E-cigarettes are big business. In 2017, American consumers bought more than $250 million in vapes and juice-filled pods, and spent $1 billion in 2018. By 2023, the global market could be worth $44 billion a year.
"My nine-year-old actually knows what Juuling is. In many cases the [school] bathroom is now referred to as 'the Juuling room.'"
Investors are trying to capitalize on the phenomenal growth. In July 2018, Juul Labs, the company that owns 70 percent of the U.S. e-cigarette market share, raised $1.25 billion at a $16 billion valuation, then sold a 35 percent stake to Phillip Morris USA owner Altria Group in December. The second transaction valued the company at $38 billion. While the traditional tobacco market remains much larger, it's projected to grow at less than two percent a year, making the attractiveness of the rapidly expanding e-cigarette market obvious.
While Juul and other e-cigarette manufacturers argue that their products help adults quit smoking – and there's some research to back this narrative up – much of the growth has been driven by children and teenagers. One CDC study showed a 48 percent rise in e-cigarette use by middle schoolers and a 78 percent increase by high schoolers between 2017 and 2018, a jump from 1.5 million kids to 3.6 million. In response to the study, F.D.A. Commissioner Scott Gottlieb said, "We see clear signs that youth use of electronic cigarettes has reached an epidemic proportion."
Another study found that teenagers between 15 and 17 were 16 times more likely to use Juul than people aged 25-34. In December, Surgeon General Jerome Adams said, "My nine-year-old actually knows what Juuling is. In many cases the [school] bathroom is now referred to as 'the Juuling room.'"
And the product is seriously addictive. A single Juul pod contains as much nicotine as a pack of 20 regular cigarettes. Considering that 90 percent of smokers are addicted by 18 years old, it's clear that steps need to be taken to combat the growing epidemic.
But who should take the lead? Juul and other e-cigarette companies? The F.D.A. and other government regulators? Schools? Parents?
The Surgeon General's website has a list of earnest possible texts that parents can send to their teens to dissuade them from Juuling, like: "Hope none of your friends use e-cigarettes around you. Even breathing the cloud they exhale can expose you to nicotine and chemicals that can be dangerous to your health." While parents can attempt to police their teens, many experts believe that the primary push should come at a federal level.
The regulation battle has already begun. In September, the F.D.A. announced that Juul had 60 days to show a plan that would prevent youth from getting their hands on the product. The result was for the company to announce that it wouldn't sell flavored pods in retail stores except for tobacco, menthol, and mint; Juul also shuttered its Instagram and Facebook accounts. These regulations mirrored an F.D.A. mandate two days later that required flavored e-cigarettes to be sold in closed-off areas. "This policy will make sure the fruity flavors are no longer accessible to kids in retail sites, plan and simple," Commissioner Gottlieb said when announcing the moves. "That's where they're getting access to the e-cigs and we intend to end those sales."
"There isn't a great history of the tobacco industry acting responsibly and being able to in any way police itself."
While so far, Gottlieb – who drew concerns about conflict of interest due to his past position as a board member at e-cigarette company, Kure – has pleased anti-smoking advocates with his efforts, some observers also argue that it needs to go further. "Overall, we didn't know what to expect when a new commissioner came in, but it's been quite refreshing how much attention has been paid to the tobacco industry by the F.D.A.," Robin Koval, CEO and president of Truth Initiative, said a day after the F.D.A. announced the proposed regulations. "It's important to have a start. I certainly want to give credit for that. But we were really hoping and feel that what was announced...doesn't go far enough."
The issue is the industry's inability or unwillingness to police itself in the past. Juul, however, claims that it's now proactively working to prevent young people from taking up its product. "Juul Labs and F.D.A. share a common goal – preventing youth from initiating on nicotine," a company representative said in an email. "To paraphrase Commissioner Gottlieb, we want to be the off-ramp for adult smokers to switch from cigarettes, not an on-ramp for America's youth to initiate on nicotine. We won't be successful in our mission to serve adult smokers if we don't narrow the on-ramp... Our intent was never to have youth use Juul products. But intent is not enough, the numbers are what matter, and the numbers tell us underage use of e-cigarette products is a problem. We must solve it."
Juul argues that its products help adults quit – even offering a calculator on the website showing how much people will save – and that it didn't target youth. But studies show otherwise. Furthermore, the youth smoking prevention curriculum the company released was poorly received. "It's what Philip Morris did years ago," said Bonnie Halpern-Felsher, a professor of pediatrics at Stanford who helped author a study on the program's faults. "They aren't talking about their named product. They are talking about vapes or e-cigarettes. Youth don't consider Juuls to be vapes or e-cigarettes. [Teens] don't talk about flavors. They don't talk about marketing. They did it to look good. But if you look at what [Juul] put together, it's a pretty awful curriculum that was put together pretty quickly."
The American Lung Association gave the FDA an "F" for failing to take mint and menthol e-cigs off the market, since those flavors remain popular with teens.
Add this all up, and in the end, it's hard to see the industry being able to police itself, critics say. Neither the past examples of other tobacco companies nor the present self-imposed regulations indicate that this will succeed.
"There isn't a great history of the tobacco industry acting responsibly and being able to in any way police itself," Koval said. "That job is best left to the F.D.A., and to the states and localities in what they can regulate and legislate to protect young people."
Halpern-Felsher agreed. "I think we need independent bodies. I really don't think that a voluntary ban or a regulation on the part of the industry is a good idea, nor do I think it will work," she said. "It's pretty much the same story, of repeating itself."
Just last week, the American Association of Pediatrics issued a new policy statement calling for the F.D.A. to immediately ban the sale of e-cigarettes to anyone under age 21 and to prohibit the online sale of vaping products and solutions, among other measures. And in its annual report, the American Lung Association gave the F.D.A. an "F" for failing to take mint and menthol e-cigs off the market, since those flavors remain popular with teens.
Few, if any people involved, want more regulation from the federal government. In an ideal world, this wouldn't be necessary. But many experts agree that it is. Anything else is just blowing smoke.
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 the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip 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."
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."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.