Friday, May 17, 2019

My Career's Double Slit Experiment (or, A Funny Thing Happened on the Way to the Drydock)

When I announced recently that I had moved over to Ginkgo Bioworks, I was compelled to leave out an important part of that story.  Indeed, by just focusing on the (still open) position of NGS Head, I could avoid the sticky subject of how exactly I ended up there.  Today the press release finally went out and the fact that Warp Drive's genome mining business is now owned by Ginkgo is public (covered nicely by Amy Feldman in Forbes).  But in the spirit of my periodic public coverage of my own journey, here is some of the rest of the story.
In the Fall of 2018 Ginkgo approached me about coming over to chat about genome sequencing and asked if I'd consider jumping away from Warp Drive.  Since I had helped launch Warp Drive back in 2011 (officially the company launched in 2012, but we were plenty busy in Fall 2011) it wasn't a trivial question.  But after many ups and downs I was starting to think about maybe doing something else, but there was one big campaign I wanted to be part of.

We were discussing a new round of genome sequencing to feed a deal being negotiated with Roche in the novel antibiotics space.  Could we assemble high quality genomes for on the order of 1000 actinomycete bacteria, given their difficult, GC-rich, repetitive nature -- and the fact that those repeats are rich in biosynthetic power and therefore absolutely must be resolved.  It was a great challenge and a nice cap for my career there and I wanted to do it.  So I foolishly told Ginkgo to check back in summer 2019 -- we'd be done by then.  And that would be a good jumping off point, because once we generated the genome sequences we'd have to digest them -- and like a python that's just re-hinged its jaws we wouldn't do a whole lot else.  I can always find a way to be useful, but the reality is the next phases of prosecution are long on microbiology and chemistry and short on bioinformatics.

Of course the project stretched out further.  Generating high quality DNA from over one thousand strains was tricky.  Methods I had developed and proven out on small pilots worked well for assembly -- but with so many genomes through the pipe the tail of failures was not tiny.  Plus it was a personally complex year for me, between the loss of my father and TNG escaping high school and getting ready for college.  Plus two mindblowingly amazing summer vacations.  And being peripheral to a major news story when gas mains went haywire where we live -- the day before we were shipping the boy off to his dormitory.  So the project was successful but had a large residue of not-quite-assembled genomes which it would be painful to walk away from.

However, other events were creeping in to deliver a surprise.  Warp Drive was getting long in the tooth -- and short in the bank account.  Management was out seeking new funding.  There was also a fundamental anomaly in Warp's business plans.  Most companies that size rigorously focus on a single clear strategy, but early on we had grown two.  They both sprung out of the initial quest to find new members of the rapamycin/FK506 family of compounds.  One branch was the genome mining effort I was in, but another was an attempt to exploit the unusual biophysical mechanism of these compounds -- they subvert cellular chaperone proteins to help bind to their real target -- using medicinal chemistry.  That effort was aimed at undruggable cancer targets.

Antibiotics and oncology -- they are both critical areas needing new drugs, but many investors will be interested in one or the other.  There was some useful swinging of expertise between programs -- I had some fun pitching in a few times on the "SMART" program (and yes, at one point I proposed christening our effort Discovering Useful Molecules Bioinformatically). And ebbs in flows in funding of each side could buffer each other.  But there was always talk of splitting up the company or terminating one half.  We were an odd duck.  Still, we all want to change the world.

Then came October and internal news -- soon released to the world -- that instead of new funding management said they'd got a real solution -- we had been acquired.  And acquired purely for the oncology effort.  And that it was unclear what would happen to Genome Mining.  As employees, we said: "We'd love to see the plan" --  but there was a lot of confusion and uncertainty (well, sadly, except the folks on the other side who were certainly being laid off) -- but when you talk about destruction (of the company I helped build), don't you know that you can count me out?

Well, that kicked things into gear -- and indeed two people I knew at Ginkgo contacted me that day.  And other folks started being nice and suggesting contacts.  So I started pounding the pavement and talking to people and its nice to have options -- but quickly those compressed into two.  Some places just stopped returning my calls and others were on timelines which didn't work well for me personally -- I wasn't looking to sit around for months while a company got funding.  And after weighing my options, I decided Ginkgo was a good fit.  Well funded.  Proven leadership.  A chance to join a big community of computational biologists.  A shop full of sequencing gear.  Cool projects and enthusiastic people in a fun environment.  Look at the boxes on a checklist of a good job: check after check after check.

There was one last issue -- when to jump?  I spent November on a last push to use Nanopore data to fix up some sequences (with an insanely good scientist doing the hard work in the lab).  But the acquirer had put in place a pair of golden handcuffs, bonuses that stoked my mercenary side.  First we had to earn them, and next they had to pay them.  And as the payment date kept being pushed out, the field of potential acquirers for the business kept shrinking -- and soon was narrowed down to just Ginkgo.  And so, despite some frustration at having little to do in the interim, I decided to just go with the group.

The double slit experiment has been described as the central mystery of quantum mechanics.  A beam of something is shown through two slits in an opaque medium.  Depending on what interacts with the slits, the system stubbornly refuses to act in classical terms -- if you think the something is acting as a particle you find the evidence for a wave or vice versa.  Not so confusing with light, but whole molecules can be shown to have this wave-particle duality.  Which means for any given molecule, which path did it take?  Or did something solid go both ways?

Did I end up at Ginkgo because I struck out on my own?  Or did I stream along with the rest of the Warp Drive team? Yes. No.  Maybe.

In any case, we've been over by the drydock -- we have a working drydock out front (and the Boston cruiseport behind us -- and the airport across the channel and the main container port -- it's a busy place) -- we've all been over here since February.  One Warper chose not to accept the offer from Ginkgo and one made the strange decision to choose to take a job in Hawaii (c'mon, is the weather there really better?).  But we're all here and integrating into Ginkgo. 

When I was being recruited to Warp, there was loose talk of sequencing a few hundred genomes in the first year of operation. We were going to hunt our quarry by degenerate PCR and would need to sequence any hits to verify them.  Maybe sequence some knowns or suspected interesting genomes.  But when the PCR stalled a bit, I proposed piloting a crazy scheme to just skim-sequence our collections -- and was told we didn't have time to burn on pilots and to just do it!  We churned through around 20,000 strains that way the first year -- and follow-up sequenced hundreds upon hundreds.  Ultimately, we built a huge database of 135,000 strains sequenced to low depth -- which is already proving to be a wonderful resource at Ginkgo.

Even if we weren't continuing the antibiotic discovery program -- which is going forward -- all of the skill sets of my talented Warp colleagues map onto high demand areas at Ginkgo.  Which is perhaps the happiest part of the story for me -- leaving the company of Warp was one emotional barrier to cross, but infinitely more difficult was the idea of leaving the company of my valued colleagues.  The acquisition bypassed that issue. Thanks!

This is also satisfying as I got to experience a start-up through nearly its entire existence -- indeed through its entire official existence.  Third Rock Ventures had been incubating the project for a while when I joined in September 2011 -- even started having a CRO grow up some bugs for a pilot sequencing -- but almost everything concrete occurred during my tenure.  There were both corporate and personal ups-and-downs which I won't go into detail here (indeed, some I'd much prefer to discuss orally and not in the U.K.  -- I'm quite familiar with the case of John Peter Zenger ).  To ride the complete arc was a privilege and an honor.  I won't rule out ever working for a startup again, but I also wouldn't be surprised if I never do.  The timing was scientifically and personally right to take the leap then and I can't assume that will ever be true another time.

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