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This week’s theme: how the social forces that make Silicon Valley a great place to create something out of nothing have also created a toxic environment for diversity and inclusion. Plus Zach Sun from Tierra Biosciences explains the incredible promise of cell-free biology.
Over the past few weeks in Snippets, we’ve been talking about the norms, rules and social codes of Silicon Valley and their critical role in making the whole place work. They collectively bring down the inertia barrier and reduce a lot of the friction that is a normal part of creating new things, and grant founders a particular kind of power that they use to go create something out of nothing. The core theme running through all of these social norms and codes is the ongoing balance between differentiation and similarity: how deep structural similarity is an essential part of reducing friction and promoting competitive drive, and simultaneously how founders have become the ultimate symbol of special differentiation that we throw our resources behind. This weird and intricate set of rituals actually works. But it doesn’t work for everybody.
Today, we’re going to talk about the dark side of this codified set of social rules: it is not equal-opportunity. It works for some people and not for others.
People in power have known for a long time that in a free society where you can’t simply use force to preserve your empire, the best tools for preserving power aren’t explicit, and they aren’t even economic; they’re social. If you leave it up to hard work and economics alone, your position at the top will erode quickly: talent, motivation and grit are distributed across the population in a way that most definitely does not favour the powerful. The world is full of people who are hungrier than you, more talented than you, will work harder than you, and want it more than you. So, naturally, we’ve evolved all kinds of institutions whose purpose is to make sure that the gates of opportunity will be favourably open for those who come from the right zip codes and who have the right parents. Institutions like elite schools and country clubs, other distinguishing factors like speech and accents, and even social graces like table manners play a real social role in making sure that “the right people” can always preserve a natural head start over the much larger (and, usually, more capable) group of people who do not have that advantage.
These days, it’s quite frowned upon to admit this openly; we like to talk about how we live in much more of a meritocracy. But a lot of the time, the “merit” that goes into that meritocracy is essentially a codified expression of existing advantage: think of elite universities that evaluate extracurricular activities in high school as admission criteria, for instance. Spending lavishly on piano lessons and educational vacations early in life, as a way of gaining admission into Swarthmore, then GSB, and then a coveted junior position on an elite career path is a fantastic way for power to buy itself another generation. Furthermore, the meritocracy perception only gets stronger, because among that peer set, the people who do the best are in fact the ones who are the most talented, work the hardest, and generally deserve it most. For the most part, among the modern elite, people look around at their peers and see a pretty good correlation between how well they’re doing and how hard they’re working. The trick is to make sure you’ve adjusted your blinders appropriately, so that the illusion remains vivid.
Is this true in Silicon Valley, too?
As we’ve been saying for the past several weeks, Silicon Valley is a place that works, in part, because we’ve evolved an intricate social system of rules, norms and expectations which all make it easier for founders to create something out of nothing. Let’s be clear here: this is a great thing, and it’s great because it gives people with talent and drive a path to create wealth that did not exist before. But with success came a new challenge: a kind of curation problem. VC is no longer the explicit gatekeeper it once was, but it’s still an important curator: as we said last week, they act almost like priests in their ability to “bestow” a particular kind of power on founders that grants them a heightened ability to hustle their way into building a great business. This is a very soft and subjective kind of power. It’s pretty routine for the priesthood to arbitrarily decide, “Oh yeah. He has the power.” Or, perhaps as commonly, “She doesn’t. I just don’t feel it.”
That’s the problem with soft power: if you don’t fit people’s preconceived idea of what “a great founder” looks and talks and acts like, then you may in fact find that the power and mystique that gets bestowed on founders through the social structure is not actually available to you. If you are not granted that founder differentiation, or if your being differentiated is not perceived as a good thing, then you’re left at a disadvantage: the relative undifferentiation of everything else (your company, your idea, your go-to-market, your growth, your results) will make it easy for prospective investors or employees to say, “Great business, and will find success somewhere, but not for me. Just doesn’t quite seem like the right fit.”
Female founders face this problem a lot. One of the most pervasive forms of modern “soft sexism” is that men seeking to differentiate themselves are typically seen in a positive light, whereas women seeking to differentiate themselves are seen in a negative one. Given that one of the most acute challenges facing founders is “how can you build the perception that you are differentiated, special, and worthy of the Founder Magic”, this is a real problem. But the math behind startups makes it hard to really pin down the problem: after all, most founder pitches to VCs are unsuccessful. Most startups have hiring issues. It’s a matter of degree, not of absolutes. But those matters of degree add up over time.
Unfortunately, the problem gets worse once you realize that success and power in the startup world compound across generations. In contrast to the old world, where generations meant people being born and having kids, our “generations” mean cycles of company building. One of the hallmarks of startups, as we’ve talked about, is that in their early days they’re a lot like little cults; indeed, they kinda have to be, because the challenges you face early on are so existential that you cannot afford any extra costs or problems or challenges that aren’t ’necessary’. What does that mean in practice? Well, it means that in the beginning of a startup’s life (and often for some time thereafter), everybody in the startup pretty much looks the same. Often they’re even close friends, and friends of friends. It’s not that there’s anything wrong with hiring somebody who’s like you, but do it enough times and you turn into a young organization whose hiring on “culture fit” creates an organizational core that’s entirely homogenous. In the very early stages of startups, diversity is quietly seen by many as a cost that’s “too expensive to bear right now; we’ll deal with it later.” Some senior figures in the startup community have explicitly endorsed this strategy. I’m not naming names, but you probably know who I’m talking about.
Once “later” comes around, though, the super-valuable pieces of early company equity will already have gone to the first employees. (And as our friends at Carta have shown, that equity will have gone disproportionately to men: while women make up 35% of equity-holding employees at startups, they own just 20% of the equity value.) Odds are that those early employees will look a lot like the founders, and odds are that the founders closely resemble the preexisting template for what founders look and talk and act like. If those early employees get envious of the founders’ status and title and mystique, like we talked about the other week, they’ll go off to start their own companies, armed with a fresh success story of having been in on the ground floor of their previous rocket ship. (They might also now be independently wealthy, allowing them that critical bootstrap period of company building that is effectively angel investing into your own startup.) If you carry this across many generations of startup building, you see something unfortunate start to happen: what may have started as perhaps a modest advantage for founders who look and act a certain way will, over time, get compounded into a massive head start that is phrased in terms of “track record”, “pattern recognition”, or other much more legitimized forms of structural privilege. Furthermore, as this successful group looks around at their peer set, they see a system that looks a lot like meritocracy! To them, there’s a clear relationship between hard work and success that’s born out among everyone they know. Survivorship bias is working overtime.
Now for the the most frustrating part of all: public calls for more diversity and inclusion in the startup world, which have grown in number and volume in recent years, get interpreted in a particularly toxic way by this community that owes a lot of its success to our social norms around similarity and differentiation. For all sorts of reasons, arguing “we should prioritize diversity in startups” gets first translated into “some groups shouldn’t have structural advantages over others”, which then gets further compressed into “everyone should be treated the same.” The crowd then retorts: “You think everyone is the same? Don’t you know how this place works? Everyone is not the same. If you force us to treat everybody the same, Silicon Valley will stop working.” It’s half lossy-compression problem and half straw-man argument: no one is arguing that everyone is the same; we’re arguing that Founder Differentiation Magic and equity-based power ought to be bestowed based on actual merit, not survivorship bias. But it’s hard to call out that straw man argument for what it is, because we don’t actually talk out loud about similarity and differentiation in the way we perhaps should. It’s all kept below the surface. That’s been one of the motivating factors for talking about a lot of these social norms and forces that drive this place. The point isn’t that they’re bad or good; the point is that we might benefit from shining a light on them and having a productive discussion about it. Lots of people have things to say, I’m sure of that much.
Some really interesting news from the scientific world this week: a team led by Stephen Benner of Firebird Molecular Sciences and the Foundation for Applied Molecular Evolution has pulled off a goal of the genetic community for quite some time, which is to create a DNA code and template that works with more than just four base pairs. In this new “Hachimoji System”, our existing genetic base pairs A/T and G/C are complimented with two new pairs: S/B and P/Z. Expanded genetic codes have been proposed before, but this marks the first time they’ve ever been built in a way that both faithfully replicates and is successfully transcribed into RNA. A lot of the publicity focused on its novelty as a breakthrough in the search for “alien DNA”, but the breakthrough could potentially have great therapeutic impact as well: being able to make DNA that human cells cannot replicate (but you can) has great potential as a way of hacking through some tricky problems.
Another story that got shared a bunch this past week was this piece from the NYT, tackling a relatively familiar subject: “Why are all these rich privileged people so miserable?” Looking at the author’s graduating HBS class, the story offers plenty of compelling anecdotes that yes, in fact, a lot of these people were miserable. But the scope is curiously narrow: the author keeps coming back to the necessity of “work that is meaningful”, or generally having a having a mission to look forward to in the office. The article mentions the possibility of finding happiness through your family or in your life outside of work a total of zero times, for instance. I can only speak anecdotally here, but in my experience the happiness people I know tend to be those whose sense of well-being is the most detached from what they do at work; not the ones most jacked into its stated missions. Anyway, NYT gonna NYT I guess.
And, of course, a great annual reading tradition: the Buffett Letter.
Brands and buying in the age of Instagram:
Podcast episodes for your listening enjoyment:
Also, like with last week, check out a podcast I recorded recently with David Perell. We recorded the episode a few weeks ago and talked a bunch about cities, including one of my favourite topics, Sidewalk Labs. Given some recent developments in the Sidewalk Labs / Waterfront Toronto story, I called David back a couple days ago to add a postscript, which you can find at the end. Enjoy!
Histories of what happened:
Other reading from around the Internet:
And just for fun (I watched the entire hour of this and it’s somehow incredibly gripping):
In this week’s news and notes from the Social Capital family, Zach Sun from Tierra Biosciences (formerly Synvitrobio) wrote a great primer on cell-free biology that we’d like to repost here. We’ve written a bunch about biology in Snippets last year and why we’re excited about it, and Zach brings a great additional level of detail you won’t want to miss.
I have always been fascinated by our ability to engineer our surroundings, how we can convert something as simple as rocks into concrete and skyscrapers. Or how a mineral, silicon, has powered the explosion of the digital economy.
Scientists made these applications possible by engineering microbes, living organisms. Living organisms are to biology as silicon has been for computers, the fundamental unit of engineering. Cells come with many attractive features — the ability to grow and divide, the ability to evolve. But the problem with living organisms is that they would rather do what 3.5 billion years of evolution have taught them to do, which is often not what we want them to do. This makes engineering them very time-consuming.
Cell-free biology is fascinating to me as a fundamental and foundational alternate to engineering microbes. As the name implies, cell-free biology is the engineering of biology without the cell. Surprisingly, biology does not need living organisms to work. Rather, the components of the organism, the basic building blocks of life — proteins, DNA, water, and food — can all be mixed together to do many of the activities we associate with biology. What is a complicated biological problem can be simplified into a simpler chemical problem. Practically, unlocking the potential of engineering molecules becomes way easier.
Currently, cell-free biology is commercially used to make existing chemicals and therapeutics more effectively and efficiently. Because cell-free systems cannot reproduce, one can make stuff that would otherwise be toxic to living cells. Two companies, Sutro Biopharma (NASDAQ: STRO) and Greenlight Biosciences have proven this point at commercial scale. Sutro has managed to produce oncology-related antibodies in fermenters of cell-free systems, at the scales that one brews beer. On the other hand, Greenlight Biosciences is pioneering the production of RNA for pest control.
However, cell-free biology does not only make it easier to make existing chemicals and therapeutics, but also entirely new ones. Commercially, companies like Synthorx (NASDAQ: THOR) and PeptiDream utilize cell-free systems to produce therapeutics that do not yet exist in nature. They do this by taking advantage of a cell-free platform’s ability to substitute naturally occurring amino acids, foundational units for proteins, for non-naturally occurring ones engineered to have therapeutic properties. This is exciting, as these therapeutics cannot be produced using other technologies.
As cell-free systems hit cost benchmarks — as they produce cheaper chemicals — one can envision future opportunities for the technology. Research is already underway to use cell-free systems to make solvents and polymers. Future aspirational goals include using cell-free biology to replace the need entirely for using animals as food, or for cell-free biology to power carbon capture.
Cell-free biology is not a new idea. In fact, it outdates cellular biology as a tool, and was the original way we understood our biological surroundings. Two Nobel Prizes were won using it: in 1968, for discovering the amino acid code, and in 2006, for describing eukaryotic transcription. But it is new surrounding technologies — to print DNA, to sequence DNA, to automate laborious tasks, to learn from massive computing power — that make this technology worth revisiting today as a foundational research tool.
Even with all of the sequencing data we have collected (and the resulting genomics, proteomics, and other -omics fields that have spawned), our understanding of biology is still extremely limited. Cell-free biology allows the simplification of complex systems into discrete units where hypotheses can be tested. The level of simplicity is tunable by the user. For basic hypotheses, a minimal, defined cell-free system can be used, while for bigger system-level hypotheses, more complex and undefined cell-free systems can be made. Critically, cell-free systems are consistent — unlike cells, every cell-free system produced in the same manner behaves the same.
The simplicity of cell-free biology allows it to be a powerful data generation tool. Not needing to wait for cellular growth means experiments can be done in hours rather than days. In addition, not needing to fight a cell’s innate desire to grow, divide, and evolve means 1000 experiments can be done in cell-free systems with the same effort it takes for one experiment in cells. This means more data to understand biological complexity.
Three elegant applications arise from using cell-free biology to understand our world. First, scientists are working to understand how life started by using cell-free biology to prototype the first cell, or “protocell.” Starting at the minimum set of items needed, can one understand life by resurrecting growth and division? Second, cell-free biology is being used to produce genetic circuits; in many ways, analogs to traditional circuits but with applications in controlling engineered cells. This has immediate applications for controlling the activity of microbes, or for engineering T-cells to activate or suppress for cancer treatments. Finally, cell-free biology can be used to help build understanding of biology, by teaching biological fundamentals to high school students. Biology becomes a programmable toy, where different instructions, encoded in DNA, allow students to produce different colored outputs. Only water and a pre-prepared cell-free system are needed to produce results.
Cell-free biology is exceptionally robust. We now know that cell-free systems can be “freeze-dried” into stable, paper strips that can be deployed, room temperature, in the same way a pregnancy test can. Additionally, unlike with cells that can grow and contaminate the environment, cell-free systems are dead and cannot replicate, mitigating concerns about the release of genetically modified organisms.
It is this intriguing feature that has been studied by groups as a way to sense biological threats without the use of expensive equipment. These can detect threats to health like Zika. In the future, one can imagine cell-free systems made in this way playing a critical role in the personal health revolution, where cell-free biology can be used to sense issues in your genomic information by functionalizing the activity of genes in real-time for your doctor. A variation of this already exists, where cell-free biology is being used to manufacture medicines “on-demand.” A freeze-dried cell-free system and an envelope of instructions can allow those in resource limited environments (places without power, or even space) to produce things on the personal-use scale that otherwise would require resource-intensive factories.
As a physician-scientist, the ability of cell-free biology to mine molecules from nature excites me the most, and drives the mission of Tierra Biosciences (formerly Synvitrobio), the company I lead. The most important compounds we use as a society are produced by the plants and microbes that surround us — things from the mundane, like caffeine, to things as important as penicillin to treat disease and pesticides to protect crops. However, we’ve been finding fewer and fewer molecules, leading to crises such as antibiotic resistance. In the US every year, at least 23,000 people die from infections we used to be able to treat.
The diversity on our planet, however, is vast, an estimated 1 trillion unique species, each with the capacity to produce new antibiotics and other molecules. However, we have only scratched the surface of this diversity. As biologists, we routinely work with only 10 species, and the vast majority of the others (99.999999%) we cannot grow. If we can unlock this diversity, can we unlock a new golden era of identifying natural products?
To me, it is exciting that the instructions for making all of the new molecules already exist. They are just encoded in a “treasure-map” that needs to be followed — DNA. Microbes use their own DNA to determine what molecules to make in order to survive in their environments. Given advances in next-generation sequencing, we now know much of this DNA, and almost all of it, including that found on New York City subways, remains uncharacterized. Here is where I think cell-free biology shines, as a tool to rapidly search this DNA for molecules. Utilizing the hyper-throughput property of cell-free biology, at Tierra we’re looking to build a search engine of sorts, that can screen through this DNA and effectively functionalize it to make molecules that nature has evolved but that we have not yet found. We envision a new golden era of natural products, that will bring new antibiotics, therapeutics, and other molecules to market.
With so many avenues of cell-free biology being developed and more future applications yet unknown, it is an exciting time to work in this field. I believe in cell-free biology because it is fundamental to our future. As the field grows, I have been thrilled to see growing numbers of cell-free enthusiasts at conferences and workshops sharing their research. We are starting to see dedicated funding from federal agencies ranging from the Departments of Defense to the Department of Energy to explore its potential. Continued government funding of this area, especially in areas of basic science and health, is critical for cell-free biology to reach its full potential.
Thanks to Zach for the primer, and best of luck to the Tierra team — they’re on a roll recently and it’s exciting to see what’s next.
Have a great week,
Alex & the team from Social Capital