The Next Massachusetts Miracle

This essay is adapted and expanded from a speech delivered at the 2022 MassBio State of the Possible Conference on May 5, 2022. An adapted excerpt was also published in the Boston Globe on May 13, 2022.

At Flagship, we start our scientific explorations by asking “What If?” The point of this starting question is to imagine a future outcome or capability, unconstrained by what seems possible today:

• What if we could uncover and use human-commensal viruses to deliver nucleic acid therapeutics safely and repeatedly? Exploring and eventually answering this question led to Ring Therapeutics.

• What if red blood cells could be used to deliver therapeutic proteins and not just transport oxygen? This question led to Rubius Therapeutics.

• What if patients could produce biologic medicines inside their own bodies? This question led us to found LS18 — our 18th life science company — in 2010. This company is now better known as… Moderna.

What mRNA vaccines have accomplished has been hailed as nothing short of miraculous, which is fitting, since the company and its innovation emerged from what I think of as the second “Massachusetts Miracle” — the rise and eventual global preeminence of this area’s remarkable biotech sector and its collective effort to fight COVID. Of course, the idea of a miracle flies in the face of the scientific community’s basic goal to explain the world through scientific and natural principles. This so-called miracle was actually the product of the ambitions of entrepreneurs and the development of a supporting ecosystem.

These same enabling factors could be leveraged again to realize the next “Massachusetts Miracle” on the horizon. For those unfamiliar, however, it may be useful to provide some reference for the first “Massachusetts Miracle” before diving into what’s next.

PART I: The Massachusetts Miracle

About 100 years ago, Boston began a long chapter of sustained decline: losing industries, losing jobs, and losing population for most of the next 60 years. Even while much of the U.S. enjoyed growth and increased prosperity, particularly after World War 2, the region faltered and fell behind. Manufacturing was moving out of city centers; the automobile was becoming the dominant means of transport, which made moving goods in high-density cities like Boston harder; and the advent of air conditioning and better public health measures made living in the sunbelt more habitable and attractive.

As hard as it might be to imagine today, by the 1970s, Boston was increasingly written off as a dying factory town, destined to decay and diminish like cities in the American Rust Belt. But those prognosticators were overlooking a critical difference, Boston and Cambridge’s dominance in the most important products of the decades to come, big brains and big ideas.

From Harvard to Mass General to MIT, Boston and Cambridge had a centuries-long head start in scholarship, education, and innovation, and in the 1980s, rising demand for college-educated workers, a concentration of scholars and scientists, and an established financial services sector able to bankroll emerging companies shifted the Massachusetts economy into high gear, and fueled what became known as the “Massachusetts Miracle:”

Unemployment shrunk from more than 12% in 1975, the highest for any industrial state, to less than 3%, the lowest
State and local taxes, which had been the highest per capita of any of the states, decreased to the eighth lowest, while personal income grew faster than in any other state
Population decline halted, housing prices rose, and new businesses based on emerging technologies started to rapidly expand.

By the 1970s, Boston was increasingly written off as a dying factory town... But those prognosticators were overlooking a critical difference, Boston and Cambridge’s dominance in the most important products of the decades to come, big brains and big ideas.

It is hard to overstate the importance of our area institutions in making this miracle happen. MIT drove innovation in the new information age and booming computing industry. Harvard Business School, churned out talented MBAs and produced the first venture capital firm, which was integral in funding successful technology businesses. Multiple universities opened off-campus labs along Route 128, drawn to newly developed industrial parks that still offered proximity to campuses.

These labs began to spin out technology companies that dotted Route 128, originally operating on government contracts to produce electronics and computer technology for the military. MIT’s Lincoln Lab spun out Digital Equipment Corp. (DEC), which introduced the first minicomputer. At about $18,000, these computers were smaller and cheaper than a mainframe, and quickly became the prevailing IT system. Other minicomputer competitors, as well as makers of parts, components, and complementary products joined the ecosystem along Route 128, including companies like Data General and Raytheon, creating what was dubbed “America’s Technology Highway.” Massachusetts was poised to become the technology and innovation capital of the world.

Except… it didn’t.

Northern California and Silicon Valley sprinted ahead through the turn of the century and the years that followed, birthing everything from HP, Intel, Sun Microsystems, Apple, Google, eBay, Tesla, and so on. While the two areas were built on similar foundations of educational institutions and government and local funding, Silicon Valley became the center of tech while Route 128 receded. According to an analysis by AnnaLee Saxenian, Dean of School of Information at UC Berkeley, diverging local innovation ecosystems were to blame.

Unlike their Massachusetts counterparts which had rigid, vertically integrated corporate structures, across the country, Silicon Valley operated with a network-based industrial system that promoted collective learning and flexibility. Companies that made specialty products adjusted designs based on input from related industries and institutions. They also fostered a free-flowing labor market that encouraged entrepreneurship, risk-taking, and experimentation, in other words, lots and lots of startups. The “startup company,” which I consider the single biggest innovation that drives economic and societal value during the past 70+ years, found its fertile soil out west. And, this wasn’t just limited to tech companies but also biotech where many of the leading startups were founded on that same fertile soil of entrepreneurship and risk capital.

But for the past couple of decades, starting with the mapping of the human genome and accelerating through many biomedical breakthroughs and novel therapeutic platforms, innovation momentum began to shift back toward Massachusetts.

PART II: The Second Massachusetts Miracle, the Rise of Biotech, and the Attack on COVID

But for the past couple of decades, starting with the mapping of the human genome and accelerating through many biomedical breakthroughs and novel therapeutic platforms, innovation momentum began to shift back toward Massachusetts. The new products and platforms now driving progress center on the personal computer known as the human body.

These technologies marry new biological insights and advanced computational capabilities to treat problems of disease as computational problems with programmable solutions. The life sciences are also becoming increasingly important, alongside clean energy innovations, in combatting climate change. As mentioned in my annual letter this year, just as there is little gained from healing an organ inside a dying body, prolonging human health and longevity won’t matter without a healthy planet to call home.

This time around, the innovation corridor is centered not out on Route 128 but in Cambridge, MA. Back when those minicomputer companies were pushing out to the suburbs, MIT took the lead in revitalizing Cambridge’s vacant factories, setting up lab space first occupied by tech companies, and later biotech. Real estate developers including Alexandria Real Estate Equities, BioMed Realty Trust, and Boston Properties also helped to establish space and facilities to house a badly needed tax base for the city of Cambridge.

Biogen became the first biotech to receive a genetic engineering license from the city and soon opened in the area. While the company was technically founded in Geneva, two of the company’s founders had close ties to Harvard and MIT. Genzyme and the Genetics Institute followed soon after.

Novartis’ move to Kendall in 2001 is noted as a major catalyst for the domination of biotech in the area. Other large pharmaceutical competitors soon followed. These large companies were critical to the success and growth of smaller startups and early-stage companies, providing funding through investment and experienced talent. They helped to fertilize a community of homegrown biotech startups — including a company founded at the tailend of the century — Flagship Pioneering.

The area in and around Kendall Square has become the epicenter of the biotech boom. The same strengths that fueled the first “Massachusetts Miracle” — top-notch academic institutions, smart people and their bold ideas, and ready funding to scale the companies that result — are fueling company creation and job growth once again.

If you walk a short distance from the Flagship offices, you will pass no fewer than 300 large- and medium-sized biotech companies packed into seven or eight blocks. I would guess the number of small biotech startups and very-early-stage companies could be double, maybe triple that number. You’ll also pass venture capital firms and private equity groups that aggregate investors and capital to grow those young companies and fund their path toward clinical products.

Real estate developers also help foster this innovation ecosystem. The city’s largest corporate tax payer today, Alexandria Real Estate Equities, has amassed a huge portfolio of Cambridge real estate dedicated to life sciences valued at more than $1.5 billion as of 2020. The company has put an emphasis on creating dedicated space for emerging companies, first stepping into Cambridge to provide affordable short-term leases at the Science Hotel building. It has continued to provide options for start-ups, including opening Alexandria LaunchLabs in 2018 and working on a new development at 161 First Street.

Demand for space will only continue as the biotech ecosystem grows. At Flagship Pioneering alone, we have spun out more than 70 companies in Cambridge, including Ring Therapeutics, Foghorn Therapeutics, Inari, Indigo, Seres Therapeutics, Moderna, and many others. Flagship and the companies we’ve founded now total more than 5,500 employees, over 100 products in various stages of clinical development, and more than three million square feet of lab and office space.

I contend that there are compelling reasons for biotech entrepreneurs to double down on this region: close proximity to the world’s leading universities, powerhouse research institutions, readily available risk capital, a rich life-sciences network, and entrepreneurial talent.

While we have been encouraged to build a presence in other states and countries, I contend that there are compelling reasons for biotech entrepreneurs to double down on this region: close proximity to the world’s leading universities, powerhouse research institutions, readily available risk capital, a rich life-sciences network, and entrepreneurial talent. The same iconoclastic thinking that challenges technological orthodoxy also stimulates social innovation, propelled by cultural diversity and manifested by leadership here in Massachusetts in everything from universal health-care coverage to fundamental human rights.

And it’s not just biotech doubling down: most large pharma companies have a major presence here, too. While smaller biotech startups can benefit from big pharma money and talent, biotech serves as the pharma industry’s innovation supply chain. An estimated 64% of drugs in late-stage development are being developed by biotech companies built around a novel technology, rather than by big pharma.

It is no wonder that when the world was brought to its knees two years ago by a fast-moving and deadly pandemic, it was the companies in this area that brought about the second “Massachusetts Miracle:” diagnostics, vaccines, and treatments to battle COVID and save lives in record speed. Moderna wasn’t the only company making an impact, though of course I am incredibly proud of the speed at which our safe and effective vaccine was developed, tested, manufactured and deployed. Companies and organizations like Ginkgo, ThermoFisher Scientific, MilliporeSigma, CIC Health, the Broad Institute, Hologic, Meenta, and others created tests and diagnostics to detect the virus and others developed new therapeutics to treat those who contracted it. These efforts, and the millions of lives saved, are simply miraculous!

A decade ago, I was asked to give a talk about what was making Kendal Square such a special space. Community, capital, connections, competence, capacity, cooperation, competition, creativity, and concentration came to mind. Since then, I have come to realize I was missing two additional words beginning with C: courage and conviction. These factors are critical to enabling true transformations, what Flagships calls, pioneering innovations. These highly elusive properties are why I believe we can speak of miracles today, and we will need to summon both if we want to do it again.

PART III. Preemptive Health and Medicine

What the second “Massachusetts Miracle” taught us is this: When we act collectively, innovate with urgency, and take risks in the name of massive potential impact, miracles can happen.

Let’s use this lesson to come together to make our region, and our companies, the architects of yet another “Massachusetts Miracle.” The miracle within our collective grasp is transforming our current sick-care system to a true health-care system. Orienting health and medicine toward preemptive interventions before illness or disease take hold, not reactionary treatments once we are sick.

Advances in biology and computation, especially the most recent advances in machine learning, make it possible. The same science, the same type of interventions, the same biomarker discovery being deployed once we are sick can be put to use upstream of disease. We must decide to secure our health instead of resigning ourselves to getting sick and only then receiving treatment.

The miracle within our collective grasp is transforming our current sick-care system to a true health-care system. Orienting health and medicine toward preemptive interventions before illness or disease take hold, not reactionary treatments once we are sick.

Ask yourself a few what-if questions and let your imagination wonder…

What if our government took responsible for securing our health the way they are responsible for our physical security through our national defense?
What if we could catch disease very early, or even before it is a disease, and intervene to delay it or completely derail it?
What if we could detect the precursors that precede most diseases and then intervene or preempt them before they advance?
What if we could, from a small draw of blood, detect pre-cancer activity in our cells, as well as the tissue of origin?
What if we could measure our antibody levels at home, evaluating our risk and planning accordingly, especially when contagious disease cases are high?
What if we could design a Global Pathogen Shield, developing vaccines for viral variants that have yet to emerge?
What if we could computationally specify potent antibodies designed to bind to the most immutable parts of a pathogenic antigen?

Once your imagination convinces you that there is vast impact to be created and tremendous value that will result, it’s easier to summon the courage and conviction to put that imagination into action. I believe all of this is possible and even desperately needed to improve our lifespan and more importantly healthspan, i.e., how long we can live in a healthy state free of disease, as well as decrease spending on healthcare. We can’t afford to spend the current 20% of GDP and, in the coming decades, likely 30% on healthcare.

Our goal should be to direct the molecular understanding and precision tools we have developed to treat late-stage disease towards pre-diseases. Can we think about eradicating, which means literally pulling up by the roots, disease? We have done this in certain cancers, many viral infections — why can’t we do it with many more? We just witnessed what disease prevention at the population scale can do in the form of vaccines, and we know what treatments to diseases can do through pharmaceutical agents, but we have yet to broadly realize the practice of eradicating a specific disease before it takes hold. We call this space Preemptive Health and Medicine.

Massachusetts has all the tools to make this miracle and more happen, if we summon the will. Our universities have the leading-edge research that powers new discoveries increasingly reliant on both biological understanding and sophisticated artificial intelligence; our companies have an increasingly comprehensive understanding of the physiology of illness and disease and its precursors to design products that disrupt disease; our hospitals carry out the most advanced translational and clinical work in the world and can facilitate the application of these new approaches; and our lawmakers have shown leadership in innovating health system reform.

Now, I know many may think this is utterly impossible, but if all we worked on were things that seemed possible, we wouldn’t be discussing miracles. Sometimes we have to be willing to make the seemingly impossible eventually possible, even inevitable. The place to do it is Massachusetts, and the time to start is right now.

Story By

Noubar Afeyan

Noubar Afeyan is founder and CEO of Flagship Pioneering. He is also co-founder and Board Chairman of Moderna. Founded in 2000, Flagship is an enterprise where entrepreneurially-minded scientists invent seemingly unreasonable solutions to challenges…