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.
[1] https://www.ll.mit.edu/news/DRACO.html [2] http://www.businessinsider.com/todd-rider-draco-crowdfunding... [3] https://www.indiegogo.com/projects/dracos-may-be-effective-a... [4] https://riderinstitute.org/
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?
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.
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.
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.
http://www.newyorker.com/magazine/2017/04/03/silicon-valleys...
D. E. Shaw Research is exactly this. Haven't heard of others, though.
Since I was doing a startup making a beam-collision nuclear fusion reactor at the time, the name kind of rings a bell...
[1] https://www.statnews.com/2016/04/28/gilead-hepatitis-c-reven...
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.[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.
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...
https://www.youtube.com/watch?v=k99bMtg4zRk
As fun as it is, Tim Blais works hard to make hardcore science engaging.
> In 2015, scientists use CRISPR to cut the HIV virus out of living cells from patients in the lab, proving it was possible. Only a year later they carried out a larger scale project with rats that had the HIV virus <sic> in basically all of their body cells. By simply injecting CRISPR into the rats tails they were able to remove more than 50% of the virus from cells all over the body. In a few decades, a CRISPR therapy might cure HIV and other retroviruses ...
Is that even close to a correct interpretation? It sounds like the technique could be used for pretty much any virus dna you wanted to target.
China is already experimenting on live humans: http://gizmodo.com/china-is-racing-ahead-of-the-us-in-the-qu...
(Most studies of genetic alterations in the broader sense have bypassed this challenge by working with animal lineages, or animals in which the editing happens in the earliest stages of development, when there are very few cells needing to be changed. The alteration then propagates during embryonic and later development).
There have been a number of very promising studies in the past year or two with regard to gene therapies to apply to adults, such as animal studies that demonstrated a cure for an inherited muscular dystrophy, but in the bigger picture, comprehensive coverage of tissues and cells is still something that the research community is in the midst of getting to grips with.
The way I understand the problem is that the lag time can be rather long, and it's always long enough for the virus to get a good running start. Symptoms, after all, don't occur until things are well under way. So in the real world, the two opportunities for antiviral therapies are (1) something that you can take long before you're even exposed, and that lasts for a long time (like a vaccine) or (2) something that you can take after you've already realized that you're sick (like an antiviral drug).
It seems like the DRACO proteins fall in between these two unless something has changed since the last time I read about this in, I believe, 2012.
It's a great podcast episode.
Being able to change DNA in cells is one thing; actually being able to show your treatment does what it's supposed to and didn't have negative effects is hard. There are a limited number of diseases where gene therapy should work great, but there are a wide range of others where it won't, until solve multiple grand-challenge class problems.
Why is this the right thing to do? What are you signifying by putting "right" in quotes?
I am reminded of the Hyperion Cantos from Dan Simmons, where most of the human race has declared that nanotech modification of the human organism/germline is a cardinal sin. Meanwhile there is another segment of humans who decided that maybe it wasn't, and they're off colonizing deep space by remaking themselves into a wild range of body types.
In fact if we don't stop dirtying up the planet, we may feel a lot more pressure to adapt our bodies to an environment whose rate of change we can't keep up with. In any event I am sure there will be a segment of humanity that does want to preserve human life in a currently recognizable form, and they should be able to choose that for themselves. That should not stop those of us who want to vary it wildly from doing our thing too!
There are a number of ethical concerns when it comes to these kinds of changes, of course. There is the world of The Windup Girl, where competing agricorps target each other's crops with tailored viruses to wipe them (or their consumers) out. So we will need to figure out how to rebalance our societies in the light of this vast new power. Yet it looks like it may also be the start of a whole new stage in treating human diseases. Imagine a world where mass-produced medicines are mostly replaced by taking some host cells, gene sequencing the target diseases, then programming and re-injecting the cells to eliminate them. I'm not well-versed enough in this stuff to know how far-fetched that is, of course. It sounds like something out of Star Trek. But it's hard not to be optimistic about what it can enable.
"right" according to whom? nature itself doesn't believe that
Why do you think that preserving human life in currently recignoziable form is something all of us are optimistic for?
For me personally, this option seems like a nightmare - and I truly hope for a transhumanist future made of humans who have very advantage. Being smart, fit and (relatively) healthy is awesome, which I'm lucky to know from experience. I wish other people would be able to experience it, and then some.
That race is already over. Technology over the last century has changed our realities so much that we can never hope to go back.
However, don't downplay the importance of the shotgun approach. In the broadest sense, it gave us Viagra for ED (common reported side effect in an unrelated trial), Aleve (intended to be a hangover treatment you'd take the night before), ...
With computer and analytical modeling, it's a much easier process to identify a problem and reverse engineer a treatment.
I see CRISPR as grepping through memory for running instruction code. Sure, the code can change, but if you see the behavior, then it's a matter of finding the new code signature manually and generating a new CRISPR variant target it. If that's accurate, the similarities to anti-malware are pretty cool. Just keep updating your virus DB.
More practically, HIV has such a high mutation rate, that it's likely very difficult to target every HIV sequence with a sequence-specific Cas9 therapy. If the Cas9 guide sequence is too generic it'll take out stuff besides HIV (stuff you need). And if the guide sequence is too specific it won't get all the viral inserts because many are degenerate. As with all things though, 95% success with viral excision via CRISPR, in conjunction with 95% success via immunotherapy [2], and 95% from standard anti-retrovirals [3], get's you pretty good 99.9999% coverage.
That's the power of convergent technologies. It's an interesting slice through a number of modern therapeutic technologies all applied to one of the most challenging of tailored foes. You see convergence of small molecule biochemistry along with immunotherapy, along gene therapy, along with cutting edge synthetic biology - all approaching the problem from different angles.
[1] www.cell.com/cell/fulltext/S0092-8674(16)31683-X
[2] https://serotiny.bio/notes/proteins/ecd4ig/
[3] https://en.wikipedia.org/wiki/Category:Antiretroviral_drugs
Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8
excised HIV-1 proviral DNA and significantly reduced
viral RNA expression in several organs/tissues of Tg26
mice. In EcoHIV acutely infected mice, intravenously
injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced
systemic EcoHIV infection, as determined by live
bioluminescence imaging.
As someone else noted, THIS is what CRISPR was evolved to do. It was a DNA-based immune system used by bacteria to explicitly identify an invading virus via DNA, and to store a record of previously unknown virus for future reference. And, it was intended to function continually, in a living organism.
HIV overcomes CRISPR gene-editing attack https://news.ycombinator.com/item?id=11453737
Great example is thalidiomide.
https://www.quora.com/What-are-examples-of-drugs-that-showed...
https://walkerma.wordpress.com/2007/04/27/animal-models/
I advise extreme caution and context on hyping this. Derek Lowe wrote a great post on this a few years ago that I still reference whenever I see HIV animal claims.
http://blogs.sciencemag.org/pipeline/archives/2010/02/03/a_m...
"Genomic responses in animal models do not mimic themselves in humans" - source? Thalidomide is just a random example of a traditional non-genetic treatment. Specifically the CRISPR mechanism clearly has no precedent of failure, as the Chinese only recently began human trials. There's no precedent of success, but there seems to be no reason to believe it won't work, since it works fine in vivo in other mammals.
And the Lowe link you provided is complaining about in vitro testing; this was in vivo. As far as I can tell, it's exactly what he suggests needs to be done before there's any hype.
If your point is simply that many things have been tried and failed in the past, sure, that's common knowledge. But CRISPR is not a similar approach, there is very little precedent, so IMO optimism is just as warranted as "extreme caution".
In practice they also often inbreed them to make them as identical as possible, and sometimes to induce specific changes. Ex: breeding mice that all get lung cancer would be an animal model of (human) lung cancer.
There are also transgenic models, where you might insert a human gene into a mouse to create a model of human disease, ex: inserting a huntingtin gene variant to induce Huntington's in mice and create a mouse model of Huntington's.
If this could be used to fight bacteria resistant to antibiotics then it is the start of something fantastic.
If it can be used to fight also diseases in animals (e.g.: foot & mouth disease in cattle) or plants (e.g.: citrus cancer) then it is even bigger.
Edit: I wanted to add a couple sources for my claims above. Once people stopped believing raw sex was an existential threat they started going nuts, falsely believing that everything else can just be cleared up with a pill. Let me also say that my SO worked on the front lines of public health for almost a decade so I might have a unique perspective on this issue because of what she experienced as part of her job.
http://www.cnn.com/2017/03/01/health/syphilis-newborns-partn...
http://www.huffingtonpost.com/entry/std-rates-in-the-us-rise...
http://www.ocregister.com/2017/01/26/syphilis-up-412-gonorrh...
The field's challenges right now in terms of STIs are addressed with more advocacy, outreach, screening, education, etc. Treatment is phenomenally effective currently for gonorrhea, chlamydia, syphilis, etc. Antibiotic resistance has been seen in some of those, sure, and will likely increase, but we deal with that as it comes -- just as we have with every other resistant pathogen. I'm not eager to keep a life-long and fatal STI around (HIV) to try to forestall that outcome.
Also: Those sources don't really support your claims. They describe an explosion of STDs that (at least as posited in those articles) are tied to decreased public health funding. There is indeed lots of discussion around risk compensation in light of improved HIV treatment, PrEP, HCV treatment, etc, but the data's a little unclear, and in my view is irrelevant to whether we should actually find and provide cures.
Maybe true, though sounds awfully spun. I think a better read is that the early years of the AIDS outbreak were ones notable for particular caution in sexual behavior, not the baseline you want to look at.
> Given that our antibiotics are losing their ability to treat many common STIs
Kinda true, though you seem to be evoking the spectre of a multi-drug-resistant syphilis that AFAIK doesn't exist. It also sorta misses the point that the overwhelming majority of STDs are viral.
> an HIV cure without some advancement in antibiotics will be swapping one epidemic for a series of others
Wat? This doesn't follow. At all. Are you one of those people who opposes the HPV vaccine too because it will lead to more sex?
What is needed is not lots of awareness training or protection, but a "morning after" instant test for every STI on the surface of the (planet/partner).
I would say the excessive mediatic exposure of HIV have definitely worked to supress awareness and care for other STIs.
For instance, I am HPV+ and didn't have a clue about the existance of such a thing before getting it.
Even with your caveat, the fact that more than 1 million people died from HIV in 2015 is probably a good signal to not use the term "minor nuisance".
Sucks for the developing world, hopefully we can cure it once and for all.
Idk where you got that number from... From the article you linked, "In the United States, 6,721 people died from HIV and AIDS in 2014". That's out of "An estimated 1.2 million people in the United States were living with HIV at the end of 2013". Since 1/8 people infected with HIV don't know it (and subsequently probably develop full on AIDS and complications), it's fair to say that most of the deaths are due to lack of treatment.
Edit: I see you were talking about worldwide, but that's still out of 36 million people living with HIV in the world.
The cost of treating an HIV+ person in the US is roughly $400K over the course of their expected lifetime. This is more than a nuisance sum. HIV treatment can also significantly affect quality of life.It is not yet time to become blase.
I don't understand how anybody can say that. HIV treatment is extremely heavy and has potentially horrible side effects that must be masked with other drugs that have their share of horrible side effects. This + the fact that many people get only diagnosed when they are terminally ill due to the nature of the disease. I'm not even talking about the cost of the treatment.
Your comment is just horrible, whatever the intent was.
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