18
Apr
2019

Life After Twitter

[Editor’s Note: David Shaywitz is a Palo Alto-based life science VC. He used to be active on Twitter. I asked him to share his reflections on leaving the platform–LT.]

Quitting carbs last year was hard. Quitting Twitter this year has proved delightfully easy.  You might even want to try it for yourself.

David Shaywitz

Twitter has tremendous upside. Most notably, it provides the chance to connect and engage with more, and more varied, people than you otherwise might, and in the process, learn things you didn’t know, and hear about interesting articles you might have missed. A real highlight of the medium was getting to know so many extraordinary people in the healthcare and biotech communities. My Tech Tonics podcast co-host Lisa Suennen (@VentureValkyrie) and I originally met on Twitter, for example.  I’m impressed by the ability of colleagues like Bruce Booth (@lifescivc) to use Twitter strategically and effectively, sharing thoughts on science and investing while steering clear of politics.  Many top scientists also enjoy the engagement of Twitter, as rock star Stanford chemist and Twitter newbie Carolyn Bertozzi (@CarolynBertozzi) recently highlighted on her captivating Long Run podcast with Luke (@ldtimmerman).

And yet.

As my economist friends (who, I acknowledge, I mostly met through Twitter) incessantly emphasize, everything is about trade-offs. The relevant question about Twitter isn’t whether there are benefits, but rather, whether the benefits are worth the costs. This analysis presumably will differ for each person.  For me, the calculus was pretty easy, and I’m hardly alone (indeed, “How I Improved My Life By Quitting Twitter” feels like a blogging subgenre at this point).

The costs of Twitter are consequent to the attention it demands and extracts, and the amount of mindshare you give over to it. Insidiously, it seemed to claim more and more of my time and emotional energy in the years since I first joined in 2011. You could say I became a very avid user. I tweeted around 45,000 times over an eight-year period, and had around 13,000 followers. Even though I carefully curated a group of just 40 accounts to follow, in effort to minimize distraction, it wasn’t working. By late February, I decided it was time to quit.

Thinking about this decision reminded me of something from my medical training. In residency, we were taught that “the longer you stay, the longer you stay,” meaning that the longer you stick around post-call trying to get everything tucked away, the more things are likely to come up and compel you to stay even later.  Similarly with Twitter, the more you engage, it seems, the deeper you are drawn in, and the more draining it can be.

Among the most destructive aspects of intensifying engagement with Twitter I noticed was the tendency towards the performative. As you increasingly share your experiences with your Twitter audience, sharing itself can become part of the actual experience.  An amusing sign, a beautiful sunrise, a travel indignity, an interesting paper — each might be shared, as the sharing becomes part of a single continuous act of experience.  It also contributes to the intimacy of the platform, providing, at its best, points of unexpected connectivity among engaged users as you discover others who might share your enthusiasm for an author, hobby, or beverage, or empathize with your distaste for a particular airline. 

Of course, the idea of performance permeates Twitter, as many if not most tweets feel like participants’ effort to publicly define themselves based on what they endorse or critique, based on who they endorse or critique, and based on the language or themes they use to do this, or their use of language demonstrating affinity with particular groups or ways of thinking.  Most obviously, this would include profile features such as “MAGA” on the right, or listing pronoun preference, on the left. But the signaling can also be more subtle, and it also seems nearly ubiquitous, to the point where at least for some users, most every tweet seems intended to announce or reify tribal affiliation.

In real life, I tend to focus on people first, with little regard for politics; while I probably shade towards the center-right, I’ve always had friends and colleagues across the political spectrum, and never thought all that much about either their politics, or mine.  Yet Twitter seems to transit in caricature, where so many participants become two-dimension versions of themselves – maybe because of how they present themselves, maybe because of how they are understood.  Participating on Twitter can feel like a constant battle to preserve dimensionality and nuance in a medium that seems determined to reduce it, and turn grey scale into black-and-white high contrast.  The medium rewards hyperbole and outrage, and seems to push everyone centrifugally towards the extremes. 

Fortunately, as Mona Charen recently noted, “Twitter Ain’t America.”  When you’re active on Twitter, you feel that most everyone in the world is on it. But this turns out to reflect a hefty degree of ascertainment bias, as users are constantly reminded of those who participate, and lose sight of the many more who largely avoid the platform — including the vast majority of senior executives I encounter.   In 2012, I argued that most CEOs didn’t need to be on Twitter; I suspect most now agree, leading many to maintain de minimis accounts largely managed by their PR departments, and utilized almost exclusively for broadcast, rather than more substantive engagement.

Immediately after I quit Twitter, I discovered a book that tremendously fortified my decision: Deep Work, by Cal Newport.  The basic thesis is that concentrating on difficult problems is hard, and requires practice; instead, we tend to avoid such “deep work” by engaging in a range of fairly superficial activities. His argument is that we would do well to deprioritize these in favor of learning how to focus.

In addition to being entirely off Twitter since February, and deleting it from all my devices (I’ve retained my account as I can envision having it managed dispassionately by a PR firm at some point simply to share articles or perspectives), I’ve also deleted both LinkedIn and Apple News from my iPhone. The LinkedIn notifications were increasingly distracting (with over 900 pending invitations, signal is increasingly difficult to detect through the noise, and I’m increasingly tempted to drop this platform as well), and Apple News always felt like a rabbit hole.  I never was a Facebook user, which saved me the trouble of quitting. 

Among the surprises I’ve encountered is that the moment-to-moment news flow is far less critical than it can seem when you’re on Twitter.  Almost nothing is all that urgent. Reading a news digest daily seems to be enough for me to stay up with current events. Once a week, or even less, would probably be fine for most things.  Perhaps it’s the “slow news” analog of slow food, and it seems to work really nicely, and it feels wise not to confuse the heat of agitation with the light of insight.

While I’m not sure I’ve yet achieved the “Deep Work” ideal, I feel that I am progressively rediscovering my ability to focus intensively, and am truly enjoying the opportunity to dive deeply into tremendously exciting areas like immuno-oncology and gene and cell therapy.  Admittedly, it probably helps that I love what I do, and I’m blessed to be in an environment that provides access to the tools I need, and in a role that affords constant opportunities to engage, in person, with so many creative and highly-motivated scientists, physicians, and entrepreneurs.

Outside of work-related reading, I’ve also enjoyed several unusually good books, including in particular: Dreamland, by journalist Sam Quinones (a superb, highly nuanced account of the opioid crisis); The Compatibility Gene, by immunologist Daniel Davis (I had recently reviewed his latest effort; The Beautiful Cure, for the Wall Street Journal, and was delighted to discover how much I also enjoyed his earlier book about the MHC); and The Secret Life of the American Musical (a guilty pleasure), by Broadway producer Jack Viertel.

While there are aspects of Twitter I miss, the benefits of restoring mindshare and attention far outweigh anything I’ve left behind.  One of my most precious resources is my attention, and I’ve recognized the importance of nurturing my ability to focus, and defending against distraction, while somehow still remaining open and receptive to exciting and orthogonal ideas.  I don’t think there’s a formula for achieving the ideal balance, but quitting Twitter has felt like a great place to start.

9
Apr
2019

The Road Less Traveled in Glycoscience: Carolyn Bertozzi on The Long Run

Today’s guest on The Long Run is Carolyn Bertozzi.

She is a professor of chemistry at Stanford University, and an entrepreneur.

Carolyn Bertozzi, professor of chemistry, Stanford University

Her research is focused on glycans – the beautiful and bewilderingly complicated sugar molecule structures attached to proteins. These carbohydrates are often underappreciated by biologists, and “orthogonal” to the way many think. But glycans are known to play a significant role in how proteins behave, and a wide variety of interactions between cells.

Whether you can aim drugs at some of these glycan targets and get the disease modifying effects that a typical medicinal chemist desires – that’s the kind of open question that has driven much of Bertozzi’s research over the years.

Bertozzi took a gamble early in her career to get here. She joined an immunology lab where it wasn’t entirely obvious that a chemist would add much. By forcing herself to think outside one discipline, she ended up bridging fields in an interesting way. The raw and messy edges of disciplines is often where big advances occur.

Without question, Bertozzi is now an established star. She won a MacArthur “genius” grant early in her career, later won the prestigious Lemelson-MIT Prize for invention, and was elected by peers into the National Academy of Sciences. She’s known for leading teams that developed tools to provide better imagery, better information, about glycan behavior in live action. When you develop tools or methods that lots of people can use and which advance an entire field – that’s the kind of thing that gets you placed in the scientific history books.

Bertozzi is also a warm and funny person to talk with. She cares about open science to speed innovation, communicating science to the wider world, and in supporting women’s advancement. I enjoyed asking her about how she got to this point in her career, and how she thinks about biology evolving to embrace the kind of complexity that once deterred people from getting serious about her chosen field.

Please sit back, relax, and join me and Carolyn Bertozzi on The Long Run.

28
Mar
2019

Postmortem: 5 Lessons Learned from a Public Benefit Rare Disease Startup

Ethan Perlstein

On February 26, 2014 the first biotech public benefit corporation was born: Perlstein Lab PBC, which would eventually be renamed Perlara PBC. Almost exactly five years later, this bold and necessary — and some might say overly ambitious — experiment in rare disease drug discovery has ended.

For now.

Perlara, a company I founded that went on to raise $9.7 million and employ 20 people on 12 discovery projects at its peak, has now shriveled down to a single employee (me). I’m trying to find other homes for some of our assets, so they might still have a chance to thrive.

Anyone who has followed the South San Francisco-based company’s journey knows that we were devoted to conducting business and research in the open. That commitment to openness persists even while Perlara is winding down operations and transitioning to a virtual company. I want to see our most advanced discoveries advance to the clinic, even if it happens in someone else’s hands.

I’d like to share the top five lessons I learned as a first-time founder and scientist CEO so that the next time an experiment like this is attempted, it will succeed. Consider these the essential biotech startup commandments, in order of importance.

(1) Don’t overdrive your headlights

Imagine yourself behind the wheel of a high-performance vehicle careening down a two-lane country backroad on a moonless night. What happens if a deer suddenly appears in front of you? Do you have adequate reaction time and stopping distance to avoid what will likely be a fatal head-on collision? Prudence and caution dictate that driving more slowly will almost always ensure the car safely reaches its destination even if it will take much longer.

Managing cash burn and team bandwidth are the hardest jobs a CEO has. When I started the company, the “lean startup” philosophy was all the rage in tech circles and the “virtual biotech” thesis was earning plaudits from life science investors. I took all of those teachings very much to heart in 2013, when I was laying the groundwork for the company’s launch. That’s why I rented lab and office space in what was then the brand new QB3@953 biotech incubator (now called MBC Biolabs), starting with just one bench/knee well and one desk in January 2014. We were then bursting at the seams in this space with nine benches/knee wells and two small offices three years later.

This is when I made the first mistake of stepping on the gas when I should have taken my foot off the accelerator. We moved out of the incubator (in fairness we were like the millennial overstaying her welcome in her parents’ basement) and into our own space. All of my peer companies that launched around the same time were also searching for their own (larger) spaces. At the time it was all we as CEOs talked about. But the only way to finance the move was to bring a subtenant in tow. The math actually looked good, or that’s what I convinced myself: we were paying 2.5X more in rent per month but we got 8X more space. No matter how you slice it, that meant our fixed costs went up and our runway shortened.

I made the mistake of stepping on the gas pedal a second time when I should have pumped the brakes.

We kept launching new PerlQuests, our term for collaborations with rare disease patient advocates to advance our discoveries into clinical development. It made sense at the time, based on the productivity of our discovery platform. So we doubled the number of PerlQuests from three in 2017 to six by mid-2018. I told myself it was okay because we had not only achieved product/market fit (patient advocates were lining up support for trials, providing needed cash and eager research subjects in some cases) but also because we were growing organically.

In retrospect, the demand for PerlQuests outstripped our supply of resources. It’s not like we were a charity taking on commitments for free. As the only PBC in this space how could we turn away any family or foundation that was willing to work with us? We almost 10X’ed PerlQuest revenue year over year, launched a dozen PerlQuests in total, and in fact we were cashflow positive for few months at the end of 2018. But P&L statements don’t lie. Like a law of nature that cannot be defied, more money was flowing out of our bank account than flowing in, and that can only end one way.

(2) Choose one variable, hold the rest constant

There are three principal axes of any biotech company: the science, the business, and the brand. I think it’s fair to say that the vast majority of biotech companies create edge with their science, whether it’s an asset-centric or platform play. At the same time, they keep the business model constant, whether than means exit by acquisition or IPO. And they basically ignore brand altogether or go with formulaic and focus-group-tested websites featuring stock photos of happy patients and slogans about patient centricity. The astute reader is vigorously nodding in agreement because there’s a reason why biotechs vary the science while holding the other two variables constant. The science is failure-prone enough!

I purposefully made the decision from the outset to tweak all three variables at the same time, continuously. The model organism science at the heart of Perlara’s discovery engine was certainly heavy lifting on its own. Indeed, just being a platform company put us a relative disadvantage because of the higher technical hurdles and longer timelines for success compared with a single-asset company.

From meetings with investors, I learned we were regularly being compared to the first model-organism-centric platform company Exelixis. That wasn’t a helpful comparison, as that South San Francisco company burned a lot of cash and dragged down a lot of investor portfolios before finally turning things around in recent years with a single asset. My standard answer to the Exelixis comparison was that it was simply ahead of its time in the 1990s and early 2000s before the advent of diagnostic whole-exome sequencing, CRISPR and social-media-enabled patient advocacy groups.

For many investors, our scientific approach was a non-starter. Too risky, too expensive, many thought. In the end, it turned out that our science was robust, and not as risky as some imagined. Two of our PerlQuests identified repurposable clinically actionable drugs that already had significant safety databases to their credit. That, includes the NGLY1 Deficiency data package I set free into the public domain as one of Perlara’s dying acts.

No, the science wasn’t the bugaboo. It was the business model that was fragile.

For starters, as a Public Benefit Company, we had an unusual corporate structure that investors needed to spend some time and energy getting their heads around. Yes, you could still make a profit, as long as your work was aligned toward a Public Benefit. Yes, one could imagine Perlara getting acquired some day and generating liquid returns to investors. That took some explaining.

Then came our PerlQuests. What we eventually called the PerlQuest started out as a sponsored research agreement modeled after Stanford University’s template. Highly motivated rare disease families, organizations and impact investors not personally affected by a rare disease, paid Perlara to create patient avatars and deploy these personalized models first in drug repurposing screens and then in drug discovery screens.

The unflattering view of the PerlQuest model was that it was just contract research, which is a brutal business: cost overruns, low or no margins, and the unpredictable twists and turns of any research plan. Although we experienced all of those challenges, we viewed things differently (and perhaps through rose-colored glasses). The PerlQuest model was a way to bootstrap a diversified pipeline of rare disease programs staggered across discovery, preclinical and clinical stages while working with patient partners who were all in.

Why did patient advocacy groups trust us in the first place? I believe it was because of our meticulous attention to brand, which was in the service of patient engagement. As the first biotech public benefit company, we hard-coded patient centricity in our Articles of Incorporation and in our PerlQuest contracts. We tweeted and blogged research updates in as close to real-time as cutting-edge science allowed. If we hadn’t invested in building a brand and patient engagement that capital would have been spent on research. I don’t regret the decision but it’s hard to know if that would have made a difference in the end. When there is little margin for error, every little bit counts. Every CEO has a fixed mental bandwidth. I wore three hats: chief fundraiser, chief scientist and chief marketer. It had spread myself too thin.

(3) Pick your partners wisely

The conventional wisdom about platform companies is that they must partner out their lead program preclinically in order to prove the value of the underlying discovery engine. I made the calculation early on that we needed a marquee Pharma collaboration to establish street cred with patient advocacy groups. I was also hoping that a Pharma deal would also include an investment, which would establish street cred with professional biotech investors. As soon as we had completed our first high-throughput screening campaign for our lead program in Niemann-Pick Type C/NPC in the summer of 2015, the preclinical partnership roadshow commenced. I must have presented to a dozen companies. Invariably the response was the same: great progress, but you’re too early for us to start working together.

In the Fall of 2015, I had my first meeting with Novartis. I’d initially assumed that we’d partner with a rare disease company like BioMarin, which already had programs in lysosomal diseases like NPC. However, after the first conversation between us and the folks at Novartis on the science side who became our biggest internal champions, it became clear that there was a fit on multiple levels. It took an entire year for the deal to coalesce, which is typical of small biotech, big pharma deal cycles. You have to have the capital to survive the negotiation, which is why any small discovery shop must identify and stick to a short list of ideal partners and be disciplined about taking extraneous meetings with unlikely partners to be. Our two-year discovery collaboration focused on target identification for a novel chemical entity for NPC, which we called PERL101. Although we came close the underlying biology proved to be too complex to unravel in the time allotted. While we are still in the process of writing up all of the discoveries we made, the collaboration itself ended amicably last Fall without a commercial path forward.

Partnering with rare diseases families is exhilarating but fraught in its own ways. Not all families are equal. Some come to the table with wealth, connections and other resources. Not all families are able to balance caretaking with foundation building and all that entails: organizing, fundraising, advocacy, assembling a Scientific Advisory Board, and ultimately NewCo creation. And then there’s the unfortunate dirty little secret about rare disease communities, even tiny so-called ultra-orphan communities: fragmentation of families and researchers.

Alas, I’ve seen it happen over and over again. Families affected by the same rare disease don’t always cooperate with each other. In fact, there are rifts and feuds which make no sense to the outside observer. Then again when your world comes crashing down in an instant after a fateful diagnosis leaves the doctor’s lips, nothing makes sense anymore. It’s not just the families who fracture. Researchers are guilty of it too. All it takes is one or two researchers to win the favor of families and effectively usurp the purse strings and research agenda, deciding which projects get funded and which don’t. In the worst cases groupthink prevails and contrarian ideas – and the researchers who propose them – are exiled.

(4) Make a beeline for the clinic

This may strike some as controversial but everything a platform company does is noise except clinical proof-of-concept, even an n-of-1 study in a single patient. There are no other key performance indicators even close to a positive signal of efficacy in a human being. When 90% of drug candidates entering the clinic fail no matter how they were discovered, nothing else matters except human data. Unless you’re Moderna or the like, no platform receives the benefit of the doubt, at least not from investors. When I tried to raise our last round of funding — at a time when we were 12 months away from realistically entering the clinic — this response from a leading VC captured that sentiment:

“We reviewed with our broader team and are not in a position to move forward at this time. We continue to struggle with novel phenotypic screening models as we see other teams behind initially productive appearing platforms struggle with the challenges of preparing for the clinic. Given what we’ve been seeing in the market, we’re not ready to make a bet yet. Thanks for thinking of us. We often get these early calls wrong, but since we are stage-agnostic we are happy to pay up in future rounds when the company becomes a better fit for us.”

On the one hand, it’s a seemingly impossible feat to capitalize a discovery engine to generate a portfolio of clinical bets and at the same time have sufficient capital left over to advance a lead program to clinical proof of concept. On the other hand, they’re issuing a formidable challenge to all platform companies that they have to figure out a way to reach the clinic in the most capital efficient manner possible. The winners of this challenge will be handsomely reward with growth capital.

(5) Make something patients want

Every lesson above is a cautionary tale of what not to do and when and where to tread carefully. This final commandment – modeled after the Y Combinator motto “Make something people want” – is an example of what we did at Perlara that should be emulated, in my opinion. Engage with patients on their level and empower them with open science. When you actually stop and listen to patients and patient advocates, they have so much to offer. The best compliments I ever received from rare disease families were to the effect of, “You think like a parent; you think like us.” That’s how I know Perlara was truly disruptive. As I consider my next move professionally, the families that inspired me over the last five years will remain my compass, my true north. Onward and upward!

26
Mar
2019

Life of a Scientific Entrepreneur: Bob Langer of MIT on The Long Run

Bob Langer is today’s guest on The Long Run.

Langer, an Institute Professor at MIT, is one of the nation’s most accomplished scientists and scientific entrepreneurs. Much of his work has focused over the years on tissue engineering and drug delivery systems.

Bob Langer, Institute Professor, MIT

It would take half this show to list all of Bob’s contributions to biotechnology, so I won’t. But the short version goes something like this. He’s one of just a handful of people ever elected by peers to all three National Academies. He’s won the top awards for science and engineering from the Queen of England and two U.S. Presidents. He’s had a hand in founding more than 20 biotech companies. He’s the most cited engineer in history, and the 6th-most cited scientist ever, according to Google Scholar’s H Index.

Langer recently turned 70 years old, and he’s still running a lab of 100 people who are thinking big. One recent project of note: A sort of biodegradable “needle” that can be swallowed, and still deliver insulin for diabetics, without the need for shots.

I’ve known Bob for about 10 years, mainly focusing on startups he’s had a hand in creating. Despite his lofty accomplishments and busy schedule, I’ve always found him courteous and responsive and a pleasure to interview. More than 600 people – former students, colleagues, partners and the like – showed up for his 70th birthday symposium last fall.

That says a lot.

Bob’s path to success, like most, didn’t always move along in a straight line. In this conversation, he’s quite open about some of the tricky junctures he encountered along the way. His resilient character – he would call it ‘stubbornness’ – has been every bit as important to his success as his intellect.

Now, please join me and Bob Langer on The Long Run.

12
Mar
2019

Seeing Lots of Single Cells, Up Close: Serge Saxonov of 10X Genomics on The Long Run

Serge Saxonov is today’s guest on The Long Run.

Serge Saxonov, co-founder and CEO, 10X Genomics.

Serge is the co-founder and CEO of Pleasanton, California based 10X Genomics. This privately held company, in a nutshell, is a fast-growing supplier for the genomics revolution.

10X, for those unfamiliar, makes instruments, chemical reagents for running experiments, and software that helps scientists collect and analyze various types of data. The tools are allowing researchers to move away from some fuzzier measurements of the past, and more toward high-resolution analysis of single cells. 10X has positioned itself to enable scientists in fields like cancer research, immunology and gene editing to ask and answer a lot of ambitious questions.

The company has attracted quite a following in the scientific community. A recent financing pegged its valuation at more than $1 billion.

Serge also happens to have an interesting life story. He was born in the former Soviet Union, and emigrated to the US as a teen, just before the collapse of the communist empire. He blossomed as a student at Bronx Science and then at Harvard, studying under the early genomics evangelist Wally Gilbert. He also had a formative early career experience at 23andMe.

This is a classic immigrant success story. I think you’ll find it inspiring.

Now, please join me and Serge Saxonov of 10X Genomics on The Long Run.