Y Combinator Bets on Biotech
nature.com
nature.com
As wiki puts it:
http://en.wikipedia.org/wiki/Drug_discovery#Drug_targets
Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on.
One thing you won't learn at school is all the complications involved in validating a target. The best resource I know of for this is the "in the pipeline" blog by Derek Lowe. I have spent 100s of hours reading all his posts (they go back 10 years) and especially the comments. It is a hard slog, but the amount you will learn is staggering.
Edit. I guess is should include the link http://pipeline.corante.com/
Things appear hard and severely constrained because we habitually fall into the trap of thinking linearly and incrementally, as opposed to, at least sometimes, multi-linearly and in bounds, by perspective shifting. To do that one has to question the fundamental assumptions of which this linear trajectory were founded on. More often than not, one finds that much of what is considered so is merely based on someone', usually a group's very convincing, albeit not necessarily correct narrative.
[it's] low-input, high-throughput, no-output biology
It's a world where lots of great ideas are underfunded (or not at all), because the traditional government sources don't have the money needed to invest in every good idea. Also, it's still generally too expensive to chase every possible business idea in biotech, and there are plenty of ideas with academic promise that don't get anywhere because the traditional sources of investment are too conservative. Scientists get punchy when they see funding going to "unproven" entrepreneurs, while they're slaving away at research that is peer-reviewed, but isn't getting any investor attention.
It's good to see YC bringing in outside expertise for this area, because the likely outcome for amateur angel investment in biotech would be investing in lots of flashy-but-insubstantial entrepreneurs, while legitimate research never gets off the bench. In my experience, it's much harder to evaluate biotech ideas than software.
Your average CS undergrad can understand the technical risks of most software startup ideas, but you need at least a graduate degree or equivalent industry experience to be able to evaluate the technical feasibility of lab research. Moreover, life science research depends on sophisticated intuition that can't really be taught in a classroom.
Maybe the highlights would be Lynn Margulis and the endosymbiosis theory, and Carl Woese finding the Archaea in 1977.
References:
JE Strick. 2004. Creating a Cosmic Discipline: The Crystallization and Consolidation of Exobiology, 1957-1973. Journal of the History of Biology 37:131-180.
http://www.researchgate.net/profile/James_Strick/publication...
M Morange. 2007. What history tells us X. Fifty years ago: the beginning of exobiology. Journal of Biosciences 32(6): 1083-1087.
YCombinator has the sophistication and time to vet their investments. If they want to back something most of the scientific community thinks won't work, all the best to them. However, raising capital from mom-and-pop investors is another story.
Let me suggest the mitochondrion as the main target to explore:
- In a very simple but accurate analogy, a computer will not work properly - if at all - if the power is not coming. You can have the best hardware; you can put endless hours to develop the best possible software, but nothing matters if the power is not coming. - Mitochondria produce 90% of the energy - ATP - we need to function. - Mitochondria are a relatively simple structures. Its DNA is way smaller and simpler than the nuclear - double helix - DNA. - Many health issues seems to be the result of a primary mitochondrial dysfunction, or - Many health issues will result in a secondary mitochondrial dysfunction.
I do have a mutation in my mtDNA (mitochondrial DNA), so
- I know what I am talking about and - Yes, I am very biased; my life depends on this.
Peter Mitchell: "Guys, I think the concentration gradient is responsible"
Everyone: "Shut up Peter"
Later, as Peter was accepting his Nobel prize for discovering one of the most most important biochemical processes, he got to say "I told you so."
I didn't realize he had to secure funding from an outside institution though, that's really interesting. Thanks for that TIL moment.
Remember the reception to the Avery/McCloud experiment- people still insisted protein was the heritable molecule. People simply couldn't understand how a "simple" polymer like DNA could encode information. it was a real mind-bender because (AFAICT) nobody really appreciated how nonuniform polymers could code for information.
Or the reception to the discovery of enzymatic RNA. How could RNA possibly be enzymatic? Well, now we know that RNA runs the game and protein is just muscle.
Then, we have anti-aging. Big business here. Mitochondria is key.
Then, we have diseases with secondary mitochondrial dysfunction. Again, big business (Alzheimer, Type 2 diabetes, statin-induced myopathy, etc)
There are many diferrent figures as "mitochondrial disease" is a broad term, but check these out: http://ije.oxfordjournals.org/content/41/1/177.long http://www.ncbi.nlm.nih.gov/pubmed/18674747?dopt=Abstract
I agree that faulty mitochondria will break homeostasis and from this point on, the problem is unsolvable.
But homeostasis will break because:
1. Plain vanilla energy deficit. Not enough energy. Babies die within the first days after birth. or 2. Inefficient - but normal - energy production. This will produce an excess of free radicals, "emitting" all kinds of weird signals to the rest of the cell/tissue/body. Most of mitochondrial diseases and diseases that cause a secondary mitochondrial dysfunction fall in this category. "The threshold effect" - mutant mitochondria outnumber healthy mitochondria as you grow older - will eventually take you to point 1.
Given this, repairing the mitochondria will bring homeostasis back. Currently, there are 3 lines of thought: 1. Repair the faulty mitochondria 2. Allotopic expression (literally, make backup copies of mitochondria DNA in the nuclear DNA and let them "express" from here instead of from mtDNA) 3. Kill faulty mitochondria. Given that mitochondria go through a fusion/fission cycles every few days, killing faulty mitochondria will restore a healthy mitochondria population in a very short period. The underlying genetic defect is still there, but it causes no harm at all.
I am for 3.; much simpler both technically and legally. The latest in this regards is http://onlinelibrary.wiley.com/doi/10.1002/emmm.201303672/ab...
Thanks for your concert. I didn´t want to be tragic in my original post. My life depends on my mitochondria, but I am doing relatively well considering my disease.
For the curious, I have CPEO + myopathy, common mtDNA deletion, 35% mutation load.
I'm a Ph.D. candidate in systems biology.
A completely baked form of allotopic expression or toolkits for glucosepane breakdown in tissues could both produce viable and highly useful technology platforms prior to being far enough along to be applied to the reversal of aspects of aging. Neither of those seems too far away to be non-viable for this sort of timescale, and meaningful biotech projects are very cheap these days if you have access to a provisioned lab.
We (longecity members) founded this project out of our pockets a few months ago. I am sure Dr. Matthew 'Oki' O'Connor will love to discuss ideas with you.
"One of the key misplaced assumptions that Valley VCs made in cleantech boom times is that the rapid progress of Moore’s Law could be created for cleantech with a little bit of VC funding and Valley smarts."
s/clean/bio/g
http://gigaom.com/2012/02/01/we-can-thank-moores-law-for-the...
I'm assuming the New Deal terms are for S14, but was also surprised to see the announcement after the applications were all in.
Can anyone clarify / point me to what I've missed?
I'd be interested in seeing some guidance for nascent biotech companies wanting to apply, given the focus has been on software for so long.
(Looking over the application again now...)
I've been doing consulting work at healthcare manufacturers. The environment is insane -- constraining, slow, unproductive, depressing. And it's used as a huge moat.
Health-related products and services are heavily controlled -- in ways completely at odds with the common practices of Internet startups. If you haven't yet had to comply with these regulations, you may want to find out how onerous they are.
Here is one example: Quality System (QS) Regulation/Medical Device Good Manufacturing Practices [1], covering: Quality System, Design Controls, and Human Factors.
They audit your compliance with their regulations. You have to document everything you do, every decision you make, every change you make. That is not how startups commonly operate.
[1] http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidanc...
http://www.reddit.com/r/technology/comments/1e5rti/whats_wro...
>This will be totally transparent project - we will introduce a novel concept called "constant peer review" - In academia no one publish things that didn't work - we will publish everything.
>We take being a good Steward of our backers funds as #1 priority. Our budget will also be publish online and you can see where the money went.
Neither of these two things has happened yet.
With respect to the budget we currently have $230,000 left in the bank. We'll publish the financials when we are ready to ship.
In the mitochondrial field, companies are going through orphan-drug designation and fast-track approval processes.
This is probably to only advantage researching for niche - rare - diseases: You can save lots of money/time to get the drug in the market. If you can then find some off-label use for you drug, much better.
http://www.reuters.com/article/2012/03/28/us-science-cancer-... Accessed 28/04
They are just a trillion times harder/expensive than writing an app.
Sure, sometimes there is a chance and an underbelly-feeling involved in whether a startup should be invested in, but to degrade investments as "betting" is probably the highest insult an investment/accelerator-firm can get.
"Biotech is getting cheaper" applies to both groups.
As for @danieltillett's comment, "What you need to do for tenure" does indeed promote some conservative and safe thinking, but:
1. Post-tenure you have a great deal more freedom. 2. I'm not convinced it's more conservative research generating than "We need to keep the VCs/Shareholders/etc." happy. 3. A big, splashy, innovative paper that makes it into Science/Nature/Cell/etc. is a high risk but high reward play.
The story of how state-run science funding is broken is exemplified by the story of Douglas Prasher.
And YC talking about funding startups in Biotech is talking about industry science, so calling is a "false dichotomy" is a little absurd.
I would say that a good portion of medical research IS technology and marketing, for better or worse.
"If the traditional science community wants to say these things aren’t going to work, they can keep doing that. That’s what used to happen with software companies. The Immunity Project may fail, and the next 30 things we fund may fail — and the whole model is such that that’s OK. We can have 31 failures and one success, and the model still works great. That’s how we’re designed."
> How many Nature papers are not reproducible? To call out a new bunch of people who are trying something different because people are afraid they’ll fail is sort of hypocritical given that we don’t really check whether anybody else’s results are correct, either.
Peer review is more about politics then reproducibility. Reproducibility is really important, but Nature doesn't seem to agree.
Peer review is completely flawed. Until it's made more transparent, like at F1000, it's going to continue that way.
Not being a negative Nancy here, but I've been on both sides of the fence (reviewed and had grants/papers reviewed) and it isn't an efficient system. Much like many other things in science, it's an antiquated process that needs to be overhauled to get back to it's "roots".
Peer review should be open, scientists shouldn't be allowed to choose who reviews/doesn't review their papers, and the process by which selection is done needs to be more rigorous.
My suggestion, open it up to everyone in the field and make sure that the reviewers are identified. Anonymous peer review has the same effect that anonymous posting on internet forums has, people become e-thugs or just say things that they shouldn't ever say because they know the reader doesn't know who they are.
This sounds like it doesn't happen, but you would be surprised that the stuff that happens behind closed doors. Scientists are people, people are flawed (which is fine), but that shouldn't hold back scientific discoveries.
Then again, you have the problem that negative results are rarely published. Many groups may repeat the same thing over and over, not realizing that many other groups have confirmed a negative result.
(Actually I think I saw a post here about a journal that aims to adress this problem).
It's a bit different if you crowdsource the whole thing. The individual backers don't have the ability and knowledge to dig as deep to actually judge the validity of the approach. So I can certainly understand that this draws some criticism.