Scientists discover the Achilles' heel (or head) of PFAS, cancer-causing chemicals
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Brittany Trang led research on a new way to destroy "forever chemicals," which cause a litany of health problems, while working in William Dichtel’s chemistry lab at Northwestern University.
Brittany Trang was staring at her glass test tube, which suddenly turned opaque white. At first, she had thought that the chemical reaction she tested left behind some residue, but when she couldn’t clean it off, she realized that the reaction produced corrosive compounds that ate at the glass. That, however, was a good sign. It meant that the reaction, which she didn’t necessarily expect to work, was in fact, working. And Trang, who in 2020 was a Ph.D. researcher in chemistry at Northwestern University, had reasons to be skeptical. She was trying to break down the nearly indestructible molecules of per- and polyfluoroalkyl substances or PFAS—the forever chemicals called so because they resist heat, oil, stains, grease, and water, and thus don’t react or break down in the environment.
“The first time I ran this, I was like, oh, like there's a bunch of stuff stuck to the glass, but when I tried to clean it, it wasn’t coming off,” Trang says, recalling her original experiment and her almost-disbelief at the fact she managed to crack the notoriously stubborn and problematic molecules. “I was mostly just surprised that it worked in general.”
In the recent past, the world has been growing increasingly concerned about PFAS, the pollutants that even at low levels are associated with a litany of adverse health effects, including liver damage, thyroid disease, high cholesterol, pregnancy complications and several cancers. Used for decades in manufacturing and in various products such as fire retardant foam, water-repellant clothes, furniture fabrics, Teflon-coated pans, disposable plates, lunch containers and shoes, these super-stable compounds don’t degrade in the environment. The forever chemicals are now everywhere: in the water, in soil, in milk, and in produce.
As of June 2022, the Environmental Working Group, a nonprofit watchdog organization, found 2,858 locations in 50 states and two territories to be heavily contaminated with PFAS while many farmers had been forced to dump their milk or spinach because the levels of these compounds were in some cases up to 400 times greater than what’s considered safe. And because PFAS are so pervasive in the environment and the food we eat, they are in our bodies too. One study found some levels of PFAS in 97 to 100 percent of participants tested.
Because these compounds were made to be very stable, they are hard to destroy. So far, the only known way to break down PFAS has been to “cook” them under very harsh conditions. The process, known as pyrolysis, requires upwards of 500 degrees Centigrade, high pressure and absence of oxygen, which is energy expensive. It involves sophisticated equipment and the burning of fossil fuels. Trang, who worked in the laboratory of William Dichtel, managed to break PFAS at 120 degrees Centigrade (248 F) without using strong pressure. After she examined the results of her process with various techniques that help quantify the resulting compounds and confirmed that PFAS had indeed degraded into carbon and the corrosive fluorine that clouded her glass, she was thrilled that it worked in such simple conditions.
“That's really what differentiates our finding from everything else that's out there,” Dichtel said about their discovery at a press conference announcing the study last month. “When we're talking about low temperatures, we're at 120 degrees Celsius and sometimes even quite a bit lower than that, and especially ambient pressure.”
The process used by Trang’s team was the exact opposite of the typical organic synthesis method.
Trang’s journey into PFAS degradation began with a paper she read about the nuances of the chemicals’ molecular structure. A long molecule comprised primarily of carbon and fluorine atoms, along with oxygen and hydrogen, it has what Trang describes as a head and a tail. At the head sits a compound called carboxylic acid while the fluorine atoms make up the tail portion, with the atomic bonds so strong they aren’t possible to break without harsh treatment. But in early 2020, Trang read that a solvent called dimethylsulfoxide, or DMSO, commonly used in labs and industry, can make the carboxylic acid “pop off” its place. The DMSO doesn’t react with carboxylic acid but sort of displaces it, leaving the rest of the typically indestructible PFAS molecule vulnerable.
Trang found that its exposed fluorine tail would react with another common chemical compound, sodium hydroxide, causing a cascade of reactions that ultimately unravel the rest. “After you have decarboxylated the head, the hydroxide is able to react with the tail,” Trang says. “That's what sets off a cascade of reactions that degrades the rest of the molecule.”
That pathway took time to figure out. Trang was able to determine that the molecule carboxylic acid head popped off, but before she was able to figure out the rest, her lab and the entire Northwestern University went into lockdown in early March of 2020. “I was able to do three experiments before the shutdown,” she recalls. For the next few months, she sat at home, reading scientific literature to understand how to continue the degradation process. “I had read a bunch of literature and had a bunch of ideas for what may or may not work,” she says. By the time she could return to work, she had a plan. “I added sodium hydroxide in my batch of experiments when the lab reopened.”
The process used by Trang’s team was the exact opposite of the typical organic synthesis method. “Most organic chemists take two molecules and squish them together to make one big molecule. It’s like taking two Legos and putting them together to make one thing that was larger,” she says. “What we are doing is kind of smashing the Lego with two bits and looking at what was left to figure out how it fell apart.” The team published their discovery in the journal Science.
Although very promising, the process isn’t quite ready for industrial applications, and will take time to adapt, Trang says. For starters, it would have to be scaled up to continuously clean large quantities of water, sewage or other substances that can be contaminated with PFAS. The process will also have to be modified, particularly when it comes to removing PFAS from drinking water because as an industrial chemical, DMSO is not suitable for that. Water companies typically use activated carbon to filter out PFAS and other pollutants, so once that concentrated waste is accumulated, it would be removed and then treated with DMSO and hydroxide to break down the molecules. “That is what our method would likely be applied to,” Trang says—the concentrated waste rather than a reservoir because “you wouldn't want to mix DMSO with your drinking water.”
There are some additional limitations to the method. It only breaks down one class of forever chemicals, but there are others. For example, the molecules of perfluoroalkane sulfonic acids, or PFSA, don’t have a carboxylic head that DMSO can displace. Instead, PFSA have a sulphonic acid as their molecular head, which would require a different solvent that still needs to be discovered. “There is certainly the possibility of activating sulphonates in similar ways [to what] we've done [with] carboxylates,” Dichtel said, and he hopes this will happen in the future. Other forever chemical types may have their own Achilles’ heels, waiting to be discovered. “If we can knock that sulphonated headgroup off the molecule and get to the same intermediates we get to in this study,” Dichtel added, “it's very reasonable to assume that they'll degrade by very similar pathways.” Perhaps another team of inquisitive chemists will take on the challenge.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman