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.
Is Carbon Dioxide the New Black? Yes, If These Fabric-Designing Scientists Have Their Way
Each year the world releases around 33 billion tons of carbon dioxide into the atmosphere. What if we could use this waste carbon dioxide to make shirts, dresses and hats? It sounds unbelievable. But two innovators are trying to tackle climate change in this truly unique way.
Chemist Tawfiq Nasr Allah set up Fairbrics with material scientist Benoît Illy in 2019. They're using waste carbon dioxide from industrial fumes as a raw material to create polyester, identical to the everyday polyester we use now. They want to take a new and very different approach to make the fashion industry more sustainable.
The Dark Side of Fast Fashion
The fashion industry is responsible for around 4% of global emissions. In a 2015 report, the MIT Materials Systems Laboratory predicted that the global impact of polyester fabric will grow from around 880 billion kg of CO2 in 2015 to 1.5 trillion kg of CO2 by 2030.
Professor Greg Peters, an expert in environmental science and sustainability, highlights the wide-ranging difficulties caused by the production of polyester. "Because it is made from petrochemical crude oil there is no real limit on how much polyester can be produced...You have to consider the ecological damage (oil spills, fracking etc.) caused by the oil and gas industry."
Many big-name brands have pledged to become carbon neutral by 2050. But nothing has really changed in the way polyester is produced.
Some companies are recycling plastic bottles into polyester. The plastic is melted into ultra-fine strands and then spun to create polyester. However, only a limited number of bottles are available. New materials must be added because of the amount of plastic degradation that takes place. Ultimately, recycling accounts for only a small percentage of the total amount of polyester produced.
Nasr Allah and Illy hope they can offer the solution the fashion industry is looking for. They are not just reducing the carbon emissions that are conventionally produced by making polyester. Their process actually goes much further. It's carbon negative and works by using up emissions from other industries.
"In a sense we imitate what nature does so well: plants capture CO2 and turn it into natural fibers using sunlight, we capture CO2 and turn it into synthetic fibers using electricity."
Experts in the field see a lot of promise. Dr Phil de Luna is an expert in carbon valorization -- the process of converting carbon dioxide into high-value chemicals. He leads a $57-million research program developing the technology to decarbonize Canada.
"I think the approach is great," he says. "Being able to take CO2 and then convert it into polymers or polyester is an excellent way to think about utilizing waste emissions and replacing fossil fuel-based materials. That is overall a net negative as compared to making polyester from fossil fuels."
From Harmful Waste to Useful Raw Material
It all started with Nasr Allah's academic research, primarily at the French Alternative Energies and Atomic Energy Commission (CEA). He spent almost 5 years investigating CO2 valorization. In essence, this involves breaking the bonds between the carbon and oxygen atoms in CO2 to create bonds with other elements.
Recycling carbon dioxide in this way requires extremely high temperatures and pressures. Catalysts are needed to break the strong bonds between the atoms. However, these are toxic, volatile and quickly lose their effectiveness over time. So, directly converting carbon dioxide into the raw material for making polyester fibers is very difficult.
Nasr Allah developed a process involving multiple simpler stages. His innovative approach involves converting carbon dioxide to intermediate chemicals. These chemicals can then be transformed into the raw material which is used in the production of polyester. After many experiments, Nasr Allah developed new processes and new catalysts that worked more effectively.
"We use a catalyst to transform CO2 into the chemicals that are used for polyester manufacturing," Illy says. "In a sense we imitate what nature does so well: plants capture CO2 and turn it into natural fibers using sunlight, we capture CO2 and turn it into synthetic fibers using electricity."
The Challenges Ahead
Nasr Allah met material scientist Illy through Entrepreneur First, a programme which pairs individuals looking to form technical start-ups. Together they set up Fairbrics and worked on converting Nasr Allah's lab findings into commercial applications and industrial success.
"The main challenge we faced was to scale up the process," Illy reveals. "[It had to be] consistent and safe to be carried out by a trained technician, not a specialist PhD as was the case in the beginning."
They recruited a team of scientists to help them develop a more effective and robust manufacturing process. Together, the team gained a more detailed theoretical understanding about what was happening at each stage of the chemical reactions. Eventually, they were able to fine tune the process and produce consistent batches of polyester.
They're making significant progress. They've produced their first samples and signed their first commercial contract to make polyester, which will then be both fabricated into clothes and sold by partner companies.
Currently, one of the largest challenges is financial. "We need to raise a fair amount to buy the equipment we need to produce at a large scale," Illy explains.
How to Power the Process?
At the moment, their main scientific focus is getting the process working reliably so they can begin commercialization. In order to remain sustainable and economically viable once they start producing polyester on a large scale, they need to consider the amount of energy they use for carbon valorization and the emissions they produce.
The more they optimize the way their catalyst works, the easier it will be to transform the CO2. The whole process can then become more cost effective and energy efficient.
De Luna explains: "My concern is...whether their process will be economical at scale. The problem is the energy cost to take carbon dioxide and transform it into these other products and that's where the science and innovation has to happen. [Whether they can scale up economically] depends on the performance of their catalyst."
They don't just need to think about the amount of energy they use to produce polyester; they also have to consider where this energy comes from.
"They need access to cheap renewable energy," De Luna says, "...so they're not using or emitting CO2 to do the conversion." If the energy they use to transform CO2 into polyester actually ends up producing more CO2, this will end up cancelling out their positive environmental impact.
Based in France, they're well located to address this issue. France has a clean electricity system, with only about 10% of their electric power coming from fossil fuels due to their reliance on nuclear energy and renewables.
Where Do They Get the Carbon Dioxide?
As they scale up, they also need to be able to access a source of CO2. They intend to obtain this from the steel industry, the cement industry, and hydrogen production.
The technology to purify and capture waste carbon dioxide from these industries is available on a large scale. However, there are only around 20 commercial operations in the world. The high cost of carbon capture means that development continues to be slow. There are a growing number of startups capturing carbon dioxide straight from the air, but this is even more costly.
One major problem is that storing captured carbon dioxide is expensive. "There are somewhat limited options for permanently storing captured CO2, so innovations like this are important,'' says T. Reed Miller, a researcher at the Yale University Center for Industrial Ecology.
Illy says: "The challenge is now to decrease the cost [of carbon capture]. By using CO2 as a raw material, we can try to increase the number of industries that capture CO2. Our goal is to turn CO2 from a waste into a valuable product."
Beyond Fashion
For Nasr Allah and Illy, fashion is just the beginning. There are many markets they can potentially break into. Next, they hope to use the polyester they've created in the packaging industry. Today, a lot of polyester is consumed to make bottles and jars. Illy believes that eventually they can produce many different chemicals from CO2. These chemicals could then be used to make paints, adhesives, and even plastics.
The Fairbrics scientists are providing a vital alternative to fossil fuels and showcasing the real potential of carbon dioxide to become a worthy resource instead of a harmful polluter.
Illy believes they can make a real difference through innovation: "We can have a significant impact in reducing climate change."
Vaccines are one of the greatest public health accomplishments of all time. For centuries, public health has relied on vaccinations to prevent and control disease outbreaks for a plethora of infectious scourges, with our crowning achievement being the successful eradication of smallpox.
The purpose of vaccine documentation is to provide proof of an individual's protection from either becoming infected or transmitting a vaccine-preventable disease. Vouching for these protections requires a firm knowledge about the epidemiology of the disease, as well as scientific knowledge concerning the efficacy of the vaccine. The vaccines we currently require be documented have met these tests; the vaccine for COVID-19 has not yet been proven to do so.
Let's acknowledge that the term "vaccine passport" is a poor choice of words. Passports are a legal travel document created by nations and governed by law for identification of the bearer to control entry and exit from nation states. They often serve as legal forms of identification and as a record of international travel. They are generally very sophisticated documents that have been created in a secure manner and may include a range of electronic and, in some cases, biometric measures such as fingerprints to ensure the holder is indeed who they say they are. Vaccine passports are medical documents used to document the vaccination status of an individual. They do not undergo the same level of administrative scrutiny and cannot be used to verify that the presenter is indeed the vaccinated individual. Some companies do have electronic methods to address concerns about verification; however, most people currently have paper records that can be easily falsified.
"Vaccine passports" as currently proposed risk giving people a false sense of security.
Successful disease control from vaccination programs relies on the ability to vaccinate at a level that prevents large-scale disease spread and the ability to rapidly identify the presence of disease outbreaks. It requires reliable, safe, and effective vaccines that are easily delivered in clinical and nonclinical settings. Keeping vaccination information as a part of the medical record, and even having a separate specialized vaccine record for personal use, is a time-honored tradition.
Keeping a vaccination record provides a method to keep track of the many shots one receives and serves as a visual reminder to help ensure the appropriate vaccine shot schedule is maintained for vaccines requiring multiple doses. The vaccine record, when combined with vaccine safety monitoring systems, serves as a mechanism to track adverse events to monitor and ensure the safety of vaccines as a consumer product. The record also serves as the official record of vaccination when required for administrative or legally prescribed purposes.
"Vaccine passports" as currently proposed risk giving people a false sense of security. In the case of the COVID-19 vaccines currently approved for use, many of the essential questions remain unanswered. While we do know the current three vaccines are highly protective against severe disease and death, and there is some evidence that these vaccinations do reduce infections and virus transmission of SARS-CoV-2, we do not yet know the full degree to which this occurs.
For example, we know there have been some cases of people that have been infected in close proximity to getting their full vaccination and rare cases of breakthrough reinfections. A breakthrough infection in a restaurant is a challenge for contact tracing, but an outbreak from a movie theater exposure or a baseball game could spark a major outbreak at our current level of vaccination. Current CDC guidance recommends continued mask wearing in order to address these concerns.
We also do not yet know how long the protections will last and if or when a booster or revaccination is required. In effect, it is too soon to know. Should an annual booster shot be required, then a vaccine passport would require annual updating, a process more frequent than renewal of a driver's license.
We also know that the current SARS-CoV-2 virus is mutating briskly. While the current approved vaccines have remained effective overall, there is evidence of some degree of degradation in vaccine effectiveness against some of the circulating strains. We also have sparse data on many of the other emerging strains of concern because we have not had the surveillance capacity in the U.S. to gain an adequate sense of how the virus is changing to fully align vaccine effectiveness with viral capabilities.
The risk of people misusing these "passports" is troubling. The potential for using these documents for hiring, firing or job limitation is a serious concern. Unvaccinated workers are at risk of this form of discrimination even from well-meaning employers or supervisors. Health insurers are prohibited by the Affordable Care Act from discriminating based on preexisting conditions, but they could probably charge a higher premium for unvaccinated individuals. There also is a risk of stigmatizing individuals who are not vaccinated or have left their vaccine documentation at home. Another concern: the opportunity to discriminate based on race, gender, sexual orientation, or religion, using one's vaccination status as an excuse.
These "passports" are being discussed as a "ticket verification" for entry to many activities, including dining at restaurants, flying domestically and/or internationally, going to movie theaters and sporting events, etc. These are all activities we already are doing at reduced levels and for which wearing a mask, hand hygiene and physical distancing are effective disease control practices. COVID-19 vaccines are indeed the measure that will make the ability to totally reopen our society complete, but we are not there yet. Documentation of one's COVID-19 vaccine status may be useful in selected situations in the future. That remains to be seen.
Finally, inadequate vaccine supply and disparities in vaccine delivery have created enormous challenges in providing equal access to vaccination. Also, the amount of misinformation, disinformation, and lingering vaccine hesitancy continue to limit the speed at which we will reach the level of vaccination of the population that would make this documentation meaningful. The requirement for "vaccine passports" is already alienating people who are opposed to vaccinations for a variety of reasons, paradoxically risking reduced vaccine uptake. This politicization of the vaccination effort is of concern. There are indeed people who, due to medical contraindications or legal exemptions, will not be vaccinated, and we do not yet have a national framework on how to address this.
Vaccine passports are not the solution for reopening our society — a robust vaccination program is. The requirement to document one's vaccination status for COVID-19 may one day have its place. For now, it is an idea whose time has not yet come.
Editor's Note: This op/ed is part of a "Big Question" series on the ethics of vaccine passports. Read the flip side argument here.