From the article by Tim Hwang: The article goes into detail about these things: In Part III, he makes some recommendations:
From the article by Tim Hwang:
This paper reckons with this incongruity: post hoc, mRNA vaccines were clearly a major breakthrough. But for a long period, investigators like Karikó and Weissman and startups like Moderna and BioNTech languished in relative obscurity. Why were mRNA vaccines not developed and made practical for use significantly earlier?
There are pragmatic reasons for asking this question: if mRNA vaccines had been available as a public health tool before the emergence of a global emergency, they would have saved many lives.2 Follow-on innovations in applying mRNA technologies to address other public health threats would have been available years earlier. By understanding the structural frictions that slowed development in this case, we may be able to identify broader reforms that allow society to capture the benefits of key breakthrough technologies earlier.
Reviewing the historical progression of mRNA vaccine development suggests three primary frictions significantly delayed the advent of the technology:
Perceived viability of mRNA: The development of mRNA vaccines took place against the backdrop of a history of disappointing results in adjacent technologies. The poor reputation of DNA vaccines, which had captured imaginations in the 1990s fight against HIV but had largely not lived up to their promise, shaped perceptions about the viability of mRNA vaccines. mRNA was also widely perceived to be a fragile molecule, difficult to work with, and impractical for mass manufacturing. This perception worked to limit academic interest, funding, and corporate support for pursuing mRNA vaccines and therapeutics as a focus of research and development.
Vaccines as an unprofitable research field: Pharmaceutical companies underwrite and set the agenda for researching the next generation of treatments. mRNA vaccines presented an unattractive business prospect, even if one considered them viable to create. Vaccines as a category tend to be less favored by pharmaceutical companies, since demand for them can be highly unpredictable and margins typically low. This worked to limit the level of industry effort dedicated to translating laboratory findings into applied practices for manufacturing and delivering mRNA vaccines at scale.
Specialization in research vs entrepreneurship: The duo of Karikó and Weissman were the first to make some of the major discoveries needed to turn mRNA vaccines into a reality. While both were gifted researchers, both appear to have been less well-suited to the task of popularizing and commercializing their work. This too delayed the development of the technology by limiting awareness of critical knowledge in the broader research community and hindering efforts by Karikó and Weissman themselves to bring their breakthroughs to market.
The article goes into detail about these things:
For one, Karikó and Weissman’s work failed to become common knowledge even within the community of researchers specifically working on the therapeutic applications of mRNA. Luigi Warren and Derrick Rossi – whose research would become the basis for Moderna – focused on how to use mRNA to reprogram cells at Harvard Medical School in 2007-8. Warren struggled to insert mRNA into a cell without rejection, the same problem Karikó and Weissman had wrestled with and solved years before. Warren was “on the verge of giving up on his project,” until a stray reference to Karikó and Weissman’s work from an assistant professor at a nearby lab put him on the right track.45 In the several years following the publication of their 2005 paper, Karikó and Weissman only received two invitations to speak about the work. Had the duo been more successful in disseminating their results more prominently, other researchers may have been able to advance progress towards mRNA vaccines faster.
In Part III, he makes some recommendations:
Intervention 1: Increase the variance of research funding
Grants and other funding allocated to mRNA vaccine research in the 1990s and 2000s were limited in part because of a general sense that the approach was impractical. The fragility of mRNA made it an unlikely candidate as a vaccine platform, and the lackluster history of related approaches in attacking HIV was discouraging.
Skepticism was likely a reasonable scientific assessment given the facts that were known at the time. But, the record suggests that pessimism was grounded more in theoretical considerations and analogies to other approaches rather than conclusive scientific failure. Failure to explore further resulted in a major missed opportunity, given the uniquely high social impact that having mRNA vaccines earlier would have had.
One institutional reform that may have alleviated this issue would be to use mechanisms that encourage funders to make higher variance, heterodox bets against this kind of scientific consensus. This might include “golden ticket” mechanisms that allow reviewers that feel strongly about a research proposal to fund a project even against the consensus of their peers.52 Similarly, funding programs might be launched to deliberately offer “last shot” funding for potentially high-impact areas that see a period of declining funding and researcher activity.53 These might counter a natural risk-aversion that leads researchers to abandon problems too early in the face of high-profile failures, as they arguably did in the mRNA case. These mechanisms might have particular applicability in cases parallel to mRNA, where expert judgments are based more on analogies to similar problems and where the technology in question would have a major social impact if viable.
The merit of such an approach is bolstered by examining the funders that unusually did choose to fund mRNA research, even during the period in which it faced major skepticism. These organizations did so in part because they were free to prioritize more speculative, high-risk exploration. The specific reasons for this vary. Dan Wattendorf – who led the DARPA ADEPT program that funded mRNA work in the 2010s – attributes the agency’s willingness to support mRNA work to an organizational norm of providing managers like himself free rein to direct their programs.
The Bill and Melinda Gates Foundation was also an early supporter of mRNA vaccines, providing a $20M grant to Moderna in 2016 and later $55M to BioNTech in 2019. These investments were based in part on the personal interest of Gates in advancing vaccine technologies, and since the foundation prioritized finding promising but overlooked methods in related fields …
Intervention 2: Address market failures in the “scientific marketplace”
Intervention 3: Support research entrepreneurialism
From the article by Tim Hwang:
The article goes into detail about these things:
In Part III, he makes some recommendations: