How mRNA Could Revolutionize Medicine
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce one of the two components that make up CRISPR — a cutting protein that snips out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Cancer Immunotherapy
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
The Secrets of a Long Life from the U.S.’s Top Longevity Hot Spot
Summit County resident Gloria Breigenzer, 75, does a yoga headstand in the Rocky Mountains while her horse looks on.
People are living longer in the world's richest countries, according to a recent Pew Report. Certain areas, in particular, have drawn the attention of researchers who study longevity because in those places, living to 100 is not unusual.
"If you want to live longer, shape your environment."
At 8000 feet up, Summit County, Colorado is a longevity hotspot. Surrounded by mountains that soar to more than 14,000 feet, the population of nearly 31,000 brags the highest expected lifespan in the United States, at 86.83 years. For comparison, the average life expectancy in the U.S. is 78.6 years.
So, what is it about living in Summit County that has brought about this high honor?
Despite popular belief, it's not about genes. Only about "20-30 percent of longevity can be predicted by genetics," longevity researcher Howard S. Friedman wrote in an email exchange. Friedman, a professor at the University of California at Riverside, co-authored a book about a famous study that followed participants for eight decades to learn what traits and factors contribute to a long life.
"About half is behavioral (including environmental)," Friedman says. "The rest is random (chance)." His longevity research is based on work that began in 1921 by Stanford University psychologist Lewis Terman. To discern the keys to longevity, Friedman and colleagues spent 20 years looking back at the lives led by the 1500 "gifted" 11-year old boys and girls who were born in 1910 and participated in Terman's study.
"We found that ambition, perseverance, and high motivation … predicted not only success but also longevity: Stressful job and hard work, long life!" Friedman says.
Longevity expert Dan Buettner agrees that an individual's environment is key. Buettner studies what he calls Blue Zones, where people "naturally live longer." But, unlike the five Blue Zones in the world -- Okinawa, Japan; Sardinia, Italy; Nicoya, Costa Rica; Ikaria, Greece; and Loma Linda, California — the majority of the Summit County population chose to move to the mountain towns that make up the region. Because Buettner believes that people can be taught to live longer, he sees Summit County as an instructive locale.
Like the Blue Zones, people in Summit County "do not pursue healthy lifestyles; [rather] it ensues," he says. "Blue Zones have the benefit of traditional patterns of eating and traditional rhythms of life. So they tend to be places where people walk to work, to a friend's house … [and] Blue Zone people eat the right food -- not because they have better individual responsibility or discipline; they simply live in an environment where beans, greens, nuts and grains are cheapest and most accessible."
"If you want to live longer," Buettner says, "shape your environment."
But an individual's environment can be affected by a number of factors, including socioeconomics, race, quality of and access to health care, as well as behavioral and metabolic risks. While the residents of Summit County smoke less and exercise more than those in regions with shorter life spans, they also have higher incomes and levels of education and lower unemployment.
"The healthiest individuals in The Longevity Project…lived meaningful, committed lives. They worked hard and played hard."
Gloria Breigenzer moved to Summit County 20 years ago with her husband. "We wanted to ski and ride horses up in the mountains," says Breigenzer. The 75-year-old still works part time as a hair dresser, goes to the gym every day, lifts weights and does yoga.
"I don't know why people don't want to get up and go out and work out and do stuff. I do," says the grandmother, who also exercises her rescue horse five days a week and for the past 15 years has done swing, country two step, and jazz dance in a group with her 77-year-old husband. She's also taking kiteboarding lessons and for the past two years has spent every afternoon studying Spanish.
Pete and Judy Rubin, both 65, retired to Summit County nearly two years ago from Cleveland. In Colorado, "socializing doesn't revolve around food," says Pete. "In Cleveland it always did…[Being outside] in summer or in winter is just easy. Skiing, on a bike, taking a hike, mowing the lawn, looking at a mountain instead of having someone else do it."
The Summit County approach resonates for researcher Friedman, who says that it's the "constellations of habits and patterns of living," that stood out most to him in his study. "Throw away your lists...The healthiest individuals in The Longevity Project…lived meaningful, committed lives. They worked hard and played hard. They were very persistent and responsible, and they were dedicated to things and people beyond themselves."
The following are some of the common denominators found in populations that live longer, including those who live in Summit County:
Plant-based diet: "Eat meat, no more than 5 times a month … [and] 95 percent of all the calories you take in should be whole plant-based foods," says Buettner.
Know your purpose: Buettner found that having and understanding your sense of purpose is worth up to seven years of extra life expectancy.
Have friendships: "You should have three to five friends who are healthy themselves who you can call on a bad day and they'll care," says Buettner.
Be on the move: Populations in zones where there is higher longevity "move naturally" as part of their day. It's not about diets. "No diet in the history of the world has worked for more than 5 percent of people after two years," says Buettner.
Relieve stress: "You should have some daily practices that help you downshift," says Buettner. It "could be taking naps, or meditation practice, or a habit of praying or a habit of doing happy hours."
Employ a family first rule: "Successful centenarians put their families first," explains Buettner. "And that means keeping your aging parents nearby, being seriously invested in your partner and if you have kids, you make them a priority."
It's these "key patterns of living [that] tend to make you both healthier and happier," says Friedman. "And health and happiness often then mutually reinforce each other."
Here's What It Looks Like to Seek Therapy for Climate Change Anxiety
Treatment for climate change anxiety looks different from treating generalized anxiety in that the concerns have a legitimate basis, therapists say.
Three months after Gretchen bought a house in Grass Valley, California, the most destructive and fatal wildfire in the state's history ravaged the towns about 40 miles northwest of her.
"For a long time, I kept on having this vision of what my town will look like if one of those firestorms happens, and I felt like I needed to work on that."
The Camp Fire of November 2018 was noteworthy not just because of its damaging scale but because of what started it all: a spark from a faulty transmission line owned by the Pacific Gas & Electric Company, which services nearly two-thirds of California.
PG&E reacted by announcing almost a year later that in advance of days with a high fire risk, it would proactively institute power outages in 17 counties throughout the northern part of the state, including the one where Gretchen lives. The binary options seemed to be: cause another fire or intermittently plunge tens of thousands of people into literal and figurative darkness, impacting emergency services, health, food, internet, gas, and any other electrified necessity or convenience of modern life.
This summer, in between the end of the Camp Fire and the beginning of the blackouts, Gretchen, who asked to keep her last name private, decided it was time to seek counseling for climate-related anxiety.
"That was a very traumatic experience to go through," Gretchen, 39, says, describing what it was like to have recently settled in this increasingly fire-prone part of her home state, and later witnessing a colleague flee California altogether after his own home burned down and he couldn't afford to stay. "For a long time, I kept on having this vision of what my town will look like if one of those firestorms happens, and I felt like I needed to work on that."
While research on climate anxiety—or, more broadly, the effects of climate change on mental health—has been slowly but surely piling up, the actual experience of diagnosing and treating it is less well-documented in both media and academia. An ongoing Yale University study of American perceptions of climate change shows an increasing proportion of concern: In 2018, 29 percent of 1,114 survey respondents said they were "very worried" about climate change, up from 16 percent in 2008. But there are no parallel large-scale studies of whether a similar proportion of people are in therapy for climate change-related mental health issues.
That might be because many would-be clients don't yet realize that this is a valid concern for which to seek out professional support. It could also be because there are no definitive or unifying resources for therapists who are counseling people on the topic. Climate anxiety is notably absent by name from the Diagnostic and Statistical Manual of Mental Disorders (DSM), the psychological gospel for everyone from clinicians to lawmakers. The manual was last updated in 2012 (and published in 2013), just when the first documents of climate anxiety were beginning to crop up.
A small 2013 study surveyed college students in the U.S. and Europe to try and answer the question: Is habitually worrying about the environment a mental health concern if it's a response to a real threat? The study concluded: "...those who habitually worry about the ecology are not only lacking in any psychopathology, but demonstrate a constructive and adaptive response to a serious problem." In other words, worrying about a concrete external concern like the state of the environment is on a different plane than habitually worrying about an internal concern, like feelings of inadequacy. Therapy may still help with the former, but the diagnostic framework could ultimately look different than what is typically used in generalized anxiety.
For now, the best resource for therapists counseling patients battling what is sometimes dubbed "ecoanxiety" is a 70-page booklet called "Mental Health and Our Changing Climate: Impacts, Implications, and Guidance," whose publication was co-sponsored by the American Psychological Association, which publishes the DSM. It's been through two editions already, the first in 2014 and the second in 2017.
"It's not clear to me that [climate anxiety] would merit its own diagnosis, at least at this point," says Susan Clayton, who was the lead author on the 2017 edition and who studies this area at The College of Wooster, but doesn't counsel people directly. However, she says, "I do think that there are some differences [from generalized anxiety], and one of the important differences is, of course, that there's some realism here."
Clayton says that group therapy may be a particularly useful way to affirm for people that they're not the only one experiencing climate anxiety, especially in communities where it might be taboo to not only affirm the existence of climate change but to be openly affected by it.
On drawing therapeutic inspiration from historical examples of other global dangers—such as the widespread fear of nuclear threat during the Cold War—Clayton says: "That was such a different time and they were thinking differently about mental health, but I think in many ways the fear is very similar. It's not like worrying about your finances, it's worrying about the end of the world. So that sort of existential component, and the fact that it's shared, both are very similar here."
There are precedents that therapists can refer to for guidance on helping clients managing climate anxiety, like the approaches used to support people dealing with a terminal illness or battling systemic racism. Such treatments need to stay rooted in the reality of the trigger.
"You don't want to say to them, 'That's not a real thing,'" Clayton explains. "So I think of [climate anxiety] like that. It does mean that the therapeutic focus is not going to be on trying to get people to be reasonable," which is to say that their anxiety is not inherently unreasonable.
"I think it is important to recognize that the anxieties have a legitimate basis," she adds.
"I feel more comfortable now being prepared, being prudent, but not dwelling on it all the time."
Gretchen's reality is now one of adapting to living an off-the-grid lifestyle that she didn't intentionally sign up for. She puts gas in her car in advance of blackouts, and waits to see week-by-week if the school where she teaches second and third grade, in the foothills of Tahoe National Park, will be closed. Her union has yet to figure out how this stop-and-go schedule will affect her salary; she has to keep rescheduling parent-teacher conferences; and she no longer knows when the last day of school will be—existing summer plans for her personal life be damned. Even her interview for this story was affected by this instability.
While trying to schedule a time to talk, she wrote, "Speaking of climate change, I may not have work the rest of the week due to PG&E power outages. If so I will have a very flexible schedule." Later, she suddenly had to decline. "As it turns out, the power's not going out. I will be at work."
In therapy sessions, she works with her counselor to focus on preparedness, where possible, and to specifically frame that preparedness as a source of regaining some of the stability she's lost rather than a sign of imminent trouble. That nuance became necessary after a training at work had the opposite effect.
"We've gone through scenarios [where] if a firestorm happens and we don't have time to evacuate, we have to gather all the children into the cafeteria and fend off the flames ourselves with help from the fire department, and keep them alive if we can't get out in time," she says. "After that day, or that training, that really scared me."
Her therapist uses a type of psychotherapy called eye movement desensitization and reprocessing (EMDR) to help Gretchen move away from traumatizing images, such as picturing her town on fire, while emphasizing what it is that she can control, such as making sure her car has a full tank, in case she needs to evacuate. EMDR has been shown to help people with post-traumatic stress disorder (PTSD) and the World Health Organization offers practice guidelines around it.
"I feel more comfortable now being prepared, being prudent, but not dwelling on it all the time," she says. "I feel a little less heightened anxiety and have stopped replaying [those images] in my mind."
Overall, the type of support Gretchen receives is based on pre-existing tools for managing other well-established mental health burdens like PTSD and generalized anxiety. Although no definitive, new practices have specifically emerged around climate anxiety on a comprehensive scale yet, Gretchen says she was nonetheless met with compassion when she first approached a therapist about the topical source of her anxiety, and doesn't feel that her care is lacking in any way.
"I don't know enough to know whether or how it should become its own diagnosis, but I feel like it's something that is still evolving. Down the road, as we see more populations having to move, more refugees, more real effects, that might change," she says. "For me, using the old tools in a new way has been effective at this point."
Gretchen hasn't yet explored with her therapist the more existential worries that climate change dredges up for her—worries about whether or not to have children, and if it was a mistake to settle down in Grass Valley. She's only been in therapy for her climate anxiety since the summer (although she has intermittently sought out professional mental health support for other reasons over the last eight years), and it will take time to get to these bigger issues, she says. She's not sure yet whether that part of her counseling will look different than what's she's done so far.
But she does wonder about the overall usefulness of pathologizing what, as Clayton said, are legitimate anxieties. She has the same question when it comes to providing mental health support for her students, many of whom live in poverty.
"Is it just putting a bandaid on something that is unfixable, or is unfair?" she ponders. But de-escalating the psychological toll that climate change can have on people is crucial to giving them back the energy to deal with the problem itself, not just their reaction to the problem. Clayton believes that engaging in climate activism can provide solace for the people who do have that energy.
"This is a social issue, and there's obviously lots and lots of climate activism," she says. "You might not be comfortable being politically active, but I think getting involved in some way, and addressing the issue, would help people feel much more empowered, and would help with the experience of climate anxiety."
"Remember that nature is not just a source of anxiety, it's also a source of replenishment and restoration."
As far as what shape this personal involvement takes, an increasingly vocal movement of people is calling for a refocus. They say the onus of reversing, or at least stymying, the situation should fall on the big businesses and governments that have been too slow to act, not on individual consumer actions, like buying sustainably made clothes, divesting from the meat and dairy industry, or driving an electric car.
But outside of formal therapy and even activism, however that looks, Clayton has another suggestion for combating climate anxiety, and it's one that is surprising in its simplicity: Go outside, and take stock of that which boldly continues to exist.
"People who are anxious about climate change, it's partly about the survival of the species, but it's partly about the sense that, 'Something I care about is being destroyed,'" she says. "Remember that nature is not just a source of anxiety, it's also a source of replenishment and restoration."