-to-consumer (DTC) genetic testing companies are continuously unveiling novel ways to leverage their vast stores of genetic data.
"23andMe will tell you what diseases you have and then sell you the drugs to treat them."
As reported last week, 23andMe's latest concept is to develop and license new drugs using the data of consumers who have opted in to let their information be used for research. To date, over 10 million people have used the service and around 80 percent have opted in, making its database one of the largest in the world.
Culture researcher Dr. Julia Creet is one of the foremost experts on the DTC genetic testing industry, and in her forthcoming book, The Genealogical Sublime, she bluntly examines whether such companies' motives and interests are in sync with those of consumers.
Leapsmag caught up with Creet about the latest news and the wider industry's implications for health and privacy.
23andMe has just announced that it plans to license a newly developed anti-inflammatory drug, the first one created using its customers' genetic data, to Almirall, a pharma company in Spain. What's your take?
I think this development is the next step in the evolution of the company and its "double-sided" marketing model. In the past, as it enticed customers to give it their DNA, it sold the results and the medical information divulged by customers to other drug companies. Now it is positioning itself to reap the profits of a new model by developing treatments itself.
Given that there are many anti-inflammatory drugs on the market already, whatever Almirall produces might not have much of an impact. We might see this canny move as a "proof of concept," that 23andMe has learned how to "leverage" its genetic data without having to sell them to a third party. In a way, the privacy provisions will be much less complicated, and the company stands to attract investment as it turns itself into [a pseudo pharmaceutical company], a "pharma-psuedocal" company.
Emily Drabant Conley, the president of business development, has said that 23andMe is pursuing other drug compounds and may conduct their own clinical trials rather than licensing them out to their existing research partners. The end goal, it seems, is to make direct-to-consumer DNA testing to drug production and sales back to that same consumer base a seamless and lucrative circle. You have to admit it's a brilliant business model. 23andMe will tell you what diseases you have and then sell you the drugs to treat them.
In your new book, you describe how DTC genetic testing companies have capitalized on our innate human desire to connect with or ancestors and each other. I quote you: "This industry has taken that potent, spiritual, all-too-human need to belong... and monetized it in a particularly exploitative way." But others argue that DTC genetic testing companies are merely providing a service in exchange for fair-market compensation. So where does exploitation come into the picture?
Yes, the industry provides a fee for service, but that's only part of the story. The rest of the story reveals a pernicious industry that hides its business model behind the larger science project of health and heredity. All of the major testing companies play on the idea of "lack," that we can't know who we are unless we buy information about ourselves. When you really think about it, "Who do you think you are?" is a pernicious question that suggests that we don't or can't know who we or to whom we are related without advanced data searches and testing. This existential question used to be a philosophical question; now the answers are provided by databases that acquire more valuable information than they provide in the exchange.
"It's a brilliant business model that exploits consumer naiveté."
As you've said before, consumers are actually paying to be the product because the companies are likely to profit more from selling their genetic data. Could you elaborate?
The largest databases, AncestryDNA and 23andMe, have signed lucrative agreements with biotech companies that pay them for the de-identified data of their customers. What's so valuable is the DNA combined with the family relationships. Consumers provide the family relationships and the companies link and extrapolate the results to larger and larger family trees. Combined with the genetic markers for certain diseases, or increased susceptibility to certain diseases, these databases are very valuable for biotech research.
None of that value will ever be returned to consumers except in the form of for-profit drugs. Ancestry, in particular, has removed all information about its "research partners" from its website, making it very difficult to see how it is profiting from its third-party sales. 23andMe is more open about its "two-sided business model," but encourages consumers to donate their information to science. It's a brilliant business model that exploits consumer naiveté.
A WIRED journalist wrote that "23andMe has been sharing insights gleaned from consented customer data with GSK and at least six other pharmaceutical and biotechnology firms for the past three and a half years." Is this a consumer privacy risk?
I don't see that 23andMe did anything to which consumers didn't consent, albeit through arguably unreadable terms and conditions. The part that worries me more is the 300 phenotype data points that the company has collected on its consumers through longitudinal surveys designed, as Anne Wojcicki, CEO and Co-founder of 23andMe, put it, "to circumvent medical records and just self-report."
Everyone is focused on the DNA, but it's the combination of genetic samples, genealogical information and health records that is the most potent dataset, and 23andMe has figured out a way to extract all three from consumers.
Edible Silverware Is the Next Big Thing in Sustainable Eating
Sure, you may bring a reusable straw when you go out to eat. But what about digesting your silverware at the restaurant? The future is already here.
Edible cutlery feels like a natural progression post-reusable straw.
Air New Zealand just added the new edible coffee cup Twiice into their in-flight service. Made from vanilla, wheat flower, sugar, egg and vanilla essence, the Twiice cups will be standard issue for the international airline.
On the ground, the new, award-winning startup IncrEDIBLESpoon has shipped more than a quarter million edible scoopers. The spoons are all-natural, vegan, and made from wheat, oat, corn, chickpea and barley.
The technological breakthrough is in creating tasty, mass-market material durable enough for delivery in an assembly line environment like airplane service, as well as stable enough to hold a hot cup of coffee or a freezing scoop of ice cream. Twiice cups can last several hours after hot coffee is added, while IncrEDIBLESpoon cutlery holds up to 45 minutes.
"We already caught the interest of a couple major ice cream chains," says Dinesh Tadepalli, co-founder of the IncrEDIBLESpoon parent company Planeteer. "If all goes well, one of them will test out our spoons at their scoop shop early this year."
Next Up
Edible cutlery feels like a natural progression post-reusable straw. And more is already on the menu.
The coffee cup company Twiice is already planning on expanding. Co-founder Jamie Cashmore says other serving items are coming later this year.
IncrEDIBLESpoon is also getting into more utensils. "We plan to mass produce the complete set by year's end: Edible straws, edible forks and edible coffee stirrers," Tadepalli says.
Most notably, Twiice's partner Air New Zealand sees the coffee cup as just a start to other sustainable solutions. The airline estimates it currently serves eight million cups of coffee annually. It's even suggesting customers bring their own reusable cup to the plane – though that isn't as ergonomic nor as attractive as eating everything you are served.
Open Questions
Making everything edible has a few challenges. First is cultural acceptance: With respect to current success, changing eating habits will require going beyond eco-focused and curious eaters.
Second, it's unclear if the short-term economics will add up in favor of airline carriers and other companies. Like alternative fuel, organizations will be more likely to adopt new science when it doesn't require a retrofitting or expensive change to their current business model – even if it does create long-term benefits.
The changes will likely be lopsided, influencing cultures at different times. Airplanes are a great start, as passengers are a captive audience interested in removing waste as soon as possible.
"Imagine eating a black pepper spoon after your soup or a chocolate spoon after your ice cream?"
We can expect edible cutlery to make an easier impact with certain cultures or foods. For instance, injera, the spongy Ethiopian bread, has served as an African plate of sorts for years. It makes sense that IncrEDIBLESpoon's four flavors, Salt, Masala, Spinach and Root, all fit in another bread-as-plate friendly culture: Indian.
Coffee and desserts sound like a good bet for now, though, especially for foodies. "People are curious to try edible spoons as they never heard or experienced them before," Tadepalli says. "Imagine eating a black pepper spoon after your soup or a chocolate spoon after your ice cream?"