Some VC needs to talk to this guy. This might or might not work, but the upside is good and the costs aren't that high.
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.
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?
If there's an ELI5 (or, ELI-college-101) I'd be interested to read it.
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".
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.
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.
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.
It is a tough call to make between what's happened and what's possible.
Experimental new treatment not yet feasible? Let's invent a whole new synthetic organ that might not even solve the problem!
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.
It's the in vitro -> in vivo part that they're anxious about wasting money on, not the FDA process.
That's not necessarily a bad thing.
Maybe you can get approved in Australia or Sweden, but that will pay negligible sums compared to getting into the US market.
Well said -- the keyword is "sense" of security.
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.
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.
I really think the whole "It's not Rocket Science" cliche would be better suited as "It's not Biology".
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.
D. E. Shaw Research is exactly this. Haven't heard of others, though.
What's a rough breakdown of costs? Salaries certainly don't seem to be the dominant factor. Is it lab equipment & facilities?
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).
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.
Edit: Hah! http://www.dailymail.co.uk/sciencetech/article-2568744/Float...
Since I was doing a startup making a beam-collision nuclear fusion reactor at the time, the name kind of rings a bell...
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.
Like making a spoken word version of a rap song...
What's probably working against it is it sounds too good to be true.
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. 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. 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.
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: