Katalin Karikó, pictured, and Drew Weissman won the Nobel Prize for advances in mRNA research that led to the first Covid vaccines.
When Drew Weissman received a call from Katalin Karikó in the early morning hours this past Monday, he assumed his longtime research partner was calling to share a nascent, nagging idea. Weissman, a professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, and Karikó, a professor at Szeged University and an adjunct professor at UPenn, both struggle with sleep disturbances. Thus, middle-of-the-night discourses between the two, often over email, has been a staple of their friendship. But this time, Karikó had something more pressing and exciting to share: They had won the 2023 Nobel Prize in Physiology or Medicine.
The work for which they garnered the illustrious award and its accompanying $1,000,000 cash windfall was completed about two decades ago, wrought through long hours in the lab over many arduous years. But humanity collectively benefited from its life-saving outcome three years ago, when both Moderna and Pfizer/BioNTech’s mRNA vaccines against COVID were found to be safe and highly effective at preventing severe disease. Billions of doses have since been given out to protect humans from the upstart viral scourge.
“I thought of going somewhere else, or doing something else,” said Katalin Karikó. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
Unlocking the power of mRNA
Weissman and Karikó unlocked mRNA vaccines for the world back in the early 2000s when they made a key breakthrough. Messenger RNA molecules are essentially instructions for cells’ ribosomes to make specific proteins, so in the 1980s and 1990s, researchers started wondering if sneaking mRNA into the body could trigger cells to manufacture antibodies, enzymes, or growth agents for protecting against infection, treating disease, or repairing tissues. But there was a big problem: injecting this synthetic mRNA triggered a dangerous, inflammatory immune response resulting in the mRNA’s destruction.
While most other researchers chose not to tackle this perplexing problem to instead pursue more lucrative and publishable exploits, Karikó stuck with it. The choice sent her academic career into depressing doldrums. Nobody would fund her work, publications dried up, and after six years as an assistant professor at the University of Pennsylvania, Karikó got demoted. She was going backward.
“I thought of going somewhere else, or doing something else,” Karikó told Stat in 2020. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
A tale of tenacity
Collaborating with Drew Weissman, a new professor at the University of Pennsylvania, in the late 1990s helped provide Karikó with the tenacity to continue. Weissman nurtured a goal of developing a vaccine against HIV-1, and saw mRNA as a potential way to do it.
“For the 20 years that we’ve worked together before anybody knew what RNA is, or cared, it was the two of us literally side by side at a bench working together,” Weissman said in an interview with Adam Smith of the Nobel Foundation.
In 2005, the duo made their 2023 Nobel Prize-winning breakthrough, detailing it in a relatively small journal, Immunity. (Their paper was rejected by larger journals, including Science and Nature.) They figured out that chemically modifying the nucleoside bases that make up mRNA allowed the molecule to slip past the body’s immune defenses. Karikó and Weissman followed up that finding by creating mRNA that’s more efficiently translated within cells, greatly boosting protein production. In 2020, scientists at Moderna and BioNTech (where Karikó worked from 2013 to 2022) rushed to craft vaccines against COVID, putting their methods to life-saving use.
The future of vaccines
Buoyed by the resounding success of mRNA vaccines, scientists are now hurriedly researching ways to use mRNA medicine against other infectious diseases, cancer, and genetic disorders. The now ubiquitous efforts stand in stark contrast to Karikó and Weissman’s previously unheralded struggles years ago as they doggedly worked to realize a shared dream that so many others shied away from. Katalin Karikó and Drew Weissman were brave enough to walk a scientific path that very well could have ended in a dead end, and for that, they absolutely deserve their 2023 Nobel Prize.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
Due to federal regulations, access to abortion medications is restricted, despite their record of safety and efficacy.
A few days before Christmas 2015, Paige Alexandria, a 28-year-old counselor at the Austin Women's Health Center in Texas, found out she was pregnant.
Alexandria had missed the cutoff for a medication abortion by three days.
"It was an unplanned pregnancy, and instantaneously I knew I needed an abortion," Alexandria recalls. Already a mother of two children, one with special needs, a third child was not something Alexandria and her husband felt prepared to take on. "Mentally, I knew my limit. I wasn't prepared for a third and I didn't want one," she says.
At an ultrasound appointment one week later, scans showed she was a little over eight weeks pregnant. Alexandria opted to have an abortion as soon as possible, and preferably with medication. "I really wanted to avoid a surgical abortion," she says. "It sounded a lot more invasive, and I'm already uncomfortable with pap smears and pelvic exams, so I initially went in wanting to do the pill."
But at the time, medication guidelines stipulated that one of the pills, called Mifepristone, could only be prescribed to end a pregnancy at eight weeks gestation or earlier – Alexandria had missed the cutoff by three days. If she wanted to end the pregnancy, she would need to undergo a surgical abortion, otherwise known as a vacuum aspiration abortion.
With a vacuum aspiration abortion, doctors dilate the cervix and manually aspirate out the contents of the uterus. Medication abortion, on the other hand, consists of the patient taking two pills – Mifepristone, which blocks the hormones that help the pregnancy develop, and Misoprostol, which empties the uterus over a period of days, identical to a miscarriage.
Alexandria was upset about the change of plans but resolute in her decision to end the pregnancy. "The fact that I didn't really have a choice in how my procedure was performed has made the experience just a little more sensitive for me," she says. She scheduled the earliest available appointment for a surgical abortion.
Paige Alexandria would have chosen to terminate her pregnancy with medication if the regulations were less stringent.
(Photo courtesy of Alexandria)
Like Alexandria, many people looking to terminate a pregnancy opt to do so with medication. According to research from the Guttmacher Institute, medication abortions accounted for nearly 40 percent of all abortions in the year 2017 – a marked increase from 2001, when medication abortions only accounted for roughly five percent of terminations. Taken 24-48 hours apart, Mifepristone and Misoprostol have a 95-99 percent success rate in terminating pregnancies up to 63 days – or nine weeks – of gestation, according to the American College of Obstetrics and Gynecology (ACOG).
But even though the World Health Organization (WHO) considers medical abortion to be highly safe and effective, the medication is still carefully guarded in the United States: Mifepristone is only available for terminating pregnancies up to 10 weeks gestation, per the FDA, even though limited research suggests that both are safe and effective at terminating pregnancies between 12 and 20 weeks.
Additionally, a separate set of regulations known as a Risk Evaluation and Mitigation Strategy (REMS) means that patients can only take Mifepristone under specific circumstances. Mifepristone must be distributed in person by a healthcare provider – usually interpreted in most states as a doctor or nurse practitioner – who has registered with the drug's manufacturer. The medication cannot be distributed through a pharmacy, so doctors who wish to provide the drug must stock the medication in-office, and both the provider and the patient must sign a form that warns them of the "risk of serious complications associated with Mifepristone," according to the FDA.
"REMS is a set of restrictions that the FDA puts on the distribution of drugs it considers dangerous or risky in some way," says Dr. Elizabeth Raymond, an OB-GYN and senior medical associate at Gynuity Health Projects. Although not always called REMS, these restrictions have been imposed on Mifepristone since the medication was approved by the FDA in 2000, Raymond says.
Raymond is part of a growing number of physicians and researchers who want to eliminate the REMS requirements for Mifepristone, also known by its brand name Mifeprex. In 2017, Raymond and several other physicians authored a paper in the New England Journal of Medicine (NEJM) arguing that Mifepristone is extremely safe and needlessly over-regulated.
"When the FDA first approved [Mifepristone] and imposed these requirements, they might have made sense 19 years ago when there was limited information about the use of this treatment in the United States," says Dr. Daniel Grossman, director at Advancing New Standards in Reproductive Health at UCSF and co-author of the 2017 report in the NEJM. "Now, after 19 years, it's clear that this medication is very safe, and safer than a lot of others available in a pharmacy."
Since 2000, Mifepristone has been implicated in 19 deaths, making its mortality rate 0.00063 percent.
According to their research, over three million people have taken Mifepristone since it was approved in 2000. Since then, Mifepristone has been implicated in 19 deaths, making its mortality rate 0.00063 percent. Even then, the risk is inflated, Grossman says.
"The requirement is that practitioners need to report any deaths that occur after taking these medications, and so you'll see deaths included in that figure which are homicides or suicides or something unrelated to taking Mifepristone," says Grossman. In contrast, Acetaminophen – better known as Tylenol – was associated with 458 overdose deaths between 1990 and 1998, as well as 56,000 emergency room visits and 26,000 hospitalizations. Sildenafil, better known as Viagra, was linked to 762 deaths in the first twenty months after it was approved by the FDA. Yet neither Tylenol nor Viagra have been burdened with the same REMS restrictions as Mifepristone.
"It's clearly about more than just the safety of the medication at this point," says Grossman. "It's more about stigma related to abortion and politics."
For people who want a medication abortion, the REMS requirements mean they often need to take off work to schedule a doctor's appointment, arrange for transportation and childcare, and then arrange an additional doctor's appointment days afterward to take the second dose of medication. While surgical abortion procedures are quicker (usually a one-day outpatient procedure, depending on gestation), many people prefer having the abortion in the comfort of their home or surrounded by family instead.
Paige Alexandria, who counsels people seeking abortions at her job, says that survivors of sexual violence often prefer medical abortions to surgical ones. "A lot of time survivors have a trauma associated with medical instruments or having pelvic exams, and so they're more comfortable taking a pill," she says.
But REMS also creates a barrier for healthcare providers, Grossman says. Stocking the medication in-office is "a hassle" and "expensive," while others are reluctant to register their name with the drug manufacturer, fearing harassment or violence from anti-choice protestors. As a result, the number of practitioners willing to provide medical abortions nationwide is severely limited. According to Grossman's own research published in the journal Obstetrics and Gynecology, 28 percent of OBGYNs admitted they would administer medication abortions if it were possible to write a prescription for Mifepristone rather than stock it in-office.
Amazingly, the restrictions on Mifepristone have loosened since it first came on the market. In 2016, the FDA updated the guidelines on Mifepristone to allow its use until 10 weeks gestation, up from eight weeks. But doctors say the REMS restrictions should be eliminated completely so that people can obtain abortions as early as possible.
"REMS restrictions inhibit people from being able to get a timely abortion," says Raymond, who stresses that abortion is generally more comfortable, more affordable, and safer for women the earlier it's done. "Abortion is very safe no matter when you get it, but it's also easier because there's less risk for bleeding, infections, or other complications," Raymond says. Abortions that occur earlier than eight weeks of gestation have a complication rate of less than one percent, while an abortion done at 12 or 13 weeks has a three to six percent chance of complications.
And even for people who want a medication abortion early on in their pregnancy, REMS restrictions make it so that they may not have time to obtain it before the 10-week period lapses, Raymond says.
"If you're seven weeks pregnant but it takes you three weeks to figure out travel and childcare arrangements to go into the doctor and take this medication, now you're at the cutoff date," she says. "Even if you manage to get an abortion at nine weeks, that's still a later gestational age, and so the risks are increased."
In 2016, at a little over nine weeks gestation, Alexandria completed her abortion by having a D&E. But because she didn't have anyone to drive her home after the procedure, she wasn't able to have sedation throughout, something she describes as "traumatic."
"I had the abortion completely aware and coherent, and paired with the fact that I hadn't even wanted a surgical abortion in the first place made it harder to deal with," Alexandria says.
"When you're just a day or two past eight weeks and you want an abortion – why is medication not immediately available?"
Today, Alexandria shares her story publicly to advocate for abortion care. Although she doesn't regret her surgical abortion and acknowledges that not everyone experiences surgical abortion the same way she did, she does wish that she could have gone a different route.
"If I had to do it over, I would still try to do the pill, because [the surgical abortion] was such a terrifying experience," she says. "When you're just a day or two past eight weeks and you want an abortion – why is medication not immediately available? It just doesn't make sense."
