COVID vaccines that use mRNA to prime the immune system to recognize SARS2 (emerging cognoscenti shorthand for SARS CoV-2) have rocked the world by the speed with which they were developed and their potency against this novel virus. The idea of using mRNA to achieve medical goals is not new but making it work has taken decades since Katalin Karikó started down this road in 1990. The timing of success could not have been better; despite the social, political, economic and logistical challenges, these vaccines will end up saving literally millions of lives during COVID’s first few years. The fact that they will not save many, many more is down to politics, economics, logistics and culture, not the brilliant vaccines themselves.
mRNA itself isn’t a single substance such as penicillin or aspirin. Instead, it’s a class of molecules with a nearly infinite number of possible variants. It serves to carry instructions from the DNA in a cell’s nucleus to the protein-making machinery outside the nucleus. Proteins are the agents that do stuff in the body: a cell chooses what to do by the proteins it makes. The DNA inside each cell in your body is the same, yet kidney cells make different proteins than ovary cells or brain cells, because the messenger RNA is delivering different instructions.
Scientists realized that they could borrow these protein factories by inserting mRNA into cells, and if they could custom-create mRNA molecules, they’d have a very powerful tool with many different possible applications. Figuring out how to get these synthetic organic molecules past the immune system without triggering a berserker response took a while, but that problem is now well-controlled. None of this was easy to accomplish, but they’ve done it: yay science! There should be Nobel Prizes coming for a few of these folks.
Mastery of mRNA technology creates a broad new landscape of preventative and therapeutic possibilities, and already a lot of intriguing R&D is underway. Some of these initiatives will pan out, some will not, but the sheer breadth of possibilities is an arresting sight. Here’s a flyover of this emerging mRNA landscape, from COVID to Infinity and Beyond.
COVID
Our battle against SARS2 is like a seemingly endless dance routine. We’re living through a real-time Pas de Cinq as the vaccines keep adapting to the virus while the virus keeps adapting to ever-evolving human immunity and behavior, and to evolving therapeutic interventions. It’s quite a dance between vaccine, virus, immunity, behavior, and medicine, with frequent rapid costume changes and a quirky score. Luckily, mRNA technology supports quick revisions of the vaccine when necessary: it may be that COVID protection will require an updated booster every year, or two, or three—the cycle time isn’t known yet. mRNA vaccines can perform exceptionally well in this Busby Berkeley model as long as their pharmaceutical masters see fit to rehearse the footwork.
Influenza
Before SARS2 arrived, many epidemiologists would have bet that the most likely cause of a new global pandemic would be some new version of influenza, and this threat remains. Even without a severe pandemic, the flu is a dangerous disease, killing an estimated 400-800,000 people annually around the world, depending on exactly which variants are surging each year. Current flu vaccines reduce the risk of infection, severe disease and death significantly, but not nearly as well as the mRNA vaccines reduce those risks from COVID. Compared to existing flu vaccine technology, mRNA vaccines can be tailored to each year’s most likely flu variants much later—that is, much closer to the beginning of the flu season. As a result, they will have a better chance to be well-suited to the variants that emerge as the most dangerous. Our current flu vaccine regimen is beneficial, but far from perfect, as the vaccines tend to only partially hit their targets each year. A significant improvement in matching vaccines to flu variants would save many lives and decrease the risk of a severe influenza pandemic.
Other Infectious Diseases
The list of diseases against which mRNA vaccines are being developed (or at least discussed in front of the investment community…) is a rogue’s gallery of obnoxious microorganisms: malaria, HIV-AIDS, HSV-1 & HSV-2 (Herpes), Zika, CMV (Cytomegalovirus) RSV (Respiratory Syncytial Virus), Epstein Barr Virus, Tuberculosis, and more. These different vaccines are in different stages of development, but some of the results so far are tantalizing. For example, in a recent trial a herpes vaccine provided virtually perfect protection in mice against both HSV-1 and HSV-2. Given that efforts to create vaccines against these viruses have been unsuccessful for forty years, protecting mice so thoroughly is a significant step forward. It’s party time for mice: human trials are next.
Orphan Diseases
Orphan diseases are those which are too rare to attract investment in prevention and cure—no pharmaceutical company or government is going to drop a billion dollars into fighting a disease which kills 50 or 100 people a year, but there are a lot of orphans, and the damage adds up. For example, there’s a virus called Nipah, which is estimated to have infected 700 or so people total since it was identified in Malaysia in 1999. It kills 50-75% of people it infects and then afflicts the survivors with various ongoing miseries. It also causes the slaughter of lots of pigs to prevent spread to humans (pigs are a vector between fruit bats and humans). It would be good to have a vaccine against Nipah, since we can’t know whether it might someday mutate to become more contagious and threaten to spread widely, but it would be hard to justify committing the resources to develop a Nipah vaccine the old (slow and expensive) way, since those resources could probably do more good deployed against a disease that kills a lot more people. mRNA technology could make it possible to develop and test a Nipah vaccine at a tiny fraction of the cost and time required to do it using traditional methods. Moderna, in fact, lists Nipah as one of its targets. Over time, a portfolio of vaccines against rare-but-bad pathogens would become part of a global pandemic prevention strategy, allowing public health services to ring fence outbreaks with a rapid surge of surrounding vaccination to cut off transmission.
Multi-Disease Vaccines
We’re already familiar with the idea of combined vaccines: children’s vaccination schedules include shots which combine protection against Diphtheria, Tetanus and Pertussis, and some of those even throw in more diseases—Polio, for example, and Hepatitis B. Several labs are now researching the feasibility of combining mRNA vaccines—one jab to simultaneously arm the immune system against two or more pathogens, such as COVID, Influenza, and RSV all at once. This would reduce the number of separate jabs/year people need to brave, which would probably increase vaccine acceptance.
Cancers
Vaccines are typically deployed preventatively, but there are also cases where they can be used therapeutically—to control symptoms or bring about a cure after the disease has begun. Cancers are a major target here, because many of them evolve the ability to elude the immune system. Considering that they begin as normal cells, this is not surprising. Researchers believe that mRNA vaccines may be especially effective against cancers, since they can be so precisely and rapidly tuned for each type and sub-type, and even for each patient. A cancer vaccine would rev up the immune system to target exactly the cancer each individual patient has. One researcher estimated that once this system is up and running, it would take “six weeks” to develop custom vaccines for individual patients’ cancers.
Before SARS2 came along, BioNTech was working on an mRNA therapy against pancreatic cancer, which is a very nasty disease. It is one of the so-called KRAS-driven cancers, named for the particular kind of mutation that causes it: other KRAS cancers include non-small cell lung cancer and colorectal cancer, so success against pancreatic cancer could lead to opportunities against several other tough customers. Research is also underway against melanoma, several head and neck cancers, and breast cancer. One promising application under consideration is to prevent regrowth after surgical removal of tumors. About 40% of surgically-removed tumors return, so this would be a highly beneficial application. If mRNA therapies are effective, the impact on cancer treatment could be dramatic.
Auto-immune Diseases
There are over 80 named autoimmune diseases, in which the immune system attacks one’s own body. The best-known include Diabetes (Type 1), MS (Multiple Sclerosis), Lupus, Crohn’s Disease, Rheumatoid Arthritis, and Psoriasis. For unknown reasons, autoimmune diseases are increasingly common in modern societies, especially in women. mRNA vaccines may be able to protect against autoimmune diseases by inducing very precise antigen-specific tolerance without causing inflammation.
Uğur Şahin and Özlem Türeci—the same awesome power couple who co-founded BioNTech, developed the Pfizer COVID vaccine and are working on mRNA cancer treatments—also found time to test such a vaccine against MS in mice, and it was startlingly effective. Their team speculates that mRNA vaccines may be able to prevent the development of autoimmune diseases in people with known high risk, stop the progression of these diseases in people who have already developed them, and perhaps roll back the diseases to some extent. They note that such vaccines would be “quick and cheap” to develop.
Tissue and Organ Repair
Many people who survive a heart attack are left with a damaged heart, which, too often, leads to their death within a few years. Unlike some species, humans do not naturally regenerate damaged heart tissue. Researchers have discovered that mRNA therapy appears able to facilitate the regrowth of both blood vessels and muscle in damaged hearts. It may also perform the same service to damaged kidneys (another major health challenge) and damaged skin.
Research is also underway on an mRNA treatment with the potential to reduce the damage done by Alzheimer’s Disease. Alzheimer’s is associated with a reduction in the prevalence of a specific mRNA molecule in a certain part of the brain. mRNA technology now exists to synthesize that molecule and deliver it to where the deficiency is found, and this appears to slow the progress of the disease.
Genetic Diseases
A technology borrowed from bacteria called CRISPR makes it possible to precisely edit DNA and RNA. CRISPR makes synthetic mRNA possible, and mRNA can return the favor by delivering CRISPR to the cells where it can correct genetic diseases. The first test of this idea in humans involved shutting down the production of a damaging protein by liver cells, and it worked. This is another case of a large category—genetic diseases—with many different challenges. The half-dozen most prevalent major genetic diseases in the US are Sickle Cell Disease, Cystic Fibrosis, Tay-Sachs Disease, Hemophilia, Huntington’s Disease, and Muscular Dystrophy. There are hundreds more. To the extent that mRNA technology can facilitate the application of CRISPR technology to these diseases, it can make yet another contribution to improved health across a broad swath of the population.
The Big Picture
Scientists right now are testing mRNA technology against a wide array of health problems to see if they can find new solutions. They won’t all work, but we can expect a wave of advances from those that do. The targets they have chosen are such big ones—infectious diseases, genetic diseases, cancers, heart disease, autoimmune disorders, Alzheimer’s, organ failure—that the total potential impact could be very substantial. The pandemic accelerated the arrival of this new banquet of opportunities by several years at least.
The COVID pandemic is teaching us lessons. One of them is that the science only goes so far: the mRNA vaccines have been far less beneficial than they could have been by now for reasons outside the labs and bioreactor facilities. We need and don’t have a systematic, global way to react rapidly and effectively against pandemic threats. We need and don’t have much more effective and respected public health infrastructure in many countries, including the US. We need and don’t have the capacity to inoculate the whole world rapidly sometimes. We need and don’t have a civil-enough society to act in concert against a huge common threat. If we want to have a healthier future, we’d better have at these don’t-haves.
Great article Tom!
Thank you for breaking it down and explaining the amazing potential of mRNA. Now we need to find out how to assure that such vaccines are available globally and that everyone will get them.
Linda Jenning–exactly. Ed Yong has a terrific story in The Atlantic about how public health lost out to medicine, and how we need to revitalize it. If people don’t take advantage of medical breakthroughs, and surround them with appropriate non-medical choices (ventilation, for example), the brilliance will do far less good than it could.
Who are some of the local leaders in developing mRNA vaccines and in expanding the uses of this technology? And are there some research institutions around the nation that deserve commendation?
Here’s the BBC playing catch-up to Post Alley… There’s some great additional info in this story about mRNA’s potential. https://www.bbc.com/future/article/20211122-could-mrna-make-us-superhuman