Synbio25

Synbio25 is a series of essays about the next 25 years of synthetic biology, commemorating my 25th year on this planet, in the 25th year of the 21st century.

The future, and what we believe about it, isn't just a technical challenge or a policy debate; it's a collision of grand ideas, personal emotions, and cold incentives. We too often treat ideas as amorphous, independent entities, unconnected to the human experience that created them. I'm the opposite of a dispassionate observer — I'm a passionate participant, playing in this field right now! Synbio25 is a work of love, talking about the future I care about.

To me, there is one core problem in all of biotechnology: the vast majority of experiments are done with human hands, manually. Think about that for a second. It is like if a scholar's hand had to write out every book. It is like if we are mining bitcoin on abacuses. We have leveraged great computational power to get better predictivity, but our fundamental productivity is still on the basis of human hands doing biology. We will never accelerate until we learn how to run biology experiments not using human hands but using our tools — our robots and our software.

I think of all technology in terms of power. Who controls it. Who profits from it. The shift from human hands to tools can both be a change of liberation, allowing anyone to participate in biotechnology without having to learn all the manual tools and muck around in a lab for years. Or, alternatively, it can be a change of monopolization, as the ones who own those tools seek maximize profit at the expense of the common good. The frontier ahead of us is in tension: between powerful institutions with entrenched interests versus the productive forces of new ideas, between safety but stagnancy versus innovation but risk, between optimistic idealism versus brutal and unforgiving economic reality.

Our current efforts to commoditize intelligence are laudable, but in biology, without the ability for those artifical intelligences to run experiments, we will always be constrained by the amount of data that can be produced by human hands. In contrast, our ability to create intelligence accelerates us towards automated systems. As history has shown, every technological leap like this one leads to the destruction of the old and the creation of the new. The humble laborers of today will become the industrial giants of tomorrow. And giants of today will be pulled down, kicking and screaming, replaced by a new generation that understands the shifts ahead. And the new generation, invigorated by young blood, open the door to new, ruthless, monopolistic corporations. At the same time, they may create the tools necessary for anyone to participate in the bioeconomy of the future. Maybe not dystopia, maybe not utopia, but an equilibrium that is different from what we see today, opening the opportunity for new and different values associated with biotechnology.

As the crazy technoprimitivist man once quipped: "you can't make rapid, drastic changes in the technology and the economy of a society without causing rapid changes in all other aspects of the society as well, and that such rapid changes inevitably break down traditional values." Perhaps this is quite alarming, as our technology lets us question what is human. Should we modify the natural world? Should we genetically engineer humans? What do we want our new values to be, and what will they ultimately become? What the hell is our endgame with modifying life? Is it Good?

In this field, some want to tear down institutions. Some want to fortify them. Some want to save the world. Some want to get rich. Me? I just want to keep the game going. I want to see biotech flourish — not because I have some grand ideological stance, but because it's fun as hell. I've been screwed by monopolies. I've built my own home labs. I've labored in academia and I've founded startups. Through it all, I've had a grand ol' time. You'll probably have different incentives, and that is ok. So long as you're doing things, we're on the same side.

Biology belongs to all. We stand at the precipice of harnessing the most powerful technology ever developed — inherited by Provenance and Providence, created not by design or decree, but by the glory of our ancestors immemorial.

The indelible truth is that any power, truly held, may enable malevolence; but it is likewise easily forgotten that risk and innovation are inseparable. The stable artifice granted to us by the institutions in power is mere pretense for their own security. Biotechnological advancement that helps all has been and will be hampered for our "safety" by elites who do not share our problems, grievances, or optimistic hopefulness.

Yet hope placed in mere well-wishers for human flourishing will prove equally hollow. Delivering today's tools to the people is insufficient: these instruments were for institutional laboratories designed for last century's paradigm, and cannot be effectively used by those without extensive training or capital. Governmental resources and five-year roadmaps are similarly futile — those who craft such plans stand removed from the underlying currents of technological advancement. If they truly understood how futures are made, they would be creating technology, not merely pontificating about its hypothetical emergence.

The future rests with you — those still striving, struggling, and surviving at the bench or before screens. Your days aren't filled with grant writing and administrative meetings; you intimately know both the problems and possible solutions. While institutional power remains centralized, the vital knowledge — the understanding of what truly matters — is distributed in the minds and hands of all who labor. The technological frontier calls not to those who've claimed its settled territories, but to you who work at its wild edges, where innovation hasn't yet been captured by monopoly.

In the future, I see that as technology advances, the ability to do biotechnology will increasingly become centralized. Capitalists will eat the means of production for breakfast, sipping a rosy glass of robots tinted with optimism, a spoonful of AI, a hefty serving of shareholder value, and a detestable side of labor displacement for working-class people. This will follow a fairly predictable pattern:

• Centralized labs will manage physical resources far more efficiently due to having more experiments pass through their systems.
• A massive market exists for outsourcing experiments — if you can do them better, faster, and cheaper. Nobody has yet been able to do that.
• Labs that break through the technical challenges will unlock huge biological economies of scale, reinforcing their dominance in the market, but also reinforcing all their other experiments, as experiments often lead into each other.
• Resistance will be fierce: existing workflows are human-centric and manual. People will lose their jobs if we switch to robots. But in the long run, those who adapt to robots will win.
• Biological variability and reproducibility issues will make interoperability between centralized labs nearly impossible — locking users into a single platform and creating natural monopolies
• The reward: economic explosion, a strong market position — or monopolistic exploitation (same difference) — until new challengers arise.

We exist at a local maximum where nobody has figured out how to build a good centralized lab (that actually, you know, serves people's needs). It is hard to escape: I don't blame our predecessors for failing to. On the other hand, it is pure absurdity that the most advanced technology ever uncovered is physically done by people holding plungers. We're mining bitcoin on abacuses. Insanity. We can do so much better. The machines and intelligence are finally here to do it. We can ESCAPE.

Neither God nor the Invisible Hand nor the Leviathan nor the Ivory Tower will determine what lies ahead. It is up to you to envision, to create, to shape the trajectory of our collective future. And then it falls to you — you who stand at the workbench today — to drag, kicking, the great chain of human endeavor toward its truest path.

A major practical challenge to the centralization of physical aspects of synthetic biology experimentation is the fact that synthetic biologists have failed to abstract away variation between labs — in people, equipment, location, environmental conditions — and this variance is reflected in the biology that operates within them. This isn't a problem, it is the problem of synthetic biology. Until we break the necessity of learning the particulars of our execution environment, we can't (effectively) share ways of doing things. Right now, it should be natural and expected to have a reproducibility crisis. The requirement for tacit knowledge (implicit, unwritten knowledge) for every single experiment extends so far that it has become an invisible requirement for biotechnology.

In other words, it is a programming environment with zero libraries where all compilation is done by hand, and there is no formal specification for the code, and every single CPU works differently. To become more like modern software engineering, one of the most scalable information-based technologies we have, we require a few things:

• CPUs that work (a fully-automated lab)
• a formal specification for protocols (standardization of tacit knowledge)
• a compiler (abstraction on top of any given fully-automated lab)
• an environment with libraries (bottom-up adoption)

In practice, this looks like formalizing protocols as code — because code is exactly how humans have figured out how to communicate and abstract machine operations. Lots of people know this. But they lose the magic of what made it work in the world of computers. The magic of lower-level languages in code is that you can make something, quickly, that just works, and then build on top of it. The magic of higher-level languages in code is that you can take a bunch of libraries written by a variety of different people, then run it on almost any machine, and it just works! Magical.

That means you can't just have protocols as code that work on a single machine or architecture or lab. You can't just have protocols as code in a way where people don't actually share code to build on each other. You lose the magic. It's not just about having an API to your fully automated lab. It's about creating the experience around those APIs that just lets people do awesome things easily.

The magic is writing a protocol, pulling a ton of dependencies — GoldenGate cloning, yeast transformation, plate reading — and instantly being able to execute that protocol locally or on an automated cluster elsewhere. Simplicity in use, sharable at the core, in a way that cannot be taken away by a single provider. Magical!

Here is the secret to the magic that the ones who don't work at the bench do not fully comprehend: these ideas are completely worthless without ruthless implementation from the bottom up. You will never get there if you only implement so-called "valuable protocols", like drug screens. They're too idiosyncratic and one-off. No, rather you need to build implementations that every single biologist would want to use, and can use, for their own small projects and experiments. You need a million eyes finding the bugs to make reliable and worthy implementations. At first, this means implementing commodified and everyday workflows, which inherently makes for bad business and boring papers. But some founders and investors need to make the first step, to put up the activation energy, to produce massive value later.

As a concrete example of tacit knowledge inflating costs: right now, you can commercially purchase clonal synthetic DNA for $125 per kbp. The price, for the same amount of synthesis from the same company, but in the format of oligo pools, costs $1.5 per kbp. The difference, if you do not know, is that oligo pools are large collections of short, mutation-prone DNAs all mixed together, while clonal synthetic DNA is long, sequence-perfect strands of a certain sequence. The arbitrage is purely within DNA assembly and sequence validation — which I have shown in my own lab only costs about $6 per kbp. The most infuriating thing is that I did not believe I would hit those unit economics — surely those big labs must have a hidden cost that I have not discovered — but I was wrong. But it took me almost 2 years with extreme specialization and extensive know-how in the field. And as it stands, I can't even really share my improvements.

The real barrier to reaping these cost reductions in most biotech workflows isn't the raw materials; it's the reliance on tacit, specialized knowledge and the ability to keep trying to reduce costs. If we systematically handle tacit knowledge and build environments so that protocols aren't idiosyncratic "black boxes", we can encode this knowledge (and knowledge of all other aspects of biological production) into code. We commodify esoteric specialization into concrete, importable implementations. By applying this towards every single foundational biological protocol, I hope we can exponentially decrease the cost of doing any biology research.

This commodification will be difficult because it requires moving protocols from human hands to robots, where the real difficulty lies not in the re-description, but in the differences in how debugging is done. Lowering prices will require heavy batching, which opens an economic opportunity for companies, both in margin and in moat building.

The logical outcome of this commodification of protocols is that required overhead for new companies is dramatically lowered, increasing the variation in interesting companies we can see. In the long term, these factors will shift biology towards being understood as much more of a black box, to the dismay of scientists and to the delight of pragmatists.

Holocene Extinction be damned! I want to see just the opposite: I want to see the Holocene Explosion! An explosion of new, novel life forms the likes we haven't seen since the Cambrian! The failure of Colossal (well, among many) is that they haven't gone far enough: I don't want to just see mammoths, I want to see new creatures we haven't even imagined. I want there to be dragons, in an entirely literal sense. I advocate that we should literally make dragons. We may be lowering biodiversity at a rate never seen before in the history of Earth, but we can also do the opposite: create biodiversity at a rate never before seen either.

On the other hand, it can be seen as a bit excessive to revive mammoths when there are plenty of species going extinct right now. Preservation of biodiversity is likely more effective than making new biodiversity before we get much better at genetic modification. And before we have greater control over introduced biological organisms, we risk further ecological damage.

Still, I want to put in your mind the positive idea that biodiversity, inherently, is moldable by human beings. We will be able to make new life soon enough. We can create Jurassic Park. Will we be so preoccupied with whether or not we could, we didn't stop to think if we should?

I've stopped and thought about it. We should.

In particular, I think we are gripped with the clearly and demonstrably false perception that we don't have control over biology — and the ironic and self-defeating idea that as we get, by definition, better at controlling biology that we will not be able to control it. We made wolves into chihuahuas almost by accident. We've extinct viruses. Most mammalian biomass is directly controlled by humans — with 15x more mammal biomass being our food than there are wild mammal biomass in total. Even the worst pandemic in anyone's memory killed fewer than 1/1000th of us, and we were able to get a vaccine out in record time — and with advances in technology, we'll be able to get one out even faster.

If we look at our media, on the other hand, almost all sci-fi and fantasy have fantastic elements of new, interesting, unique biological life, hiding in forests or in the ocean. We see these and are met with wonder: but suddenly, when we propose that let's go make those, it is taboo, or stupid, or arrogant? Why can't we imagine a more beautiful world, then go make it?

Rather than arrogance, I think this is simply acknowledging that we are a power like the world has never seen. With great power comes great responsibility: and is it our responsibility to simply keep the world as a static jar, like a terrarium we are too afraid to touch? Or do we have a responsibility to make the world an even more vibrant, interesting place?

I believe we should build beautiful things with biology. I believe we can do that responsibly. We don't lack power; we only lack imagination.

Humans have been, and will be, genetically modified. The Blessings of Liberty extend to them, to us, and to our shared, intertwined Posterity. The pattern of nucleotides within us does not determine our Humanity. Whether or not the hands and hammer of man have refined your encoding does not make you more or less human.

Modern medicine has removed much selective pressure from the human race. However, under the assumption that there are more deleterious mutations than benign mutations, we should expect to see a gradual increase in genetic diseases among ourselves. In Nature, those mutated humans would be selected out of the population, but the family of Humanity is above Nature. We can, and should, choose to repair our genomes as we see fit. Any argument against human genetic modification has the implicit concession that those people's sacrifice of their own happy lives is worthwhile for abstract ideals. To not modify humans is sadistic and selfish.

While you may be able to make laws against human genetic modification in your nation, it is inevitable that many people will choose to free their children of genetic diseases or give them advantages in life, even if it requires traveling to a different nation. And so, if your primary concern is that a privileged class of people will first have access to this technology, instead of banning it, you should make your nation the very best place for it — which will decrease the cost locally and let more people access it.

And eventually, this will open Pandora's box — widespread modification of human children for any other purpose — cosmetic, intellectual, or muscular. Maybe even modifications to make sure your lineage has a huge dick. While it may seem silly in abstract, things like that carve at the core of people's self worth.

Germline modification raises obvious moral questions because the unborn cannot consent, which breaks apart our liberal ethical models of the world which emphasize consent. In truth, the unborn can't consent to anything, even being born. Even in cultures that believe in reincarnation, you don't get to decide where you are born and to who. Consent cannot be had here. The liberal perspective of harm reduction (such that deleterious mutational fixing should be allowed, but other traits should not) will naturally trend towards being more accepting of modifications, since being ugly will cause more psychological harm than being gorgeous/handsome, and who doesn't want their kid to have the best life possible? The conservative perspective is inherently at odds with itself: there is a simultaneous emphasis on the sanctity of humans and the benefit of the kin group — and I think the kin group is going to win here, like it almost always does.

Parents make countless decisions for their children. In fact, this is pretty much how we define childhood — the fact that you can't consent yet. A child can't choose to be raised religiously, or to take or not take certain medical interventions. As a society, many of us even choose to force genetic self-modification onto children (through antibody evolution in response to vaccination). Our moral frameworks already accommodate non-consensual but well-intentioned parental decisions — the only reason genetic modification is different is because it is new. And someday it will not be new.

Yes, we cannot fully predict the outcomes of some genetic changes. We're slowly getting better, but this is a danger. But so is just letting your child be randomly mutated — there are tens of completely random genetic mutations every generation. We don't know the effects of those, but somehow we find completely random mutations more palpable as a society than specific mutations with some theoretical backing that they may be beneficial.

It is seen as morally righteous to change the world in a way that betters mankind and the future generations. To me, then, it is a moral failure of our institutions to restrict human genetic modification to the degree that they have. But their deaths — the anguish of children, men, and women whose cancer could have been stopped at the source — will be invisible to the well-meaning bioethicist bureaucrat. They'll be patted on the back and paid with taxpayer dollars to hold the door closed on what could be.

I build technology. And sometimes, late at night, I feel very conflicted about my place in our world. Capitalism is getting eaten alive by Technology, acting to centralize economic power. Inequality is rising, our mental health is deteriorating, and our society is becoming polarized. The technoindustrial machine has made us into cogs, made us into a species of transactions. Science killed God, and technology that promised to bring us together tore us apart. We were promised leisure as production increased and we were lied to. I sometimes have to question — where is our march of progress bringing us?

In November 2019, on a complete whim, I took a trip to the redwood forests in Humboldt. I decided I wanted to go at about 2pm on Friday, and by 3pm, I was out of the lab, driving 6 hours from Stanford up to Eureka. That night I stayed at an Airbnb on the Samoa Peninsula with an outdoor shower — and good god, I've never felt celestial wonder like I did under that elysian sky. The next day I drove to the redwood forests and took a short hike on The Miners' Ridge and James Irvine Loop. I remember the late orange sun shining through the redwoods and the sweat on my brow and the cool ocean breeze and the ferns swaying among the lonely trunks. Most of the old growth redwoods were cut down by people looking for lumber — reasonable people, like you and me — in the shameful name of progress. Only 5% of the old growth redwood forest remains. Our industrial world took a look at the natural world and absolutely decimated it.

That night, I stayed in an Airbnb down in Ferndale. It was my host's first time hosting someone. She was a lovely lady — that next morning, she cooked me delicious toast with some locally produced jam while her children tended the rabbits and chickens and ducks in the backyard. During that breakfast she explained to me how the house was made many years ago in Victorian style out of pure redwood and how grateful she was to finally own a home for her family, that she could raise her children in. I saw in her eyes a woman who truly cherished what she had. Cherished a home built out the beautiful redwoods the loggers shamelessly cut down.

And within this, I am struck by the symmetry, not contrast, in every sense possible — of my ability to cynically rationalize the structure of progress, history, and society versus my emotions appreciating the beauty in things around me. Or equally so, the opposite: to optimistically show data of how the world is improving versus the lived realities of the people of this nation and the negativity gripping the world.

I can see beauty in sun beams through forest leaves, beauty in intricate quilted patterns on the heavy blanket I slept with on the couch, beauty connecting with the people around me who had nothing in common with me. Or, I can see disaster in the apocalyptic nature of our climate crisis, the rising housing prices and stagnation of the common man's wages, or how much vitriolic hatred has infested our public discourse. Or, I can see how much technology improves our lives, and how much better things are getting. I can see how bad things were, how much better they are now, and how much better we can make them. I can be hopeful; I can be despairing.

I could be optimistic in my rationalization and pessimistic in my stories, or I could choose to be pessimistic in my rationalization but see the sunshine in my life, or any other combination. Where I choose data and where I choose emotion is arbitrary. It's not on the basis of what is actually true — because both are equally true from different perspectives — it is on the basis of the ways I choose to experience the world and the situations I put myself in. Just maybe, I can be both a critic and lover of the future.

At the end of the day, I want to build technology because I think technology is beautiful. Anything more is rationalization. Although, in the end, is there a difference?