Concerns about the vaccines and the overall handling of the pandemic are well-founded, but don’t let that take away from a once-in-a-generation medical breakthrough that will power new, innovative treatments for decades.
Concerns about the vaccines and the never-ending coronavirus crisis shouldn’t detract from the accomplishment of creating them: The new mRNA technology powering the Pfizer and Moderna vaccine is a once-in-a-generation breakthrough, complete with promise for innovative new treatments in the future. The ability to create synthetic strands of the molecule that instructs our cells to create proteins is a potential revolution in medicine close to 50 years in the making. For the first time ever, we’ve reprogrammed our bodies at a cellular scale and done so in a way that is easily injectable into hundreds of millions of people.
The incredible story behind these vaccine treatments actually starts in the 1970s. Scientists have long believed it possible to take advantage of the body’s natural process to build proteins, offering treatments tailored uniquely to the ailment. The idea is brilliant in its simplicity: Our cells already use messenger RNA to construct the substances they need from organic molecules in their cytoplasm.
In the natural process, the mRNA is transcribed from our DNA in the nucleus of the cell, think of it as copying a recipe. The DNA in the nucleus is the master cookbook. It contains the recipes for all the proteins our bodies are capable of producing, but like secret family recipes passed down from generation to generation, DNA is far too precious to actually take into the kitchen and risk getting damaged. The equivalent of a spill or a spot of grease would destroy it and the entire cell would be corrupted, unable to operate properly.
Instead, mRNA is a print out of the recipe whenever a protein is needed. The mRNA exits the nucleus and instructs the machinery of the cell on the ingredients (and the order of assembly) required to build the protein. The beauty of the process is that mRNA doesn’t actually build the protein or include any of the molecules or cellular apparatus to do so, the ingredients and appliances are all in the kitchen of the cytoplasm. As its name suggests, mRNA purely a messenger.
Therefore, if we were able to harness this natural process, all we need to do is send new instructions into the kitchen to produce the proteins we want. To some extent, this is exactly what viruses do. Viruses don’t store their genetic material in DNA like we (along with all of the animals, plants, and protozoa on the planet) do. They only use RNA. The virus attaches to the membrane of the cell, inserts the RNA and then hijacks the machinery, taking over the kitchen and instructing the cell to make copies of the virus rather than the normal proteins required for healthy operation. Ultimately, so many copies of the virus are produced that the cell explodes, and the new copies repeat the process on other cells.
The idea of harnessing the power of mRNA for medical purposes was first proposed by Katalin Karikó in 1978. At the time, she was a young scientist in Szeged, Hungary who ultimately migrated to the United States in the early 1980s. From there, she wallowed in obscurity for decades: The prospect always made sense in theory, but in practice it was incredibly difficult, especially before modern DNA reading techniques and encoding technology first pioneered by the Human Genome Project.
Though researchers at the University of Wisconsin managed to get the process to work in mice in 2001, human applications remained daunting. There were two key problems. First, mRNA floating around the body is attacked mercilessly by the immune system for obvious reasons. The body doesn’t like foreign objects in general, and foreign genetic objects look an awful lot like potentially disease causing viruses. Second, if the body did mistake the synthetic RNA for a virus, it could trigger an out of control immune response, making the situation even worse for the patient.
Dr. Karikó was undeterred, however, even after she was demoted by the University of Pennsylvania in 1995 because of an inability to raise funds for her cutting edge research. “Every night I was working: grant, grant, grant,” Karikó recalls of the need to retain funding. “And it came back always no, no, no.” On top of the demotion, she also had a cancer scare and her husband was stuck in Hungary with a visa issue. “I thought of going somewhere else, or doing something else,” she explains. “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.”
She pressed on, and in 2005 the promise of her research began to bear fruit. Working with a long-time collaborator, Drew Weissman, an MD and PhD, they discovered what was triggering the body to attack the synthetic RNA. Messenger RNA is made up of four building blocks known as nucleosides, but for some reason one of them was out of whack in the synthetic version, a gear that didn’t fit into the body’s machinery and caused it to respond. Ultimately, they were able to replace the ill-fitting gear with a substitute and avoid the immune-response.
The achievement still remained largely under the radar in little read research papers, but enough people started to take notice that two companies were born, Moderna (literally taking its name from “modified” and “RNA”) and BioNTech. BioNTech is a German company, founded by a married couple, Ugur Sahin and Özlem Türeci. “There was a lot of skepticism in the industry when we started, because this was a new technology with no approved products,” Türeci told The Atlantic. “Drug development is highly regulated, so people don’t like to deviate from paths with which they have experience.”
Somehow, both companies soldiered on for a decade and a half before one of their products was finally approved, the coronavirus vaccines. Fortuitously, Pfizer had signed a deal with BioNTech in 2018 to create an mRNA vaccine for the flu that has not been released to date. Philip Dormitzer, head of Pfizer’s viral-vaccines research and development told The Atlantic, “The technology initially appealed to us for the flu because of its great speed and flexibility. You can edit mRNA very quickly. That is quite useful for a virus like the flu, which requires two updated vaccines each year, for the Northern and Southern Hemisphere.”
This research was repurposed for the coronavirus vaccine. “It was really a case of our researchers swapping the flu protein for the coronavirus spike protein,” Dormitzer explained. “It turned out that it wasn’t that big a leap.” Armed with decades of research and modern supercomputers, Moderna created the blueprint for their vaccine in only 48 hours. They were in clinical trials less than 2 months after receiving the genetic code of the coronavirus.
The coronavirus vaccines work by instructing our bodies cells to create the distinctive “spike” protein that gives the virus its unique look. The mere appearance of the spike protein prompts the immune system to respond as if it were dealing with the real virus, though the virus itself isn’t present, just the spike. In essence, the vaccine tricks the body into thinking it’s sick by offering a distinctive marker to produce the necessary antibodies. Because our cells already deal with mRNA all the time, the strands dissolve in the cytoplasm after the spike protein is created. In addition, cells have existing processes in place to prevent mRNA from entering the cell nucleus and affecting the genetic makeup.
In short, the vaccine delivers a recipe to ourselves to produce a piece of the virus, and our bodies take over from there. The process leverages cellular machinery that evolved over billions of years, meaning major long term side effects highly unlikely. The real risk is that your body thinks it’s sick and responds accordingly, but that’s a risk of every vaccine.
To be clear: Personally, I think vaccinating healthy people with no chance of dying from the disease is an asinine waste of time, money, and effort. If it were up to me, I would vaccinate only high risk groups like seniors and people with comorbidities, but that shouldn’t detract from appreciating the breakthrough in medical technology we’ve achieved, a breakthrough almost 50 years in the making.
The question now is what comes next for synthetic mRNA technologies.
Malaria seems to be the first application after a patent was approved for a treatment last month. Malaria is a tricky disease, technically caused by a plasmodium that shifts its shape to defy our immune systems, responsible for more than 400,000 deaths per year. The potential malaria vaccine uses a new spin on mRNA, known as self-amplifying RNA, which further replicates in the body. “The replication function of saRNA is critical, because it’s not vaccines that prevent infection but vaccinations that prevent infection,” said Richard Bucala, co inventor of the treatment and a scientist at Yale School of Medicine. “The Pfizer and Moderna vaccines need a lot of mRNA, and it’s expensive to make…With saRNA, we could inject one-hundredth of the material to have the same effect. That would make it easier to scale against a widespread disease.”
Individualized cancer treatments are also on the horizon. In fact, BioNTech is already working on them right now, though the situation is much more complex than a traditional vaccine. In order to treat cancer, every patient would get their own custom mRNA, designed to match the unique genome of the cancer in our bodies. Given that Moderna turned around the unique mRNA for coronavirus in 48 hours, BioNTech believes they can develop a unique therapy for each patient in a similar manner.
Future applications are limited only by our own imagination. If we can instruct cells to create proteins, it is conceivable we can instruct them to create insulin in diabetes patients, neurotransmitters and other brain chemicals for Alzheimer’s and Parkinson’s, even regrow tissue. Of course, mRNA technology has its detractors. “The technology that works for one epidemic might not work for the next one, and you won’t know what works until you try it,” said Peter Hotez from the Baylor College of Medicine. “That’s why I say it’s too soon to call mRNA vaccines a miracle. They might not work against the next target.”
One thing is for sure: Karikó will be leading the charge. She’s currently in a well deserved post as Senior Vice President at BioNTech, overseeing all of their mRNA work. Given she’s devoted her life to the subject, I’m willing to bet more miracles are in store.
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