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Noubar Afeyan is founder and CEO of Flagship Pioneering, and cofounder and chairman of Moderna.

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For an industry generally characterized by low probabilities of success and long timelines, how did this approach succeed on its first try against the SARS-CoV-2 virus, and in record time? What can be learned from this experience and how can it enable more effective, preemptive interventions to health threats?

For more than a quarter century, the vast majority of medicines used to treat or prevent disease came in one of two forms: small molecules or proteins. While DNA, short RNA, viruses, bacteria, and even human cells are all under active scientific and clinical development, their uses have been limited by various technical challenges to their safety, efficacy, or manufacturability. Alongside these alternatives, messenger RNA (mRNA) had also been considered for over 2 decades, but the adverse immune response caused by exogenous mRNA introduced into mammalian cells rendered those efforts unsuccessful.

By 2010 experiments in two academic labs (at the University of Pennsylvania [1] and Harvard University [2] ) had shown that mRNA with certain chemical modifications could be translated more efficiently into an encoded protein with lower adverse immune response. These findings led my colleagues and me to initiate a project we named LS18 (the 18th such scientific platform undertaken by Flagship Pioneering and the precursor to what became Moderna). Our aim? To invent the necessary chemical modifications, in vivo delivery technologies, mRNA design and optimization software, and automated fabrication and large-scale manufacturing process needed to render mRNA into a class of new human medicines.

Moderna spent the past decade combining bioengineering, chemical engineering, and systems engineering advances to create its mRNA platform and a large development pipeline of 24 mRNA-based therapeutics and vaccines. Many engineering advances and inventions were enabling to our technology, including the computational design of mRNA constructs for in vivo expression, automated systems to produce thousands of different mRNAs, purification and analysis technologies for this new class of molecules, the process for GMP manufacturing of lipid nanoparticle–encased mRNA, and the overall systems needed to go from sequence to product efficiently.

Despite the progress and over $2 billion spent, mRNA had still not yet been approved for use as a human medicine by early 2020. Covid-19 changed that almost overnight. Beginning in late January 2020 and at the urging of public health officials and scientists tracking the alarming spread of a mysterious virus, Moderna’s platform was put to use to design, fabricate, test, and scale up the production of mRNA-1273, the first vaccine against the SARS-CoV-2 pandemic virus to enter human trials. By leveraging the decade of platform development as well as an ongoing partnership between scientists at Moderna and the National Institutes of Health (NIH)’s National Institute of Allergy and Infectious Disease (NIAID), the company was able to design the mRNA vaccine 2 days after receiving the viral RNA code, produce and test small quantities during the following weeks, and deliver the vaccine to the NIH for the start of Phase 1 trials on human subjects within 42 days of sequence selection.

This speed and precision of vaccine design and production represented a significant performance leap compared to prior vaccine technologies. Nine months later, and after extensive Phase 3 testing in a diverse cohort of 30,000 subjects, the Moderna vaccine showed 94 percent efficacy and no severe adverse effects. The FDA authorized it for emergency use on December 18, 2020. To date more than 115 million doses have been administered in the United States.

What can we learn from this experience?

It is still quite early to draw all the lessons, but four observations about the past year may be worth considering.

First, when platform development precedes product development, the potential benefits are enormous. Although mRNA had not been used previously as a human medicine, there was an enormous body of platform development and research, without which the probability of success and immunological performance would not have been possible, especially at lightning speeds. Many of the advances made by the company were described in a large number of patent filings, enabling others to rapidly employ mRNA technology in their own covid-19 vaccine development efforts. To accelerate efforts to make and deploy vaccines across the globe, Moderna announced in October 2020 that it would not enforce its patents on mRNA vaccine technology during the pandemic period, allowing others to benefit from our decade of experimentation and refinement.

Second, information molecules hold the promise of reimagining medicine as we know it. As a code molecule, mRNA represents a completely novel class of medicines. An essential part of the flow of information from its stored form in cells (DNA) to the structurally and functionally active form (proteins), information encoded in mRNA is programmable, modular and predictably processed in all cells. These properties are not found in small molecule or protein drugs and offer great promise for future code-based medicines and therapeutics.

Furthermore, the synthesis of mRNA involves a single biochemical step converting a template DNA, after which purification and encapsulation into lipid nanoparticles using well-established manufacturing steps results in the final product. While unprecedented, the large-scale manufacture of mRNA vaccine proved less complex than the harder-to-scale cell or viral production approaches often used in biotechnology.

Third, accelerating drug development and responding quickly and effectively to pandemics relies on strong public-private partnerships. In Moderna’s case, established partnerships with the Defense Advanced Research Projects Agency and Biomedical Advanced Research and Development Authority, both of which funded mRNA programs, and collaborations with NIAID all preceded 2020, and flowed smoothly and productively in ways that accelerated development and deployment of the vaccine.

In addition, partnerships were forged with the NIH clinical network supporting the Phase 3 trials, highly engaged professionals at the US Food and Drug Administration advising on how such trials should be organized and performed, the Operation Warp Speed team’s coordination, logistical, and distribution support, as well as numerous commercial partners (e.g., Lonza and Catalent). The extensive and unprecedented collaboration network that helped Moderna succeed proved what can be achieved when the right incentives and determination for success are put in place.

Fourth, when facing a novel and uncharacterized threat, it is essential to run the experiment and have the courage to go “all in” rather than surrendering to conventional wisdom. Although there is much known about respiratory viruses and vaccine development, the uncertainty faced early in 2020 could have led to a very different outcome if Moderna and others had bowed to conventional wisdom about vaccine development timelines (slow), about deploying new technologies (risky), whether T cells were more important than antibody responses (likely), how long the effect would last (unclear), and so on. Despite the headwinds of skepticism and fear of the unknown, leaders at Moderna and other companies forged ahead, prioritizing the life-saving possibilities of being proven right while risking public rebuke and embarrassment if they were proven wrong.

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Taking RNAi from interesting science to impactful new treatments

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There are many hurdles to clear before a research discovery becomes a life-changing treatment for patients. That’s especially true when the treatments being developed represent an entirely new class of medicines. But overcoming those obstacles can revolutionize our ability to treat diseases.

Few companies exemplify that process better than Alnylam Pharmaceuticals. Alnylam was founded by a group of MIT-affiliated researchers who believed in the promise of a technology — RNA interference, or RNAi.

The researchers had done foundational work to understand how RNAi, which is a naturally occurring process, works to silence genes through the degradation of messenger RNA. But it was their decision to found Alnylam in 2002 that attracted the funding and expertise necessary to turn their discoveries into a new class of medicines. Since that decision, Alnylam has made remarkable progress taking RNAi from an interesting scientific discovery to an impactful new treatment pathway.

Today Alnylam has five medicines approved by the U.S. Food and Drug Administration (one Alnylam-discovered RNAi therapeutic is licensed to Novartis) and a rapidly expanding clinical pipeline. The company’s approved medicines are for debilitating, sometimes fatal conditions that many patients have grappled with for decades with few other options.

The company estimates its treatments helped more than 5,000 patients in 2023 alone. Behind that number are patient stories that illustrate how Alnylam has changed lives. A mother of three says Alnylam’s treatments helped her take back control of her life after being bed-ridden with attacks associated with the rare genetic disease acute intermittent porphyria (AIP). Another patient reported that one of the company’s treatments helped her attend her daughter’s wedding. A third patient, who had left college due to frequent AIP attacks, was able to return to school.

These days Alnylam is not the only company developing RNAi-based medicines. But it is still a pioneer in the field, and the company’s founders — MIT Institute Professor Phil Sharp, Professor David Bartel, Professor Emeritus Paul Schimmel, and former MIT postdocs Thomas Tuschl and Phillip Zamore — see Alnylam as a champion for the field more broadly.

“Alnylam has published more than 250 scientific papers over 20 years,” says Sharp, who currently serves as chair of Alnylam’s scientific advisory board. “Not only did we do the science, not only did we translate it to benefit patients, but we also described every step. We established this as a modality to treat patients, and I’m very proud of that record.”

Pioneering RNAi development

MIT’s involvement in RNAi dates back to its discovery. Before Andrew Fire PhD ’83 shared a Nobel Prize for the discovery of RNAi in 1998, he worked on understanding how DNA was transcribed into RNA, as a graduate student in Sharp’s lab.

After leaving MIT, Fire and collaborators showed that double-stranded RNA could be used to silence specific genes in worms. But the biochemical mechanisms that allowed double-stranded RNA to work were unknown until MIT professors Sharp, Bartel, and Ruth Lehmann, along with Zamore and Tuschl, published foundational papers explaining the process. The researchers developed a system for studying RNAi and showed how RNAi can be controlled using different genetic sequences. Soon after Tuschl left MIT, he showed that a similar process could also be used to silence specific genes in human cells, opening up a new frontier in studying genes and ultimately treating diseases.

“Tom showed you could synthesize these small RNAs, transfect them into cells, and get a very specific knockdown of the gene that corresponded to that the small RNAs,” Bartel explains. “That discovery transformed biological research. The ability to specifically knockdown a mammalian gene was huge. You could suddenly study the function of any gene you were interested in by knocking it down and seeing what happens. … The research community immediately started using that approach to study the function of their favorite genes in mammalian cells.”

Beyond illuminating gene function, another application came to mind.

“Because almost all diseases are related to genes, could we take these small RNAs and silence genes to treat patients?” Sharp remembers wondering.

To answer the question, the researchers founded Alnylam in 2002. (They recruited Schimmel, a biotech veteran, around the same time.) But there was a lot of work to be done before the technology could be tried in patients. The main challenge was getting RNAi into the cytoplasm of the patients’ cells.

“Through work in Dave Bartel and Phil Sharp's lab, among others, it became evident that to make RNAi into therapies, there were three problems to solve: delivery, delivery, and delivery,” says Alnylam Chief Scientific Officer Kevin Fitzgerald, who has been with the company since 2005.

Early on, Alnylam collaborated with MIT drug delivery expert and Institute Professor Bob Langer. Eventually, Alnylam developed the first lipid nanoparticles (LNPs) that could be used to encase RNA and deliver it into patient cells. LNPs were later used in the mRNA vaccines for Covid-19.

“Alnylam has invested over 20 years and more than $4 billion in RNAi to develop these new therapeutics,” Sharp says. “That is the means by which innovations can be translated to the benefit of society.”

From scientific breakthrough to patient bedside

Alnylam received its first FDA approval in 2018 for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, a rare and fatal disease. It doubled as the first RNAi therapeutic to reach the market and the first drug approved to treat that condition in the United States.

“What I keep in mind is, at the end of the day for certain patients, two months is everything,” Fitzgerald says. “The diseases that we’re trying to treat progress month by month, day by day, and patients can get to a point where nothing is helping them. If you can move their disease by a stage, that’s huge.”

Since that first treatment, Alnylam has updated its RNAi delivery system — including by conjugating small interfering RNAs to molecules that help them gain entry to cells — and earned approvals to treat other rare genetic diseases along with high cholesterol (the treatment licensed to Novartis). All of those treatments primarily work by silencing genes that encode for the production of proteins in the liver, which has proven to be the easiest place to deliver RNAi molecules. But Alnylam’s team is confident they can deliver RNAi to other areas of the body, which would unlock a new world of treatment possibilities. The company has reported promising early results in the central nervous system and says a phase one study last year was the first RNAi therapeutic to demonstrate gene silencing in the human brain.

“There’s a lot of work being done at Alnylam and other companies to deliver these RNAis to other tissues: muscles, immune cells, lung cells, etc.,” Sharp says. “But to me the most interesting application is delivery to the brain. We think we have a therapeutic modality that can very specifically control the activity of certain genes in the nervous system. I think that’s extraordinarily important, for diseases from Alzheimer’s to schizophrenia and depression.”

The central nervous system work is particularly significant for Fitzgerald, who watched his father struggle with Parkinson’s.

“Our goal is to be in every organ in the human body, and then combinations of organs, and then combinations of targets within individual organs, and then combinations of targets within multi-organs,” Fitzgerald says. “We’re really at the very beginning of what this technology is going do for human health.”

It’s an exciting time for the RNAi scientific community, including many who continue to study it at MIT. Still, Alnylam will need to continue executing in its drug development efforts to deliver on that promise and help an expanding pool of patients.

“I think this is a real frontier,” Sharp says. “There’s major therapeutic need, and I think this technology could have a huge impact. But we have to prove it. That’s why Alnylam exists: to pursue new science that unlocks new possibilities and discover if they can be made to work. That, of course, also why MIT is here: to improve lives.”

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• Published: 10 March 2016

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Escaped GMO canola plants persist long-term, but may be losing their extra genes

Us survey of roadside populations finds canola without engineered resistance to pesticides.

Populations of canola plants genetically engineered to be resistant to herbicides can survive outside of farms, but may be gradually losing their engineered genes, reports a new study led by Cynthia Sagers of Arizona State University, US, published May 22 in the open-access journal PLOS ONE.

The hypothesis has been put forward that if any genetically engineered crop plants escape farm fields, they will be short-lived. This would make them unlikely to take over wild areas or spread their inserted genes, called transgenes, to wild populations of closely related plants. However, there have been few studies to see if populations of these "feral" crop plants can in fact survive in the wild long term.

In the new study, researchers conducted a large-scale survey of populations of genetically engineered canola living along roadsides in North Dakota, repeating a survey they initially conducted in 2010. They found that the total number of feral canola plants in the sample had decreased and populations of the plants became less common over time. When they tested the plants for herbicide resistance, they saw that the types of herbicides the plants were resistant to had shifted over time, likely due to changes in the varieties farmers were planting. Importantly, almost one quarter of the feral plants were not resistant and did not contain transgenes -- up from 19.9% in 2010 to 24.2% in 2021 -- suggesting that these populations may be losing their transgenes.

The researchers hypothesize that feral canola populations may be under evolutionary pressure to shed the transgenes, which could happen if the engineered canola are at a disadvantage once they are no longer being cultivated on a farm. Further genetic analysis could help clarify the plants' origins and yield more information on how long transgenes can persist in the environment.

Steven Travers adds: "The assumption that transgenic crop varieties will be restricted to the benign conditions of ag fields and not inter-mix with natural plant populations can be rejected. Self-sustaining, long-term feral populations of canola (some transgenic and some not) are a world-wide phenomenon and as such emphasize the need for more research on how de-domestication works, the extent to which it impacts natural populations, and the risks that the adventitious presence of transgenes might represent to agriculture."

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Journal Reference :

• Steven E. Travers, D. Bryan Bishop, Cynthia L. Sagers. Persistence of genetically engineered canola populations in the U.S. and the adventitious presence of transgenes in the environment . PLOS ONE , 2024; 19 (5): e0295489 DOI: 10.1371/journal.pone.0295489

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