Biotech for the Biocurious

A field guide for the great biological century (with Shak Lakhani)

“History is hard to know … it seems entirely reasonable to think that every now and then the energy of a whole generation comes to a head in a long fine flash, for reasons that nobody really understands at the time—and which never explain, in retrospect, what actually happened.” -- Hunter s. Thompson, Fear and Loathing.

There’s something unique happening in biotech right now. Some once in a generation moment where low cost of capital, a century of maturing discoveries, and a global pandemic collide.

Figuring out exactly what is happening beyond regurgitated headlines remains difficult. Even outside of vaccine progress— rate of new company formation, new discoveries, and cash inflows in the field are all growing at breakneck pace. We literally have no playbook for what the next decade of biotech will look like.

There is no better time to get into the field. We’ve written the following guide to take someone from a weak recollection of how the mitochondria is the powerhouse of the cell, to being conversant enough to navigate the field with confidence. To be clear, this isn’t a guide on how to build a biotech (Kolchinsky already wrote that), or how to be a biologist (need a PhD for that one)— but to get from 0-60 in understanding the field as quickly as possible.

Basic Biology 

Unless your memories of high school are primarily concerned with the Krebs cycle (ours aren’t)— we’ve got to get back up to speed with the basics. Read the short Quickstart Molecular Biology: An Introductory Course for Mathematicians, Physicists, and Engineers (preferably) in addition to the longer Molecular Biology of the Cell. These are both classics that are helpful in getting our feet under us before we continue.

To go deeper, The Eighth Day of Creation is a fantastic book that tells the story of modern biology from the discovery of the double helix to the sequencing of the genome. It’s long, dense, and lovingly crafted— everyone reads at some point— but if you find yourself getting stuck, its not critical to moving forward. Genome serves as a great booster or alternative, providing a more modern history of the genome.

Now before we continue, it’s important to delineate between biotech and healthcare. While the two fields are intimately tied, an understanding of the practice of any of the two does not necessitate an understanding of the other. You should figure out which of the two you care for— and learn it before trying to understand the nuances of where they meet.

While we will concern ourselves with biotech here— some great works on healthcare include Atul Gawande’s Being Mortal, Complications or Better, Siddhartha Mukherjee’s The Laws of Medicine, and Stat News. You should also follow Eric Topol, Sek Kathiresan, Scott Gottlieb, and Christina Farr on twitter.

Baby Steps

If you were a university student learning biology— you’d next go from the intro textbooks to a series of more and more complicated courses where you learned how those basics were wrong in weird and nuanced ways before stumbling onto one nuance you loved enough to build your career around.

If you’re looking to become a biologist, this is the correct way to learn. That is not our goal here, so let’s get moving.

Understanding industrial biotech requires reading a hell of a lot of literature. Reading literature is a skill, the only way to get better at it is to read more literature. We’ll likely go into how to read a paper well at a later date— but for now pick a topic of interest and track it. Follow Nature, Science, Cell, PNAS and NEJM or bioRxiv and medRxiv. Pubmed publishes a daily index of trending papers, and Meta can provide interesting supplementary feeds on particular topics. The 80/20 rule applies here, aim for big ideas, concepts, and cross field connections— exact details will follow later.

Big enough government

Biotech is a regulated industry, from top to bottom. Understanding the regulatory environment is critical in any real understanding of how the industry moves.

FDA is a progressive and a relatively easy to work with agency. This isn’t sarcasm, nor has it always been the case. The FDA isn’t Dikembe Mutombo trying to swat away shots on net - rather, they’re just trying to stop Shaq from breaking the backboard. 

It’s worth understanding how a drug gets approved. FDA, unlike many federal agencies, is extremely transparent and well documented. They furnish a treasure trove of information regarding clinical and preclinical trials, regulation, long form advisory committee briefs, and a variety of open data sets. 

If you find yourself wanting to understand how we got here— Hilt’s Protecting America's Health is also a classic. You’ll also want to understand the changes the agency experienced under Scott Gottlieb, and its modernization around Real World Evidence. STAT News has great coverage of both.

For understanding clinical trials— reports active and completed trials. The European equivalent is the CTR. All are query-able to various degrees. It’s worth your time to dig through a few trials to understand, across phases, how data is reported, patients recruited, and studies conducted. Learn about inclusion/exclusion criteria and why they matter, what a p-score is, and why statistical power is one of the most important concepts in the field. 

Industrial biotech

Industrial biology has a rich history of peanut galleries of various quality. Some of the higher quality ones are:

The truth is outside of STAT and few others, most of these are just grinding republished press releases. Find the writers you like and stick with them, you’ll get 99% of what matters. What matters here is getting a gut sense of the players and firms making up the industry.

For more speciality coverage:

For additional depth, the additional books are great:

Helpful supplements including In The Pipeline, Drug Truths, Curious Waveform, PlengeGen, and Bob Nelsen’s Twitter are self recommending, highly followed, and high quality blogs covering discovery through commercialization.

We would be remiss to not recommend Kolchinsky’s Entrepreneurs guide to a biotech startup. Perhaps the most widely read industrial playbook in existence, it has been critical to both of our and hundreds of others careers.

Deep Dive: Biotech Foundries

A number of household names in therapeutics are the product of a small subset of biotech investors uniting with leading academic institutions, commercializing advances in research at breakneck speeds. This incubation process doesn’t have a clean parallel in tech investing (Atomic may be the only close parallel), so it’s worth digging in. 

Firms like Flagship Pioneering (Moderna, Denali, Editas), Third Rock Ventures (Insitro, Thrive, Foundation Medicine), Arch Venture Partners (Illumina, Alnylam, Juno, Beam), Atlas (Alnylam, Momenta, Intellia) are what we call newco creation funds— investors that are primarily building and funding new firms internally.

These firms often operate with a revolving door system, with key positions at their incubated companies filled by experienced dealmakers and ex-big pharma vets with a strong understanding of their industry’s pain points and emerging trends. Within any given firm, there are often a number of ideas being incubated in parallel, and a partner may be serving as the “fractional CXO” of 6-10 companies at once.

They’ll cycle EIRs (entrepreneurs-in-residence) with notches on their belts into companies to serve as founding executive teams and build the base for institutional fundraising rounds or public market launches - sometimes, the process is EIR-led (ie. a given person wants to take an idea to market), other times it’s tech-driven, and an EIR is matched to the problem space based on their background and expertise.

In most cases, a small syndicate of venture-creation specializing firms will fund the company to its Series A or B, and maintain ownership of ~80% of the company, with the remainder reserved for executives, employees, and new investors, with a goal of maintaining ~50% ownership post IPO. 

A few labs, especially out of Harvard and MIT and southern California, are factories for churning out commercializable/ venture-creation friendly IP; it’s no surprise that Boston and San Diego are the world’s biotech dualing Meccas as a result.

The Langer lab has touched almost every branch of nanomedicine imaginable, leading to the creation of over 40 companies and influx of a few billion into the biotech ecosystem (Moderna, Momenta, Kala, Lyndra, to name a few).

The Church lab holds a similarly exalted status in the world of genomics and synthetic biology, leading to the creation of Dyno Therapeutics, Editas, Gingko Bioworks, Nebula Genomics, Poseida Therapeutics and many more.

The Liu lab is quickly approaching similar levels of prominence over time while riding the wave of the gene editing revolution, based on involvement in the founding of Beam, Editas, Prime Medicine, and more.

Of course, we’d be remiss not to mention recent Nobel Laureate and CRISPR pioneer Jennifer Doudna and her growing family of gene editing co’s, including Caribou, Intellia, Scribe, Editas, CRISPR Therapeutics, Mammoth Biosciences and more. 

All are worth watching, and make up a critical mass of new company formation, exciting new modalities that could change the way we handle diseases today, and of course, flow of investment dollars into the space.

Up Next: Shak and I intend to do a few more of these diving into mental models, specific companies, and frameworks for understanding what is happening within the industry. Feedback is very much appreciated.

on august

brief notes on summer walks

August has always been hostile. The place that I’ve come to know as the last pocket of pure beauty possible in an American city morphs into a sick, sweltering maze of tangled sidewalks drowning in stagnant, hot air.

There’s a walk I like to do on these days, when leaving anytime but at dusk is impossible. I leave the AC whirl of my apartment and wander a few miles out along the river. Even as the sun drops, the air is still unbearably hot and the river breeze putrid from the summer algae blooms.

The walk is miserable. The bench that marks the end of the loop is hardly a destination worthy of the effort. A small grove of trees behind a rowing club provides almost total silence save for the splashing of oars, and enough distance from the river to not fill your lungs with its stench. It’s an imperfect, but tolerable spot to sit down with a book for a few hours.

Once the light has fully faded, the walk home begins. Which is, in whole, the only reason why leaving my icebox during this month at all is worth it. None of Boston’s streets can be described as anything close to a line. A drunken stumble, a zig-zag— sure, but not a line line. And it is impossible to not backtrace many of them as I wander home. It is staggeringly silent.

On these nights it’s rare to run into a single person, a particular blessing in a year like the one we’ve had. These blocks seem to swell even tighter with homes on every walk. There are no street lights, not that you need them anyway. The lives being lived within, diffused through curtains blown out of open windows is enough to light the entire way back.

The walk back doesn’t last long. But there is something close to perfection about it. An almost total disembodiment from the month that makes our bodies almost unavoidably real. Even as the air is still thick and hangs low as to make your skin feel much more like skin— all of these pieces assemble into the most fleeting of joys. The ability to escape the too hot, too loud, too busy life lived in a city for something that feels just a little closer to a home.

It is nearly October now, and the with the brutal chill setting in early this year and dark coming earlier and earlier these nights are all but gone. To mourn it is foolish, the months ahead are the most beautiful here, but I can’t help but be thankful for what I will soon have and lose again.

My infrequent writing here has never intended to serve as a life update. The 30 or so you that hung onto these over the past year have almost all been folks that I am lucky enough to have present in my life.

However, after the last newsletter fiasco, the first I ironically didn’t write— we’re now at a couple orders of magnitude more than that so a life update might be in order. Cascade, now nearly two years old, has grown to a point where its existence will soon see daylight. This is as thrilling as it is terrifying, and will make for a busy fall.

Outside of this, I’ve been finally getting back into a daily practice of bookbinding. I hope to return to write about this in a few months, but in the mean time, there’s much too much to do.

longevity, and resets.

cheating husbands and informational suicide

Many friends have taken a serious interest in longevity.

I get it. But I've always been more interested in the other lever; resets.

There's little reason identity should persist across 80 (or 200) years. French Foreign Legionnaires and cheating husbands have always presumed new identities. Identity persistence has only recently happened as a result strong government record keeping and centralization.

If we are going to pursue biological longevity-- we should allow a diversity of lives to be lived. Many folks achieve this with an 'alt'-- see LARPing and trail names. But if life is to be radically extended, information resets seem almost necessary. That is to allow total amnesia as a choice. Total reset.

I see it as an extension of what we do online. We can have different avatars/profiles/etc in different spaces, and there are also different spaces for different purposes. Online games are not necessarily meant to be a place where you live your entire life (although it does happen), but they are meant to be places where you can explore different parts of yourself or engage in different types of play.

Not taking this seriously feels like the same type of failure the anti-longevity often traffics in. That is to refuse to believe that the way we are living life now could not be better because it lack's biological precedent. Sometimes all you need is to reset the game.

So maybe it's just that I don't see why our first lives should be the only ones that we can explore. Maybe we can have lives for different spaces in our limited time. Or maybe this is just wishful thinking on my part?

This entire post was written by GPT-3 without editing, primed with a post from Nadia Eghbal.

a pandemic of confirmation bias

COVID-19 proves you right-- and this isn't a good thing.

It's time to admit you were right. Every single one of you.

COVID-19 represents the end of offices and neoliberalism. The final fall of the deep state, and both the ascension and decline of the West.

If you thought about pandemics at any point in the last decade ― while reading an article about bacteria-resistant superbugs, or as you checked off that gen bio requirement ― you were right.

Your entire worldview and theory of history is, undeniably, correct.

The irony here is that none of this is ironic. COVID is about the furthest thing from a black swan imaginable ― a veritable buffet of confirmation bias for whoever cares to sit down and dig in.

Any theory of history, given a weak enough epistemic spine and a margin of error, saw this coming. So as folks take victory laps celebrating their perceptivity, let us remember that predicting the past by no means indicates they’ll be any better at seeing what comes next. In fact, likely the opposite.

What next? That’s the only question that matters now, and the past isn't helping us. So let us be careful of mask-wearing charlatans, no matter how early they put those masks on.

we were promised flying cars and all we got were apps

thoughts on Big Sky Health's recent raise, and what it means to me

It's easy to be cynical about Big Sky Health's recent funding announcement. The narrative writes itself: another Silicon Valley health trend catches favor with the Tim Ferris crowd and scores a few million in funding.

I'm not in the business of litigating if this reaction is correct. I don't know the company, its founders, or anyone doing the financing. But I do know that Zero, Big Sky Health’s fasting app, is the single most important piece of software I've used in a decade.

When I began working on the company that has dominated the last few years of my life, I was sitting at 300 pounds. Calorie restriction, running, and exercise had made little impact on that. I was on a one-way train to a health disaster.

I started using Zero in January of that first year. I was skeptical of intermittent fasting, but the increased focus it promised seemed worth chasing.

Within weeks, the added focus was clear in my day-to-day work. Within a year, I was down 100 pounds with only limited lifestyle change. I was also feeling better than I ever had.

Now two years later, that figure is closer to 120 pounds, with 438 fasts completed. My resting heart rate is half of what it was.

Just occasionally, an app is enough to make a major change in someone’s life. This one sure made a change in mine. Congrats to the Big Sky Health team, and hopefully this new funding allows many more stories like these.

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