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Navigating the Polycrisis

In Flagship’s 2024 Annual Letter, Founder & CEO Noubar Afeyan reflects on navigating the polycrisis and how to harness uncertainty and disequilibrium to propel progress and make the impossible possible.

Growing up in Lebanon, I learned English as a second language after Armenian (and before Arabic and French) and I delight in discovering new English words (and sometimes, to the dismay of my family and colleagues, even inventing my own). Though The Financial Times referred to polycrisis as “the year in a word” for 2022, I didn’t discover the term “polycrisis” until 2023, and it would be my nominee for the 2023 word of the year.

The term is thought to have been introduced by complexity theorist Edgar Morin and coauthor Anne Brigitte Kern in the mid-1990’s, but was more recently popularized by historian Adam Tooze, who described the phenomena this way:

A problem becomes a crisis when it challenges our ability to cope and thus threatens our identity. In the polycrisis the shocks are disparate, but they interact so that the whole is even more overwhelming than the sum of the parts. At times one feels as if one is losing one’s sense of reality.

The current polycrisis encompasses the confluence of economic turbulence, climate change, deeply fractured politics, two global wars, threats to democracy, loss of trust in institutions, and the continuing dislocations triggered by the Covid pandemic. While these mutually amplifying crises may unsettle our sense of the future, the polycrisis has me mining my past.

While an engineering undergraduate at McGill University, my classmates and I learned to understand systems influenced by temperature changes, forces, or variations in concentrations. When these factors are not balanced or equal, we say the system is in a state of disequilibrium. Disequilibrium naturally resolves itself toward balance, and engineers learn to harness this change, transforming it into useful energy that propels vehicles, powers smartphones, or produces useful chemicals.

I see our current state of interwoven crises — or polycrisis — as a state of disequilibrium. While this state feels charged, chaotic, and uncomfortable, it indicates great potential — if properly harnessed — for change and transition. For “poly-opportunity.”

At Flagship Pioneering, we persist in this state of discomfort — probing at the edges — knowing that it is at the edge where opportunity lies. We intentionally throw ourselves off balance to stimulate the ingenuity and creativity needed to invent transformative technologies and companies.

What will it take to survive and thrive in the face of polycrisis? In this letter, I offer my thoughts on that question, and detail the tools and mindsets that my colleagues and I are sharpening and deploying to survive extreme challenges, embrace uncertainty, and accelerate efforts to reshape a future in which we can thrive.

1. It Will Take Ecosystems of Our Own Design

For more than two decades, Cambridge, Massachusetts, has been commonly viewed as a vibrant life sciences “ecosystem.” In biology, the term “ecosystems” refers to “all the living things in an area and the way they affect each other and the environment.” As in nature, industrial ecosystems emphasize the mutual interdependence of the inhabitants: Our interactions elevate us to more than merely the sum of our parts. And as in nature as well, industrial ecosystems can be fertile or hostile; they can foster or inhibit growth; they can stimulate or stifle innovation.

The complex networks of interrelated systems composing natural ecosystems are emergent and arise without specific control or manipulation. Many organizations think of the industrial ecosystems in which they operate as a “given” element of their environment, that while important, is beyond their control or ability to shape. At Flagship, we have long taken a different view. We believe that ecosystems can be designed and constructed to suit the inhabitants’ needs. We see ourselves as co-creators of the ecosystem in which we operate. A deliberately designed ecosystem can generate value and provide a robust defense against vulnerabilities in difficult conditions through pooling of resources and leveraging complementary strengths. It is this mutuality — practically accomplished through partnerships and alliances — that is key to resilient ecosystems.

The Flagship ecosystem is constructed to pioneer life sciences innovations that transform society. At the heart of this ecosystem is our unique process for inventing new platforms based on unprecedented areas of science. We invest our financial, intellectual, and organizational capital in new ventures formed around these platforms. The expansive, ever-growing ecosystem of Flagship-founded companies, now more than 40 strong, with a dozen founded each year as “ProtoCos,” five to six wholly owned early-stage companies that we capitalize with Series A funding we call “NewCos,” and more advanced companies that have raised large pools of external capital we call “GrowthCos.”

Partnerships between biotechnology companies and larger pharma companies and academic and research institutes have historically been key parts of the life science ecosystem. Flagship and its companies have long engaged in these sorts of partnerships to create impact. That impact is exemplified by a partnership forged in 2016 between Flagship-founded Moderna and Merck. This collaboration developed an experimental personalized mRNA cancer vaccine, now in Phase 3 trials, that when paired with Merck's Keytruda cut the chance of recurrence or death from melanoma by nearly half after three years, offering an encouraging improvement over the standard of care of Keytruda alone.

In 2023, we significantly accelerated our partnering efforts. Recent examples include Harbinger Health and Dana-Farber Cancer Institute, Valo and Novo Nordisk, Generate:Biomedicines and Roswell Park Cancer Center, KSQ and both Roche and Takeda.

We also recognize that, as in nature, our ecosystem needs to continue to evolve and adapt as circumstances change. Thus, our habit of asking “what if … ” about scientific questions — the heart of our exploration process — also extends to organizational questions and the design of our ecosystem. We’ve turned that same questioning mindset toward partnerships themselves, wondering: What if partnerships were conceived as an ecosystem of innovation that encompasses every aspect of discovery and drug development, from far-flung idea through to research and testing all the way to manufacturing and commercialization?

This widened aperture led us to design a novel form of partnership in 2023 — an Innovation Supply Chain Partnership (or ISC partnership). Collaborations of this nature have four key characteristics: They start EARLIER in the innovation process, long before there is a proven therapy; they build on BIOPLATFORMS that, once proven, promise the likelihood of many new medicines; and they are FLEXIBLE and LONG TERM in nature, following discovery wherever it takes us and capitalizing on novel insights and modalities that emerge from collaboration.

These principles anchored last year’s Pfizer-Flagship Pioneering partnership to create a new pipeline of innovative medicines. Under this partnership Flagship and Pfizer are each investing $50M upfront to explore opportunities to develop up to 10 single-asset programs by leveraging Flagship’s ecosystem of more than 40 biotechnology companies. Pfizer will fund and have an option to acquire each selected development program. Flagship and its pioneering platform companies will be eligible to receive up to $700M in milestones and royalties for each successfully commercialized program.

This unique partnership came to fruition through Flagship’s Pioneering Medicines division, as did the partnerships announced last week between Novo Nordisk and two Flagship-founded companies, one with Omega Therapeutics and another with Cellarity, and Generate Biomedicines announced an expansion of its collaboration agreement with Amgen. Each of these meet the ISC partnership bar: They are exploratory in nature, long term, and anchored in bioplatform development.

It isn’t just pharmaceutical company collaborators who will play a critical role in our ecosystem; we are also forging partnerships with life science technology providers. Just today, Flagship announced a collaboration with Samsung to support Flagship-founded companies and advance their groundbreaking bioplatforms. And late last year, Flagship announced a significant expansion of its partnership with Thermo Fisher to pioneer enabling technologies and to propel bigger leaps in the life sciences industry.

Through this network of strategic alliances, we are constructing a unique life sciences ecosystem that enables us to make even greater leaps by leveraging our distinctive capabilities and processes at unprecedented scale. We are continuously experimenting to innovate the very way by which we innovate.

2. It Will Take Embrace of Adhocracy

To thrive in the age of polycrisis, we will need to boldly pioneer new organizational structures — what I call new organizational life forms — to position ourselves for bigger leaps and next generation biotech breakthroughs.

More than 50 years ago, the futurist Alvin Toffler forecast the replacement of traditional bureaucracies with a far more nimble, kinetic model called Ad-hocracy, reflecting the ad hoc nature of the fluid, flexible, evolving structures that are its hallmarks. Here again, an invented English word that captivates me, not just for its originality but for its meaning, and the implicit nod to the upsides of disequilibrium: “As machines take over routine tasks and the accelerative thrust increases the amount of novelty in the environment, more and more of the energy of society (and its organizations) must turn toward the solution of non-routine problems,” Toffler wrote in his iconic 1970 bestseller Future Shock. “This requires a degree of imagination and creativity that bureaucracy, with its man-in-a-slot organization, its permanent structures, and its hierarchies, is not well equipped to provide.”

From the start, Flagship has embraced this ethos, and today, it assumes new prominence as we adapt our structure and operating model to quickly leverage the vast powers of new technologies. Our companies are devising a shared language between computation and biology, expanding and diffusing decision-making authority, and assigning people to work cross-functionally, in service of harnessing disequilibrium and driving velocity across the Flagship ecosystem.

As Toffler so aptly noted, we need both imagination and creativity. Building vibrant adhocracies is far more than a managerial challenge — it requires new ways of thinking, seeing, partnering, and exploring.

Such qualities fueled the creation of our new Pioneering Intelligence (PI) division, officially launched in November and designed to unleash the full power of artificial intelligence (AI) and machine learning (ML) at Flagship. To be sure, AI and ML play a role in all 40+ Flagship-founded companies, many of which are AI-driven. With this new initiative, we will vastly expand this focus, with a new generation of AI-first companies.

History is rife with examples of promising new technologies being locked away within incumbent organizations. At best, they emerge more slowly, at worst, they perish. At Flagship, we are learning the art of adhocracy, continuously innovating our organizational structures and processes to ensure this never happens.

3. It Will Take Global Reach

Late last year, Flagship marked a milestone with the launch of Quotient Therapeutics. The result of yet another novel partnership, in this case with the Sanger Institute. Quotient is the first Flagship-founded company to be founded in both Cambridges — Cambridge, MA, and Cambridge, UK.

While our teams of scientists hail from more than 20 countries, 90% of Flagship companies have been born and bred within 10 square miles of where I am drafting this letter in Kendall Square.

That is changing. Why? Because the nature of scientific discovery is changing and the necessary components for biotechnology company-building are diffusing globally. As part of our strategy to globalize our ecosystem footprint, we signed a memorandum of understanding with the UK government six weeks ago. The enthusiasm and determination embodied by those present — from top scientists to policymakers to regulators — was striking: They intend to combine recent financial reforms and post-Brexit regulatory independence with longstanding scientific depth to make the UK a leader in the next era of drug development. Flagship now has its first office outside the US in London.

The feeling was similar in Singapore, where in November we announced the creation of an Innovation hub to strengthen our connections and collaborations in the Asia-Pacific region. Pharma and diagnostics powerhouses from Japan and Korea are helping seed and nurture the sector in a region that already boasts tech strength, large and diverse patient populations and massive datasets.

Our agricultural technology (agtech) companies were the first with global reach in our ecosystem; Indigo, Inari, and Invaio have been working with farmers and other partners in Argentina, Belgium, Brazil, Chile, India, Italy, and Spain for a number of years. Moderna is, of course, now the most global company in the family, with operations in more than 17 countries around the world.

The feeling on these trips to the UK and Singapore was that of glimpsing the future — a future in which the capital, talent pools, and research centers that fuel novel biotechnology will be distributed across the world. Moreover, comprehensive longitudinal medical records from countries with single-payer systems offer unique data to analyze and derive insights for both discovery and patient segmentation. Those countries with strong clinical trials infrastructure and engaged patient populations have the potential to revolutionize the way trials are recruited, conducted, and reported.

Those who want to lead the next revolution in drug development will need to orient much more globally than has been biotech’s history to date. Flagship intends to lead the way.

4. It Will Take Both Forms of AI

For all the recent media fervor, AI and ML are not new. What is new — and growing every day — is the scope and scale of opportunity to advance human and planetary health faster and more powerfully than ever before through generative AI (e.g., large language models).

Human intelligence evolved not just for reason but also imagination. Trained on both, with AI, our growing ability to embrace complexity and unstructured large-scale data rather than attempting reductionist science, which has limited biology research for years, allows us now to mimic nature and for the first time conceive new natural phenomena. Augmented Imagination as well as Artificial Intelligence are the two AIs we foresee propelling our future.

Methods to reliably control and enhance our imaginations have eluded us, but AI is helping us to unravel nature’s complexities that have evaded human understanding. We are seeing this in many places: drug design, optimization, diagnostics, and biomanufacturing, to name just a few. Yet, at Flagship, we are finding one of the most tantalizing capabilities of AI is its potential to expand imagination. For example, what if … AI hallucinations can operate as a feature, not simply a bug? When AI-generated responses to prompts go “off-script” and start spit-balling, that “bug” can actually be a feature in creating novelty — and it is novelty that leads to breakthroughs.

Last year Flagship decided to make a bigger, more expansive leap into AI with the formation of our Pioneering Intelligence initiative, officially launched at Flagship Pioneering’s inaugural AI Summit. Like all Flagship creations, Pioneering Intelligence started with a “what if … ?” question: What if we could harness the latest advances in AI to create breakthroughs and accelerate innovation across the Flagship ecosystem? We are now starting to find out.

Through new technologies, we are replacing traditional drug research — a trial-and-error process with an estimated 3–10% chance of success — with a digital data-driven AI approach that should dramatically improve the odds. Simply put, we are moving from artisanal and probabilistic to engineerable and deterministic drug discovery. This can be revolutionary.

5. It Will Take Paranoid Optimism

Pioneering new technologies and creating transformative companies often requires us to grapple with seemingly contradictory elements. To name just a few: thriving while surviving, urgency in action with patience in expectation, confidence and doubt, strategic planning and emergence, prioritization, optionality and adaptation.

In our experience, the ability to exist in the gray area between black and white — to shift as the opposing tensions of wins and losses tighten and go slack — is critical to both surviving and thriving. The people who develop this capability have a form of self-confidence founded, not in what they have accomplished, but in their ability to learn and lead despite many uncertainties and inadequate knowledge.

In my role, I toggle between two states so often that I created a moniker for it — paranoid optimism. Optimism and paranoia require the dissolution or suspension of the other. The extremes of each lead to being reckless or paralyzed. But, if you can nimbly shift between the two, you can leap into the unknown with a better chance of a good landing.

I was with a room full of fellow paranoid optimists at our AI Summit, and I was energized by the palpable optimism that electrified the discussions during and between sessions. These AI “yaysayers” brimmed with enthusiasm focused on how to harness the extraordinary potential of emerging tools, while being vigilant (and even paranoid) about the risks.

The temperament of the yaysayers served as a powerful reminder for me that, while we can be sober about our current problems, it is not at odds with the ability to be fundamentally optimistic about humankind’s ability to invent our way out of our current problems and into a more peaceful, prosperous, equitable, and sustainable future.

In fact, I believe particularly that when it comes to the sustainability of our planet and global food supply, biotech is likely to be the vehicle for invention that is acutely needed to solve our current problems. Biotech can move quickly to develop solutions for healthier crops, lower resource consumption, and decarbonization, offering near-term and measurable benefits that will bridge the chasm between today and the sweeping global policy-changes that will take decades to come to fruition. Flagship’s ag tech companies are already delivering on that promise, creating delivery technology that reduces human and environmental exposure to pesticides, decreases water use, increases crop resiliency in the face of extreme weather events, and incentivizes carbon sequestration by giving farmers the tools to measure and benefit from sustainable practices.

Invention and optimism, in combination, may in fact be the most powerful tools available in navigating through the uncertainties and disruptions of the polycrisis. We talk a lot about “bigger leaps” at Flagship — discovery and creation in non-adjacent areas of science ripe for disruptive impact.

We enter 2024 fueled by optimism and committed to invention: We anticipate launching five to six new bioplatform companies this year — the same rate as we have in biotech boom times.

We may not be in the so-called boom times today, but Flagship was designed to navigate through challenges and harness the energy of disequilibrium. We leap toward and beyond the edges of knowledge into the unknown and uncertain in the same way astrophysicists faithfully probe the edges of the universe for beacons of life.

Because it turns out, disequilibrium is not just a fact of life, it is a sign of life. One way researchers seek indications that we are not alone is by measuring for atmospheric disequilibrium on distant planets. Huge telescopes like the famed James Webb search for the presence of gases such as methane and oxygen that would typically rapidly react with each other and form other compounds, so their coexistence indicates a potential source of replenishment. Disequilibrium, in fact, propels life.

Let’s together propel forward into the unknown and uncertain future to weather the inherent discomfort, share the potential risk, and transform this chaotic energy into progress for human and planetary health.

I don’t tend to invent words in French the way I do in English, but I do sometimes turn for inspiration to the French that animated my schoolbooks in Beirut and my everyday life in Montréal after our family emigrated there. “A coeur vaillant rien d’impossible” roughly translates to: With a courageous heart, nothing is impossible. I believe that, and believe that embracing uncertainty, courageously and together, will make the seemingly impossible not just possible but inevitable.


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…