I've met so many entrepreneurial rare disease parents over the years that I’ve lost count. They have moved or are moving medical mountains to save their kids and others like them. But rare parent founders get no love from institutional players. Those days are done. Science, talent and compute are no longer limiting. Priority Review Voucher alpha makes the economics work. The missing spark is access to cure capital. That's why I’m incredibly pumped to relaunch @1000cures with my cofounder @ryan_1000cures! Ryan and I teamed up to create a “YC for Rare” that unites our biotech houses with complementary expertises, experiences and networks. 1000 Cures is an accelerator for lean startups led by parents on mission to cure pediatric rare diseases. We ride at dawn. Let’s go!

If libraries were smart they’d all have popup cafes and support a popup ecosystem! Why does it have to be one (legacy choice) or the other?

It is with a broken heart but defiant spirit that I announce the wind down of @PerlaraPBC. After 5 unforgettable years this ambitious, hopeful, necessary experiment is over. We lived as the first biotech public benefit company and we die as the first biotech PBC.

So excited to announce my next patient-inspired adventure as Chief Scientific Officer @ReeveFoundation!! prnewswire.com/news-releases… It’s time to retire the wheelchair. I can’t wait to help translate basic science into new treatments and ultimately a cure for spinal cord injury!

It’s only n-of-1 (as of now) but I still can’t totally wrap my head around the concept that we discovered a drug that’s working in an actual human being! And she’s the first child with her rare disease to ever take this drug. I just want to do it again, and again, and again..

We welcomed baby Luca to the world at 10:55am PT this morning!!! 6 lbs 7 ounces Scheduled C section went perfectly. Thanks Kaiser Walnut Creek docs and nurses! Mom is recovering. And Kai is excited to finally be a big brother.

Are there any scientists left in academia after today’s announcement?

How it started (2014): How it's going (2022):

Someday grad students will realize that being a postdoc sucks unless you’re academia or bust. The market will reward PhDs with great salaries and great science. There’s no reason to do a postdoc unless you want to be a professor.

STUDY MAY PROCEED!!!

As one of our dying acts, I am open-sourcing all data, discoveries from the #NGLY1 PerlQuest which was denied a commercial home, starting with this preprint describing 3 therapeutic approaches: NRF2, catecholamine and anti-inflammatory pathway activation biorxiv.org/content/10.1101/…

Hey @bloomberg what kind of bullshit sexism is this? You list me as Dr but my PhD colleagues @NinaDiPrimio and @IyerSangeetha are listed as Ms? (h/t @jessplao)

A year ago we were fundraising for @PerlaraPBC’s Series B. I failed my team and our partners. I couldn’t tell a story that excited VCs. Now that I’m firmly settled and over the moon in my new role — and I’ve had a year to reflect — here’s the deck, with lessons learned:

Yesterday FDA said the three magic words: Study May Proceed Here’s how we went from a hit in yeast and worm drug repurposing screens to a single-patient IND study to the start of a pivotal Phase 3 in less three years..

Thoughts on decentralized biotech 🧬📲 The era of DeBi is here 🧵👇

With this round (finally!) behind us, a few choice learnings from pitching VCs. Listen up pre-A BioPharma companies, this thread is for you:

Not sure which cracks me up more about academic conferences: Assistant professor who acts like they - let's be honest, HE - has already won the Nobel Prize. OR Professor emeritus who's an actual Nobelist but looks like they came in off the street for the free coffee.

Let’s just call masks “cloth vaccines” in blue states and “freedom shields” in red states.

It's hard to describe the feeling of having achieved clinical efficacy and safety in humans. You feel differently about yourself as a scientist making real-world impact, even if limited to a few patients at first. You start to believe the impossible is possible.

PMM2-CDG pioneer Maggie has been on epalrestat for almost two years as part of an ongoing single-patient IND study. Her first dose was January 2020. See the results with your own eyes 👇

Just got a text from the parent of a child who started taking epalrestat 3 months ago, and watched the video of his son walking his first 3 unassisted steps. 🤯😂🥰

I've been waiting for years to announce news like this on a #RareDiseaseDay. Maggie's been epalrestat for 14 months now and the evidence is in: the drug is working better (and more safely) than we ever imagined! 🧵👇 maggiescure.com/post/1-year-…

Mike Eisen just got canceled for dissent by his own people. While I don’t agree 100% with his politics and we’ve had our fair share of Twitter tussles over the years, his rock-solid commitment to open access and open science has endeared him to me and countless scientists around the world. Mike has always spoken truth to power. I still remember that feeling when first meeting him during one of my grad school interviews at Berkeley in 2001. In my book, he is a mensch. Congrats, Yaniv and Oded, you won. Does it feel good? Are happy now?

Here’s a crazy idea for #PostdocAppreciationWeek: starting now, every NIH-funded PI must pay their postdocs at least 75K per year, and at least 95K per year in places like Boston and the Bay Area.

$2M SBIR Direct to Phase 2 grant just got final funding approval for the @epalrestat trial — woohoo!!

Your annual reminder that Martin Shkreli (in jail awaiting sentencing) and Elizabeth Holmes (bankrupt) were once #30under30!

Last week was a scientific first for drug repurposing! Monday AM: receive yeast hit list Monday PM: yeast hits independently confirmed in patient derived iPSC astrocyte/neuron Tuesday: family orders top hit OTC, doses child Wednesday: first babbling since it was lost at 8 months

First one in, last one out. Goodbye 6000 Shoreline Court. It was fun while it lasted.

A VC-funded biotech platform startup backed by the biggest names in the business and led by seasoned management vaporized $213M in 10 months. I’ve seen rare disease parents discover or create medicines and treat their kids in that same amount of time for 0.1-1% of the cost.

My biggest and proudest professional achievement just happened today: “First patient first dose” for the @epalrestat Phase 3 trial for kiddos with PMM2-CDG — let’s do this!

My Mom died in 2002. Shoutout to all those who lost their mothers too soon. #HappyMothersDay

I can’t possibly convey the depth and breadth of gratitude I feel toward everyone who rooted for us over the years. Thank you. A million times thank you. I’ve livetweeted the odyssey this far so I’m not going to stop now. Onward!

Just had coffee with a friend and biotech CEO. They’re moving operations out of the Bay Area and California entirely, decamping for sites back East, eg RTP. It’s gotten to the point where you have to be a Pharma or enjoy setting cash on fire to operate a lab in the Bay Area.

What if rare disease families/foundations pooled their $$$, rented lab space, built common lab infrastructure, hired scientists to do assay dev and standardized drug screening at a fraction of CRO costs and many times faster than academic labs? Pirate pop up labs for cures!

Anything CRISPR or gene therapies can do, small molecules can do better. No delivery challenges. Cheaper to manufacture and distribute. And more accessible to patients anywhere in the world.

💵 Cashflow positive again this month PerlQuest revenues: 2016 - $60,000 2017 - $190,000 2018 - $1,275,000 to date

I lost my Mom in 2002 to a decades-long struggle with addiction and mental illness. Today she would have turned 70. I hope I’ve done you proud!

We have access to our SVB funds!

Let’s goooo 💊🧬🚀

A year ago, our Series A fundraise took flight. At the time I was (naively) optimistic. 9 bruising months and 2 pitch pivots later, we closed a skinny A last October. I thought it would be useful to #sharethedeck, slide by slide with commentary

My antidote to imposter syndrome is simple: partner with rare disease families. Nothing clarifies my mind and focuses my heart like knowing my higher purpose is to save a life when everyone says it’s impossible to do.

Too many doctors who see rare disease patients seem to believe that drug repurposing rarely works. I think that is a perception based in risk aversion not a conclusion supported by the science. Here are 5 not-talked-about-enough examples of rare-purposing working:

Science ≠ Academia Plenty of science happening in startups and nonprofits!

All the techbio VCs tripping over themselves with their new AI platform portcos do realize that the ultimate bottleneck is clinical trial recruitment, right? It doesn’t matter how kickass your tech is. If you can’t recruit study participants your platform will be a museum piece.

An over-the-counter drug sitting in practically every medicine cabinet in the world improves symptoms of autism in kiddos with an ultra-rare genetic disease. Oh, and we used a fly model of the disease to discover the drug. This is why drug repurposing/multipurposing is going 📈

“Congratulations, your manuscript has been accepted!” Hereby ending my 6 year publication slump. More preprints and papers on the way..

Interesting see the bimodal reactions of scientists to the Altos Labs announcement: 1) Boo selfish billionaires who want to watch to the earth burn and inequality grow wider! 2) Wow a massive injection of unexpected funds to work on biology’s biggest problem!

You thought @PerlaraPBC died a quiet death 2 years ago... Well turns out genetic diseases didn’t get the pandemic memo. A new family is introduced to me every week. So, Perlara is coming back to life! I just need to find lab space to meet the surging demand for new PerlQuests.

The biotech founder narrative is finally changing: Open networks, free sharing of knowhow, operators backing operators, no academic or investor gatekeepers, no credentialism. Love it!!

Noticing some interesting new trends among @ycombinator S20 bio companies that speak to a new kind of biotech founder and a new kind of biotech investor.🧵👇

Date mRNA, marry small molecule

Brief modern history of biotech trends: 2010-11: Repurposing 2012-13: Big Data 2014-15: Cloud Labs 2016: CRISPR 2017: AI the shit out of it

Today was my first onsite visit @ReeveFoundation. Pictured below is Christopher Reeve’s chair. I will be thinking of it each day moving forward, a daily reminder of my new mission.

The first AI-powered drug platforms arrived on the scene a decade ago promising “faster, better, cheaper” — and yet none of them has gotten a novel chemical entity hitting a novel target across the approval finish line.

Want to see what a direct-to-patient biotech pipeline looks like? 22 programs funded by pioneer families, 12 in various stage of 1-to-N clinical studies, and half of hits are clinically actionable nutraceuticals. This is how you start to do drug repurposing at scale.

DeSci is the primordial scream of our collective inner scientist reverberating on blockchains.

Contact tracer will be 2020's Job of the Year.

Last day of my 30s....Started the decade single, childless and still an academic trainee. The last ten years have been a helluva ride!

If the rare disease community will have me, I want a second act. I don’t know what other scientific problem is worthy of my passion and attention than the unmet medical needs of rare disease communities around the world. I know there are others out there like me.

Single patient IND submitted. The CDG embers of Perlara burn on.. I should mention again that we made this repurposing discovery in less than 6 months using yeast, worms and patient fibroblasts. At a cost of ~$200K. No AI or $100Ms of capital required. And it’s truly scalable.

$MIRA is a watershed moment, and just the beginning of DeSci Spring. Starting to think there are enough degens to take on all 10,000+ rare diseases.

We used jargon instead of plain English to prove that a decade of grad school and postdoc made us smart. #overlyhonestmethods

As a therapeutic modality, small molecules get no respect. Quietly doing yeoman’s work, even the heavy lifting of other modalities, but without fanfare or glitz. Small molecules need a rebrand — the word “small” needs to go. Any ideas?

Listening to @ycombinator President @gralston (my group partner in W16!) giving the State of YC address. His last before @garrytan takes the reins. 3500+ startups over 17 years 9000+ founders 300+ companies > $150M 80+ YC alum valued at over $1B Total YC Co’s valued > $600B

A founder friend is raising her Series A and just asked me for a list of the VCs I pitched last year, so I thought I'd just tweet out my investor rejections and save everyone the trouble of asking! First up: tech VCs/Sand Hill Road

Academia is now a cult of productivity. But the # of papers one publishes is not a measure of knowledge and/or utility created for humanity.

Tip to VCs: don’t ghost on founders, especially after multiple warm intros and double especially after the first pitch call/meeting. If you don’t have the capacity to reply to or send emails with professionalism and timeliness, you’re doing it wrong

Aren’t billionaires tired of having their names plastered on some university building? So 20th century.. If they crave real legacy and being remembered by posterity, I have an idea for them: a “1000 Cures Fund” by the ultra-rich for the ultra-rare.

Next adventure update: I’m interviewing for a once-in-a-lifetime opportunity. Hope to be able to say more about it soon. I’ve been consulting for a few families as a CSO for hire on their n-of-1 cure odysseys and will share more in the weeks ahead.

Remember the ALS Ice Bucket Challenge that netted @alsassociation $120M? They spent most of that massive war chest on research which is now culminating in clinical trials, right? WRONG. They’re sitting on 80% of the windfall. How many ALS patients have died waiting for action?

Waiting for the DAO that will collaborate and fundraise to extend the healthy lifespan of the most studied eukaryote on Earth by 10-100X: a yeast cell. It’s a science project that has no obvious business case today but if it worked it would have multiplicative enabling effects.

It’s endlessly amusing to see tech VCs appoint themselves philosopher kings with 7-minute-read Medium posts about “radical empiricism” and other such malarky when 10-15 years ago they would have been anonymous traders on Wall St or engagement managers at McKinsey.

To all the people casting aspersions on biotech startup founders for not managing multiple bank accounts while trying to make new medicines — like @VivekGRamaswamy who knows better — I have a simple message: FUCK YOU

The outpouring of love for @PerlaraPBC has touched me to the core. 🙏 I wish VCs had loved the company as much as everyone else. Sad that an unabashedly rare disease discovery engine — even one with clinical-stage assets — wasn’t seen as compatible with venture scale returns.

I know I’m doing my job right when rare disease parents tell me: “you think like us.” Not a day goes by that I don’t imagine myself in their shoes.

If all the “we use AI to discover drugs!” companies have been identifying new lead compounds in the blink of an eye and shortening the time to IND and making all the other claims they make in press releases — for years now — then where all the FDA approved AI discovered drugs??

Going to spend most of #JPM22 week preparing for our pivotal Phase 3 trial at Mayo Clinic. No press releases, no presentations, no fundraising announcements. Just nose to grindstone: bringing a new medicine to patients with unmet need. That’s what it’s all about it, right?

Not to be outdone by @nature, @sciencemagazine announces new #OpenAccess partnership w/ @Snapchat: you have 30 seconds to read any paper.

I get asked a lot about Perlara’s fundraising history and my decision-making process. So, here it is in one thread:

A little girl in Hong Kong with the rare genetic disease PIGN-CDG has been seizure-free for a year while taking ascorbyl palmitate aka fat-soluble Vitamin C. Still blows my mind everytime I hear case reports like this, especially because we went straight from a yeast hit in the lab to an international parent-organized observational study involving 11 families. Despite several dozen real-world success stories out there based on @PerlaraPBC’s drug repurposing programs, we’re still mostly flying under the radar. That will change soon as we mature beyond 1-to-N observational studies toward more structured — yet still decentralized — Phase 1/2 studies where outcome measures can be validated in the wild, and a pivotal Phase 3 go/no-go decision can be made quickly and cheaply based on data. This is where @endrarediseases enters the equation by accelerating clinical trials beyond the family-led N-of-few proof-of-concept stage. The market has at this point fully discounted the N-of-1 approach and will only be swayed by statistical significance. I wish it were otherwise, but I can’t deny reality. I’m confident we can accelerate clinical trials in rare and even in ultra-rare, but the investment of time and money necessitates having drug candidates with large effect sizes. No squinting, the benefit has to be obvious and the response rate high. Coming up behind PIGN-CDG and ascorbyl palmitate is DHDDS and NMN. And there are more disease/drug pairs working their way through the pipeline. We’re up for the challenge! 💪💊🚀

~40 drugs are approved by FDA each year. That number has been essentially flat for decades. One day in the future, individual companies/teams — and one day even individual operators — will develop 40 medicines each year. We’ll look back on today like the Stone Age.

“AI for drug discovery” sounds great and all…till you have to develop an actual medicine. Not dissing AI, just hoping the next-gen companies with more valuable and predictive data moats and models emerge as winners soon.

Dude, who cares expect journos who lost their precious blue checks? You still have your 400K+ followers. All those people still like you. But keep dunking on the platform that gives you a massive audience FOR FREE 🙄

I repeat this at every conference I go to: all grad students and postdocs need to be on Twitter. #ASHG16

I would love to see those options in Oakland. If they exist in my back yard and I don’t know another them, someone please me!

Super thrilled to finally announce that @PerlsteinLab is a YC company! tcrn.ch/1Lv7yG9

If you’re a professor and you’ve got the entrepreneurial spirit plus an idea (or ideas!) that you’ve been incubating for years, now is actually the perfect time to leave academia to start a biotech startup.

Best conference poster title EVER 😂👍🙌

I announced the wind down and virtualization of @PerlaraPBC on Rare Disease Day. 6 months later, two of our PerlQuests are entering the clinic — and the papers describing how yeast, worms and flies made this first-of-its-kind drug repurposing possible will be published soon.

If you have revenue Newtonian accounting rules apply. If you don’t have revenue quantum accounting rules apply. Say hello to Schrödinger's startup

Why did it take an outsider like @mcuban to shake up drug pricing? Where was that leader from Pharma?? Seems like successful bio CEOs go on to become VCs or sit on a bunch of Boards.. If today’s expensive innovations aren’t tomorrow’s cheap generics, the system is broken.

Drug repurposing is cool again thanks to #COVID19.

So glad to hear Perlara people are landing on their feet at amazing jobs or are interviewing at amazing places. All their employers should consider themselves supremely lucky. I’ve never worked with a better group of humans. 🙌 ❤️

Founder-led Bio movement, welcome to San Francisco!

For fuck's sake: micromolar is µ not u!!! You can't be a real scientist and keep getting this wrong. Option + M, people, Option + M....jfc 🤦‍♂️

Paper accepted for publication!!

Thanks for the incredible support despite the brutal market conditions! Time to get back to work..

There is hope after the Postdocalypse. Assemble an exceptional team and anything is possible

Orphan Drug Designation/ODD application has been submitted. If granted, it will be the first time worm and fly data were the centerpiece of the animal/in vivo data package. #NGLY1 #DrugRepurposing