We need a global network of ‘living’ biofoundries.
Distributed, multi-product, RNA-based manufacturing capabilities will provide increased access to diverse biologics and sustainable pandemic response.
In one of the greatest scientific accomplishments of our generation, mRNA technology has demonstrated the ability to change the timeline for developing and delivering a new vaccine from years to months. And the entire world was witness to that demonstration. The development of an mRNA-based vaccine for COVID-19 took just 63 days from release of the virus sequence to first dosing in humans, leading to accelerated clinical trials and ultimately billions of doses manufactured. The new mRNA vaccines have demonstrated efficacies in the high 90s, with minimal side effects, and have been manufactured by two different RNA technology firms to date, with others adding further production capacity.
The scale of this on-going achievement was made possible because, unlike the established existing vaccine manufacturing techniques, RNA technology shifts the most difficult and complex parts of manufacturing — the key proteins needed for a vaccine — to the natural bioreactor that is the human body. This shift meant the mRNA vaccine could deliver the instructions for how to make the antigen, or spike protein, needed to train our immune systems rather than the antigen itself. The development of lipid nanoparticles (LNPs) ensured that instructions would arrive intact to our cells – a critical element of the mRNA vaccine delivery and effectiveness. Importantly, this RNA-based approach holds promise for treatments beyond vaccines and infectious diseases to diverse biologics as treatments for cancer, metabolic disorders, cardiovascular conditions, and autoimmune diseases.
Given this vaccine breakthrough, it would be reasonable to expect a wave of activity to discover, develop, and deliver new RNA-based biologics – a diversity of organizations; academic, small biotech, private and public research centers around the world flooding clinical facilities with novel, investigational products. All these products could then be tested against diseases that cause millions of deaths per year; thus providing access to these new products, while also securing protection against the next pandemic.
While we see continued and increasing global investments to scale existing mRNA manufacturing capabilities, such investments alone will not be enough to increase the number, diversity, affordability, and pace of discovery for these new biologic treatments, or to provide continuing access to agile, state-of-the-art manufacturing processes likely needed for rapid response to another pandemic.
What’s holding us back? The discovery and development of RNA-based products is still subject to the same, existing limitations chronically afflicting biologics: difficult access to current good manufacturing practices (cGMP) material for clinical trials as well as long and large investments (4-8 years and $300-$500 million dollars) in bespoke, manufacturing processes at dedicated facilities. This limits innovation and creates prohibitive production costs.
Today, RNA scientists trying to develop an innovative product are limited to using laboratory-grade materials in pre-clinical studies. Outside of one of the few biopharma corporations investing in cGMP for RNA-based biologics, most researchers have limited or no access to the know-how and resources required to develop a small-scale manufacturing process required for clinical trials. And even within those corporate environments, lacking a product with an expected net present value nearing a billion dollars, it would be challenging to get priority in the large-scale manufacturing strategy of the company.
R3 seeks to change the dynamics and costs of biologics development and production, addressing the limitations of current manufacturing by establishing RNA as a versatile, deployable, standardized, multi-product platform technology, that: 1) in non-emergency times provides developers and researchers with access to cGMP-formulated RNA for the development and production of a diversity of viable RNA-based products, and 2) in emergency times shifts to needed products at speeds & quantities sufficient to mount a globally coordinated, regionally focused response to a pandemic.
The opportunity for R3. The limitations in today’s RNA-based production bears similarities with the limitations faced by the semiconductor industry at the end of the 1970s. In the twenty years following the invention of the first integrated circuit in the late 1950s, the design of semiconductor-based products was almost exclusively confined to a handful of large, vertically integrated companies that could afford the investments required by customized ISO-certified manufacturing processes. Designing a new semiconductor-based product was limited to employees within those companies and often came with adjustment and refinements to manufacturing processes. As one measure of how access to manufacturing constrained innovation, on average there were only 3 to 4 new semiconductor start-ups created globally each year during the decades between 1958 and 1978.
Then, in the decade after 1978, the number of new start-ups more than tripled – tens to dozens of new semiconductor start-ups. What happened to accelerate the number, diversity, and pace of semiconductor innovation?
Two related developments changed the rules of the game for the semiconductor industry. The first was the publication in 1978 of “Introduction to VLSI Systems” by Mead & Conway, outlining the elements of Very Large Scale Integration (VLSI) for the design of semiconductor circuits. Mead & Conway decoupled the design of a circuit from the fabrication of a circuit using digital design, simulation, and verification tools. These tools also captured and characterized different, specific fabrication processes using high-level, parametric descriptions for those processes. The decoupling of design from fabrication and the parametric abstraction of fabrication processes made it possible for a greater number and diversity of people to design integrated circuits (in the decade following publication, 1,000 to 10,000 times more people, ranging from students to experienced chip designers). Just as importantly, the decoupling and parametric abstraction enabled any of these designs to be fabricated at any of a multiplicity of fabrication sites at scale and seamlessly.
The resulting demand for fabrication services from chip designers created the market space for a second breakthrough. In 1987, the first “pure-play” foundry was stood up – a semiconductor company exclusively manufacturing third-party designs, without developing or marketing their own products. With the availability of pure-play foundries, it became possible for a new type of company to emerge – fabless semiconductors companies. These companies designed and delivered chips as their products – notable examples include Broadcom and Nvidia – but had no fabrication facilities of their own.
Vertically integrated companies with captive fabrication facilities thrived alongside the new fabless companies as both types of companies delivered a greater number and diversity of semiconductor products, growing the semiconductor industry at a compound annual growth rate of more than 10% over the last 40 years.
Since then, continued process improvements, the emergence of different lines for different classes of products, and optimization of production load balancing, has led to new speed and vibrancy in the ecosystem, further fueling additional breakthroughs. Indeed, whenever an industry has succeeded in raising the level of abstraction to allow more innovators to participate and reduce the barriers to product delivery, seemingly explosive growth of innovation has been the result. We need this type of technological advance for RNA-based products.
The R3 program has two goals: one, to increase exponentially the number of biologic products that can be designed, developed, and produced every year, reducing their costs and increasing equitable access; and two, to create a self-sustaining network of manufacturing facilities providing globally distributed, state-of-the-art surge capacity to meet future pandemic needs.
Duccio Medini, PhD has expertise in extracting knowledge from biomedical data with advanced data analytics, and co-founded the pangenomics discipline. He led global teams contributing to the successful development of vaccines from early discovery to post-implementation surveillance, including the development of the first universal vaccine against serogroup B meningitis. He earned his PhD in Physics from the University of Perugia, with a residency at Northeastern University.
Who are eligible Wellcome Leap program performers?
Performers are from universities and research institutions: small, medium and large companies (including venture-backed); and government or non-profit research organizations. We encourage individuals, research labs, companies, or small teams to apply in program areas best aligned with their expertise and capabilities. It is not necessary to form a large consortium or a single team to address all thrusts or an entire program goal in an abstract or proposal. Indeed, one of the benefits of our programs is that we actively facilitate collaboration and synergies dynamically among performers as we make progress together toward the program’s goals.