Rich Mancuso suffered from herpes for most of his adult life. The 49-year-old New Jersey resident was miserable. He had at least two to three outbreaks every month with painful and unsightly sores on his face and in his eyes, yet the drugs he took to control the disease had terrible side effects--agonizing headaches and severe stomach disturbances.
Last week, the FDA launched a criminal investigation to determine whether the biotech behind the vaccine had violated regulations.
So in 2016, he took an unusual step: he was flown to St. Kitt's, an island in the West Indies, where he participated in a clinical trial of a herpes vaccine, and received three injections of the experimental therapeutic during separate visits to the island. Within a year, his outbreaks stopped. "Nothing else worked," says Mancuso, who feels like he's gotten his life back. "And I've tried everything on the planet."
Mancuso was one of twenty genital herpes sufferers who were given the experimental vaccine in tests conducted on the Caribbean island and in hotel rooms near the campus of Southern Illinois University in Springfield where the vaccine's developer, microbiologist William Halford, was on the faculty. But these tests were conducted under the radar, without the approval or safety oversight of the Food and Drug Administration or an institutional review board (IRB), which routinely monitor human clinical trials of experimental drugs to make sure participants are protected.
Last week, the FDA launched a criminal investigation to determine whether anyone from SIU or Rational Vaccines, the biotech behind the vaccine, had violated regulations by aiding Halford's research. The SIU scientist was a microbiologist, not a medical doctor, which means that volunteers were not only injected with an unsanctioned experimental treatment but there wasn't even routine medical oversight.
On one side are scientists and government regulators with legitimate safety concerns....On the other are desperate patients and a dying scientist willing to go rogue in a foreign country.
Halford, who was stricken with a rare form of a nasal cancer, reportedly bypassed regulatory rules because the clock was ticking and he wanted to speed this potentially life-altering therapeutic to patients. "There was no way he had enough time to raise $100 million to test the drugs in the U.S.," says Mancuso, who became friends with Halford before he died in June of 2017 at age 48. "He knew if he didn't do something, his work would just die and no one would benefit. This was the only way."
But was it the only way? Once the truth about the trial came to light, public health officials in St. Kitt's disavowed the trial, saying they had not been notified that it was happening, and Southern Illinois University's medical school launched an investigation that ultimately led to the resignation of three employees, including a faculty member, a graduate student and Halford's widow. Investors in Rational Vaccines, including maverick Silicon Valley billionaire Peter Thiel, demanded that all FDA rules must be followed in future tests.
"Trials have to yield data that can be submitted to the FDA, which means certain requirements have to be met," says Jeffrey Kahn, a bioethicist at Johns Hopkins University in Baltimore. "These were renegade researchers who exposed people to unnecessary risks, which was hugely irresponsible. I don't know what they expected to do with the research. It was a waste of money and generated data that can't be used because no regulator would accept it."
But this story illuminates both sides of a thorny issue. On one side are scientists and government regulators with legitimate safety concerns who want to protect volunteers from very real risks—people have died even in closely monitored clinical trials. On the other, are desperate patients and a dying scientist willing to go rogue in a foreign country where there is far less regulatory scrutiny. "It's a balancing act," says Jennifer Miller, a medical ethicist at New York University and president of Bioethics International. "You really need to protect participants but you also want access to safe therapies."
"Safety is important, but being too cautious kills people, too—allowing them to just die without intervention seems to be the biggest harm."
This requirement—that tests show a drug is safe and effective before it can win regulatory approval--dates back to 1962, when the sedative thalidomide was shown to have caused thousands of birth defects in Europe. But clinical trials can be costly and often proceed at a glacial pace. Typically, companies shell out more than $2.5 billion over the course of the decade it normally takes to shepherd a new treatment through the three phases of testing before it wins FDA approval, according to a 2014 study by the Tufts Center for the Study of Drug Development. Yet only 11.8 percent of experimental therapies entering clinical tests eventually cross the finish line.
The upshot is that millions can suffer and thousands of people may die awaiting approvals for life saving drugs, according to Elizabeth Parrish, the founder and CEO of BioViva, a Seattle-based biotech that aims to provide data collection platforms to scientists doing overseas tests. "Going offshore to places where it's legal to take a therapeutic can created expedited routes for patients to get therapies for which there is a high level of need," she says. "Safety is important, but being too cautious kills people, too—allowing them to just die without intervention seems to be the biggest harm."
Parrish herself was frustrated with the slow pace of gene therapy trials; scientists worried about the risks associated with fixing mutant DNA. To prove a point, she traveled to a clinic in Colombia in 2015 where she was injected with two gene therapies that aim to improve muscle function and lengthen telomeres, the caps on the end of chromosomes that are linked to aging and genetic diseases. Six months later, the therapy seemed to have worked—her muscle mass had increased and her telomeres had grown by 9 percent, the equivalent of turning back 20 years of aging, according to her own account. Yet the treatments are still unavailable here in the U.S.
In the past decade, Latin American countries like Columbia, and Mexico in particular, have become an increasingly attractive test destination for multi-national drug companies and biotechs because of less red tape.
In the past decade, Latin American countries like Columbia, and Mexico in particular, have become an increasingly attractive test destination for multi-national drug companies and biotechs because of less red tape around testing emerging new science, like gene therapies or stem cells. Plus, clinical trials are cheaper to conduct, it's easier to recruit volunteers, especially ones who are treatment naïve, and these human tests can reveal whether local populations actually respond to a particular therapy. "We do have an exhaustive framework for running clinical trials that are aligned with international requirements," says Ernesto Albaga, an attorney with Hogan Lovells in Mexico City who specializes in the life sciences. "But our environment is still not as stringent as it is in other places, like the U.S."
The fact is American researchers are increasingly testing experimental drugs outside of the U.S., although virtually all of them are monitored by local scientists who serve as co-investigators. In 2017 alone, more than 86 percent of experimental drugs seeking FDA approval have been tested, at least in part, in foreign countries, like Mexico, China, Russia, Poland and South Africa, according to an analysis by STAT. However, in places without strict oversight, such as Russia and Georgia, results may be fraudulent, according to one 2017 report in the New England Journal of Medicine. And in developing countries, the poor can become guinea pigs. In the early 2000s, for example, a test in Uganda of an AIDS drug resulted in thousands of unreported serious adverse reactions and 14 deaths; in India, eight volunteers died during a test of the anti-clotting drug, Streptokinase—and test subjects didn't even know they were part of a clinical trials.
Still, "the world is changing," concludes Dr. Jennifer Miller of NYU. "We need to figure out how to get safe and effective drugs to patients more quickly without sacrificing too much protection."
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.