The reason this isn't getting funded is because it's extremely unlikely to work in reality. They've engineered synthetic protein sensors of dsRNA that induce apoptosis on detection - this mimics the natural viral detection systems that all cells use to prevent viral infection. The argued benefit is that this artificial protein avoids the common hacks that many viruses use to circumvent the natural detection pathways. For this to work you have to (1) inject a ton of this foreign protein into the blood, (2) have it persist and be taken up by many cells in an organism, (3) not elicit a negative immune reaction against cells expressing this foreign beast on their MHCs (4 - for prophylaxis) have it persist long enough to provide realistic protection against future viral infection events (5) hope that the distribution of protein-transduced cells overlaps enough with the natural viral targets to provide some clinical utility.

The costs of trying to turn a novel therapeutic approach into a real therapy are extremely high - hundreds of millions of dollars. I'm unaware of any approved therapy that utilizes protein transduction of cells - I also suspect existing protein transduction methods aren't very efficient. There is a tiny pile of evidence that this method "works" in vitro in cultured cell models of infection, I can imagine a hundred ways it will fail in bodies.

There's a reason some ideas are left unexplored by industry.

>There's a reason some ideas are left unexplored by industry.

But your argument essentially boils down to "We haven't yet discovered an effective delivery method, therefore this technique will never work".

Isn't that one of the basic problems facing all clinical genetic modification research? Is it unreasonable to assume that this problem could be solved by some future breakthrough, or does it somehow violate the laws of physics? If so, should we then discard all basic science research in this field because there is no clear route to market?

I fully support basic science pursuing crazy ideas. I think this is a very interesting piece of basic science, it's just at an incredibly speculative stage that's unsuitable for clinical investment. Efficient delivery of novel proteins into a cell by genetic methods, nanoparticles, or direct transduction is -the- challenge for a lot of novel ideas. Massive effort is ongoing to find breakthroughs here. The proteins in this study face this challenge, but there are other serious issues as well: - Introducing a large amount of a foreign protein, esp. some with viral domains in them, potentially carries risk of an adverse immune reaction... especially since these proteins might quickly transduce themselves into antigen presenting cells. - Most importantly, for a viral prophylactic, it's not clear that the short persistence of these proteins in the cell really makes for an effective approach to defend against viruses. - If you administer it acutely to try and slow an ongoing infection in a stimulated immune system, I suspect the body would raise antibodies against the proteins, preventing them from being used again.

This is fascinating. How in the world does the body "raise antibodies" that are effective against arbitrary proteins it hasn't seen before? How does this get "remembered" and how does the memory get communicated through the body?

If there's an ELI5 (or, ELI-college-101) I'd be interested to read it.

Very over-simplified: You have a random library of many billions of cells each making a single unique antibody that was created via random combinatorial genetic shuffling early on. The ones that accidentally bind to your own natural proteins are filtered out by killing them before they leave the bone marrow, so the circulating cells remaining form a library that could only bind -foreign- proteins. When one of these foreign-binding-cells in the library actually binds a foreign protein this cell multiplies like crazy and eventually the clones secrete free floating versions of the antibodies that neutralize the protein it detected, some of these clones stick around in the bone marrow to form a long-term memory-library of previously activated antibodies.

There are actually two separate systems: the T cells and B cells. I recommend the very readable Lauren Sompayrac's "How the Immune System Works". Or google/wiki "clonal selection" and "VDJ recombination".

Also google "somatic hypermutation". That multiplication process for B cells is inexact, and introduces mutations into the DNA (and therefore structure) of its children. There's a process which indicates whether any of these new antibodies binds better than the original one, which becomes a new candidate for multiplying.

There's fairly recent technology to sequence these antibodies en masse, which gives you a whole load (~10^6) of these antibody DNA sequences. It's a fascinating and frustrating exercise to try and reconstruct the mutation history and families of related cells from this data.

Is there concern that those long-lived antibody clones become pathological themselves?

Yes and no. Yes in that some of the many billions of combinations of antibody genes can recognize self proteins, which is a problem. However, during maturation of B cells, the immune system has a mechanism for killing of those B cells which would produce anti-self antibodies before they mature. There are times when this fails to work--think Grave's Disease, many forms of lupus, alopecia, etc.

I think in the sense you are asking, though, is that any long-lived plasma cell or memory B cell that is active will probably not change to the extent that they would attack self. I don't know off the top of my head if there are examples of this, but I can't think of any.

> How does this get "remembered" and how does the memory get communicated through the body?

https://en.wikipedia.org/wiki/RNA

Seems XKCD was on point this week: https://www.xkcd.com/1831/

To be fair, a lot of breakthroughs happen by people outside the field in question applying new ways of thinking to that field.

Sure, these people can be kind of annoying, but I think we lose more than we gain by discouraging cross-pollination between fields of science.

Definitely; I was thinking that earlier while reading this post. On the one hand, you have newcomers who might have an answer no one thought would work, but on the other hand experience nets wisdom that often is more accurate than the newcomer's logic.

It is a tough call to make between what's happened and what's possible.

Douglas Crockford should learn from you and use the term cross-pollination instead of promiscuity. That would have saved him a lot of trouble

alevskaya. we've got a great direct transduction technology. when are you going to test it out?

It's more "We haven't yet discovered an effective delivery method, therefore this technique is in the same place as a hundred other techniques that kill things in cell cultures."

Yeah, they can only imagine a brute force approach like used in early stage research? How about creating a accepted organism (a synthetic gland - made from body extracted cells) that produces these sCISPoRs in small dosages?

And now you've magnified the costs and financial risk a thousandfold.

Experimental new treatment not yet feasible? Let's invent a whole new synthetic organ that might not even solve the problem!

Sounds like if it is attempted it will violate, to put it mildly, some ethical barriers...

This is the type of innovation we exchange for a sense of absolute security in having highly-vetted decade-long bio R&D and extensive backlogs at the FDA for approvals to sell products on the market. It's go big or go home because the regulatory risk/timeline is so extensive.

Most of these things die quietly or never get started so we never really see the true costs of what it takes to push the pharma world forward. It likely has a big effect on reinforcing existing monopolies as they are the only ones who can play that game (and pharma has been dominated by the same six companies since the 1800s). Usually R&D happens via a single trajectory which is either expensive internal labs at these companies or via anointed universities. There is very little variation on the source.

There's rarely an investment market between small scale seed stage and high growth phase. Which is where these bio R&D projects die.

Maybe there is an opportunity for a YC-style org to disrupt here. But I doubt it given the requirements to get to market.

This is nowhere near the "This is getting tangled up in the FDA" phase. Funding speculative science is hard, and expensive, and this is the type of innovation we exchange for wanting more certain returns on investment, and nothing more than that.

No, this hasn't gotten anywhere near human testing yet. The FDA isn't involved.

FDA rules increase barriers to entry to the market, resulting in fewer companies (especially fewer smaller companies) who would be interested in funding such a project.

If you got DRACO to work in animals, there isn't a pharmaceutical company (or VC) on the planet that wouldn't buy you a small island just to get you to the table. This is probably the worst example you could choose for trying to demonstrate FDA regulations chilling development next to CRISPR.

It's the in vitro -> in vivo part that they're anxious about wasting money on, not the FDA process.

But FDA rules loom large in every decision in medicine. Avenues of research that are going to produce results that will be difficult to bring to market are likely to be abandoned even before the government is involved by law.

That's not necessarily a bad thing.

Obviously it will be in the future, which deters any small scale seed investment...

Are there other nations which have less demanding requirements, but still decent vetting? Why can't these kinds of ideas go there?

My scientist friends tell me China is paying well, making funding available, and has a lower go-to-market burden. Innovation appears to be literally moving to China as talent is being drained away from the US & Europe.

They have a lower go-to-market burden because the regulators don't much mind if you literally fabricate long-term clinical trial results out of whole cloth. The only innovation occurring is in the field of separating fools from their money.

Russia, too. http://www.cardiobrief.org/2017/04/26/serious-questions-rais...

I've seen how clinical trials take place here in India and yes, it's not always pretty. There are plenty of people who mean well and do good work, but the pressure to reduce cost invariably leads to shortcuts.

Just for biotech?

I'd count commodity electronics in there.

One factor is that by far the biggest profits are to be had in the US.

Maybe you can get approved in Australia or Sweden, but that will pay negligible sums compared to getting into the US market.

Could try for market pressure - for example, that male birth control being developed in India we keep hearing about. I bet it'll get approved here faster than normal because of how desired it is.

Related anecdote: to this day, in Japan access to the Pill remains limited because of vague "safety" concerns, despite decades of use. However, when Viagra appeared, it was approved in months...

Well, they do have a shrinking population problem...

> sense of absolute security

Well said -- the keyword is "sense" of security.

There's also the small matter of profiting from desperation with unproven remedies that do unknown, possibly permanent damage. There are good reasons and historical precedent for strong medicine safety regulations; it's not just bureaucracy.

This was covered in Sam Peltzman's "Regulation of Pharmaceutical Innovation" book, where he goes over the statistics before/after the 1962 FDA Amendments. Statistically, the percentage of drugs that later prove to be ineffective or damaging is no different, just the aggregate amount of new drugs, good and bad, is way less.

Preventing fraud is one thing. Holding fraudsters responsible is a thing. However, barring access outright to (properly labeled) experimental medicine is completely different, and that's what the FDA does (as well as enforce a bunch of monopolies).

Given billionaires running their own space programs it makes me wonder why there aren't more billionaires running biologic research companies. Between life extension and immunity to (or protection from) really pathological conditions it seems like their interests would be aligned with folks like this.

Other than D.E. Shaw Research, I can't think of any where the namesake is actually doing lab work.

There are plenty of foundations and the like though. The Schwartz Foundation funds a lot of neuroscience (particularly computational), but through grants to universities and researchers; Jerry Schwartz isn't really spending any time at the bench.

For basic research, this might make more sense. We know that, in principle, rockets can be built. Improving them isn't easy, but with enough time/money/effort, it can be done. For things like life extension, we don't know if it can be done, nor do we know the things we'd need to know to decide that (recuse as needed here). It'd be better to fund a broad portfolio of ideas than focus on your own enterprise.

It's also possible for these engineering-based companies to make money en route to their goal. Mars would be awesome, but there's money to be made in geosync or even low earth orbit too, which helps keep the business going. In contrast, there's no market for 1/3 of a possible antibiotic.

> Other than D.E. Shaw

That guy is hella badass. Shunned by your academic department? Fuck it, go make billions and use that money to fund the development of custom hardware to run high powered geometric integrators on biological systems.

>Given billionaires running their own space programs it makes me wonder why there aren't more billionaires running biologic research companies.

I really think the whole "It's not Rocket Science" cliche would be better suited as "It's not Biology".

Not just billionaires.

One of my besties is directly funding early stage Lyme Disease research. Directly to the lab and researchers. Bypassing orgs, foundations, panels, etc.

He has a vested interest in accelerating the process and has already benefitted from their findings.

This direct funding model will become a significant strategy, as it becomes ever easier to find and connect interested parties.

I'm glad your friend is able to do that. It makes sense to directly fund the research when you directly benefit from their findings. I'm curious about the direct funding process. Does the lab approach him saying "we need money for this equipment"? Or is it like an ongoing regular donations sort of thing?

My friend found the researches himself, built relationships. He's done both one-time donations and ongoing commitments. Pretty much whatever he can help with.

You might be interested in a New Yorker article about just that.

http://www.newyorker.com/magazine/2017/04/03/silicon-valleys...

> billionaires running biologic research companies

D. E. Shaw Research is exactly this. Haven't heard of others, though.

I still remember the surprise I felt when I idly Googled the author of some computational chemistry paper, only to find he was a billionaire :-)

Take a look at the Howard Hughes Medical Institute, which uses a well-known billionaire's money for funding basic research in biology and neuroscience.

You mean the tax dodge that only started doing research when the government started investigating?

Owner of JetBrains is running his own biotech company focused on improving human health. Not a billionaire yet though.

This is happening. Sergey Brin reportedly invested over $1B in Calico (biotech / life extension).

An engineering investment is way, way lower variance than bio research investment.

I almost wonder if running your own space program is cheaper. As in the amount of regulatory BS you have to go through due to the monopolistic behavior of the large pharmaceutical companies...

And yet, if you're not really planning on selling the techniques you find on the open market could you save yourself a lot of time by ignoring the FDA?

You can spend hundreds of millions of dollars before you even get to the point where you can ask the FDA if you can start human trials. Even having spent all that time and money, you still won't have any guarantee that your drug will prove to be safe, effective, or better than any existing drugs.

> You can spend hundreds of millions of dollars before you even get to the point where you can ask the FDA if you can start human trials.

What's a rough breakdown of costs? Salaries certainly don't seem to be the dominant factor. Is it lab equipment & facilities?

I'm not a chemist, but here's how I understand it to work.

It's all trial and error. You start with some model about how your target disease works. Perhaps, for the sake of argument, your model is that disease Q is caused by a deficit of protein N. Protein N is broken down by enzyme F, so obviously if you found a drug that suppressed enzyme F, you could cure disease Q. Now all you have to do is try every chemical you know how to make to see if it reacts with enzyme F.

Of course, you have to be a little more picky than that. Elemental Flourine would probably react with the enzyme, but might react with other important parts of the patient's anatomy as well; probably there would be side effects. So you screen millions of compounds against your enzyme, and against thousands of other molecules commonly found in the human body that you _don't_ want it to interact with, looking for the one that interacts with as few of them as possible. These days this part is somewhat automated. Machines can squirt thousands of chemicals into thousands of test cells every second, and automatically check them for chemical reactions. There are apparently whole companies that do nothing but this, on a contract basis. They maintain a library of compounds to test against, you ship them a big bottle of your enzyme F in solution, and they run all the tests for you. That takes a big logistical problem off your plate, which is nice. Since this is all they do, they can really specialize and increase their efficiency.

Now you've spent a couple of years on the project and identified a few dozen likely candidates. The next step is to optimize them to improve their effect. You're basically trying to guess what part of the molecule is most important (hopefully backing that guess up with some data), then changing the less important looking parts of the molecule to see what happens. Think of all the different combinations of side groups you could add to it, or remove from it, or swap out with other groups, etc, and try them all. Lots of synthesizing small batches of chemicals nobody else has ever synthesized before, determining their structures to make sure you synthesized what you set out to synthesize, lots of assays to see what kind of reactions they get up to, lots of failures.

After a few years of that and you might have something you can start testing in a real biological system. For this step you use cell cultures, rather than going immediately to the full complexity of an animal model. Your drug isn't much good if the liver immediately thinks it's a poison and dismantles it, or if it kills the cultured liver cells, etc.

If none of that goes wrong, then maybe you do tests in an animal model (provided you can find some animals that are susceptible to disease Q, or something close enough), and then later do human testing. Hopefully your disease model was correct; not all of them are. Look at all the alzheimers drugs that have failed, for instance. It seems that none of our hypotheses for how alzheimers works are correct.

Also, don't forget that at some point you also have to work out how to synthesize your drug efficiently, safely, inexpensively, and in large batches.

Labs are presumably a big part of the costs, but a lot of the cost of a lab is the people, not just the equipment.

I think changing the way the FDA works is a hopeless cause, because the real costs are at the beginning of the process. Fund basic research instead, so that we can find new types of chemicals to build, new ways of building them, new natural products, etc. Maybe someone will even crack the simulation problem (the problem is that accurate chemical simulations take months and years to run, and simulations that are faster than physical tests are inaccurate).

Thanks, that's great.

You know there are many other countries where the FDA doesn't apply?

Perhaps I should be more clear. You can certainly avoid dealing with the FDA if you like, but it won't actually save much time or money. You'll still spend hundreds of millions of dollars on the basic research needed to find something that might be a useful drug. All of that spending comes before you do any kind of human testing.

Also, doing your research in other countries carries its own risk. Here's a recent article about human trials conducted in North America, South America, and Russia: <http://blogs.sciencemag.org/pipeline/archives/2017/04/27/a-c.... I'm pretty sure I saw something about fraudulent pre-clinical research in China a few months back as well.

There's a metric ton of other regulations, at least in the US, mandating how any human level research is done. Depending on what one is doing, it's not necessarily less annoying

That wouldn't slow down a self-respecting multi-billionaire, though, would it? Couldn't you just set up your lab in Malaysia / Brazil / Belarus? You don't even need a country without regulations against your research direction, just one that doesn't (consistently) enforce any such laws...

Or just create your own country. Failing that, there's always international waters. Bonus points if the lab is underwater.

Edit: Hah! http://www.dailymail.co.uk/sciencetech/article-2568744/Float...

ANVISA (Brazilian equivalent of the FDA) has more regulations than FDA for most subjects.

I bet Putin at age 64 with his 200 billion dollars has a spare body growing in a vat somewhere.

Human Longevity INC San Diego, run by Craig Venter. http://www.humanlongevity.com/about/management-team/

Both Google and Apple have biomedical venture efforts. Google founders are 40 and feel mortal.

He also coincidentally happens to be the guy who wrote a dissertation on why beam-collision nuclear fusion reactors won't work as a viable path towards self-sustaining nuclear fusion: https://dspace.mit.edu/handle/1721.1/11412

Since I was doing a startup making a beam-collision nuclear fusion reactor at the time, the name kind of rings a bell...

So, was he right?

Short answer: Yes.

Longer answer: When I first read it, I didn't think that the limitation that he had proposed applied to the type of device that we were making. He was really criticizing a similar but-not-identical type of fusion concept, and I clung to the differences. However, as our work progressed, I saw that the basic concept applied, which is that the scattering which would occur in a plasma (or a beam) would dissipate the energy concentration faster than the fusion rate would compensate. In short, a beam would thermalize with its surrounding plasma at an energy rate faster than the fusion rate.

We looked at using van de Meer beam cooling to try to keep the beam in a highly collimated state which would reduce the thermalization rate, but this wouldn't work. We also tried using Landau damping to make self-reinforcing waves that could, in theory, keep the energy concentration, but this really didn't work.

Gotta say, this is why I love HN. People admit they were wrong about an important thing to them and explain how they were wrong. Thanks for this. Makes me feel slightly less bad spending so much time here​ :)

That sounds dope though, I have no idea what kind of materials you guys worked with but I imagine the kinds that raise eyebrows from the local governments. How did you overcome that sort of stuff? Strict safety requirements, etc.

This antiviral is extremely promising, and it boggles the mind how this has not gotten real funding. My cynical side thinks it would cut very deep into a lot of profits for all the various viral medications for lifetime diseases such as the HIV cocktail, herpes meds, and other viral illnesses, so there isn't much upside for a large company to fund this.

Companies like Gilead have made a fortune on anti-viral cures. Case in point: their recent Hepatitis C vaccines, which pulled in $4B in one quarter last year [1]. So a lack of money to be made on cures is not why this isn't funded.

[1] https://www.statnews.com/2016/04/28/gilead-hepatitis-c-reven...

That theory would work except that if that were the case they would've bought him out and shut it down. Everyone wants to make money, as it stands someone will and they can be from any sort of background. Why hasn't a silicon valley head given this guy a few million though is beyond me.

In the 1970s the conspiracy theorists were all convinced that oil companies bought the patents to 100 mpg carburetors in order to keep them off the market. My father (ex military) laughed at the idea, as a huge problem for the military is fuel consumption, and they would not let a little old thing like patent rights stand in the way of using it.

It wasn't just the 70s, my father's picked up on it from all the conspiracy theory YouTube channels and rants on about it today. That, and the Zero Point Energy system that was developed and bought, then hidden away by the oil companies. No physicist can convince him that this is wrong, because "The designer found a way to do it."

Like making a spoken word version of a rap song...

Yeah that's true too it's difficult to stop technology once it's been discovered, someone will make use of it. Genie out of the bottle so to say.

Of course there's upside — if it really does cure all viral diseases it could be a trillion-dollar pill. Not to mention they'd want to introduce it before the competition.

What's probably working against it is it sounds too good to be true.

Might point him towards Propel(x) (https://www.propelx.com/). Its a newer syndicate model marketplace that focuses on "deep tech" investment. The team is knowledgable / motivated, and working to attract angels and institutional investors who understand these type of investments.

RCTs are 10-20K/patient.

The funding the scientist is seeking is a pittance compared to MIT's endowment, especially considering they own his patents, they should be funding it.

MIT Lincoln Labs is owned by MIT but operated relatively independently. It is funded, AFAIK from defense spending. Although I'm slightly surprised it wasn't moved to MIT the University.

I believe that Lincoln Labs was intentionally setup separately because MIT pledged not to do any weapons/defense related research. We have something similar with Georgia Tech and GTRI, but probably not for the same reason.

under Bayh-Dole I would expect them to get 33%-33%-33% or 60%-40%, something like that? That's how it works for mine.

He should just start a crypto coin. He'll get funded immediately.

The expensive part of getting a drug to market isn't proving that it can kill cells in a petri dish. Lots of stuff can do that, bleach, hydrogen peroxide...

The expensive part is the clinical trial. You try out the compound in the chemical woodchipper that is the human body, and see what happens. Almost all drugs fail at this point: http://blogs.sciencemag.org/pipeline/archives/2017/01/23/i-d...

>The timing of this report from the FDA is surely no accident, but it’s always a good time to think about this: the great majority of all drugs that enter clinical trials fail. They fail because they don’t do anyone any good, or because what good they might do is outweighed by some serious and unexpected harm. Around 90% of all compounds that start in the clinic never make it out. Even by the time you get to Phase III – and these are drugs that have apparently already worked in sick patients by that point – the failure rate is still nearly 40%. Drug projects fail constantly.

Nobody can predict if a drug will make it through the clinic, and if they say they can, they're lying. There's no way to model it, at all, it's just hugely computationally intractable.

And even if you make it through the first three formal phases of clinical trial, you can get bit in the "fourth" phase: regular patients buying it retail, and maybe dying at statistically higher rates. Consider the Vioxx debacle: https://en.wikipedia.org/wiki/Rofecoxib

>Rofecoxib /ˌrɒfᵻˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhea. Rofecoxib was approved by the U.S. Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx.

>On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and has set aside $4.85bn for legal claims from US citizens.

VC's could spend hundreds of millions on clinical trials for DRACO, make it on the market... and only then discover that it gives patients incurable brain cancer 20 years after they take it.

This is all true.

The flip side of this, however, is that "trial phase failure" does not conclude "ineffective biologic." There are many other variables to Clinical Trials, including flaws in trial design, time spent and difficulty in operations, and biased reporting:

https://well.blogs.nytimes.com/2013/01/14/clinical-trials-fl...

http://www.outsourcing-pharma.com/Preclinical-Research/Parki...

https://www.iths.org/blog/news/avoid-common-biostatistical-f...

Huge amounts of the cost of clinical trials could in theory be cut by automating many of the tasks. A lot would be done if all computer systems across hospitals (and lab equipment) could seamlessly talk to each other, medical records were completely standardized and contained all necessary information in machine readable formats etc, not that I see this happening in the near future though.

An aside -- I think machine-readable formats will get less and less relevant. Machines can almost read what humans can read. Just screen-shot it.

If he's not getting funding perhaps his work doesn't hold up under scrutiny? I'm a geologist and biology is greek to me so I don't know what to make of it.

This is correct. Everybody I know in the biz has said his work doesn't pass a wide range of sniff tests.

Agreed ... it seems insane this guy has not received all the funding he needs. Very curious if there's something more here that has spooked investors.

It's suspicious that in 6 year he hasn't received any substantial funding. Anyways here is a link for donations: https://riderinstitute.org/pages/donate-to-draco-antiviral-r...

his first target is HSV. HSV is a cash cow. innovators dilemma applied to pharma-cash

If it actually worked or was promising, people would be throwing money at him.

If his research is any good, then how can he not get any NIH funding? I'm skeptical that a missile defense researcher will suddenly achieve a breakthrough in AIDS treatment. Not that it couldn't happen, but it's unlikely.