Back in 2011, there was an announcement from MIT about a new approach to a broad-spectrum antiviral that appeared to work.[1] This goes way beyond an AIDS-specific cure.
But it was at MIT Lincoln Labs, which doesn't usually do bio. So the researcher moved to Draper Labs, but didn't get much funding. Then that funding ran out. Now the guy behind this is trying to get funding on Indiegogo.[3] The problem seems to be that it's too far along for small-scale YC-sized funding, but not far enough along to sell to Big Pharma. The guy behind it clearly doesn't know how to get funded. He has a web site [4] and keeps trying for crowd funding.
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 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.
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.
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.
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?
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.
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.
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.
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.
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...
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.
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.
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.
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.
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.
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).
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...
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...
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.
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...
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.
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.
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 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:
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.
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.
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.
This video was published in 2016-10, and contains this exquisite quote (around 6'):
> 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 ...
I'll add a nod to the Kurzgesagt CRISPR video recommendation. It is really nice introduction to the discovery of CAS9, CRISPR as a DNA editing technique, and the fast evolving possibilities of CRISPR.
Wow, I had not connected the idea of using CRISPR genome editing with targeting virus dna segments. If I understand the technique correctly (and I am not a biologist for sure!) they used an adeno virus modified with a specific Cas9 setup to elide HIV DNA from cells it infected (normally I associate viruses with adding DNA rather than removing it :-)
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.
Correct. You can also use CRISPR to edit a person's own cells in a lab for injection back into the person's body to combat a slew of diseases, including cancer.
Question: Do different counties have different governing bodies on qualifications for human experimentation? I assume so but am not well versed in this domain.
International Compilation of Human Research Standards (2017 edition)
- Office for Human Research Protections, U.S. Department of Health and Human Services
It could be used for any DNA at all. The step from "medical breakthrough" to "germline altering bioterrorism" is particularly shallow for this technology.
It is worth noting that the real challenge in gene therapy at this time is not editing the genes, but in getting sufficient coverage of edited cells (and especially progenitors and stem cells) in an adult individual to achieve the therapeutic goal and make it last.
(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.
Is the problem you are describing that CRISPR antiviral therapies aren't effective because you don't usually know that you've been infected until, well, after you've been infected?
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.
This might be the biggest issue with CRISPR right now. The other issue is that we are not close to knowing what effect manipulating a single gene has on other areas. Especially if this gene is a switch for multiple genes.
Gene therapy (and CRISPR) is ultimately going to eliminate most if not every ailment/issue/genetic problem that we have, including aging and eye problems. Very thankful we are reaching the point where we can go into our cells and fix ourselves.
I dedicated a significant fraction of my life to the idea that gene therapy would become a viable medical treatment. It seems unlikely to really become a high-impact treatment.
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.
A disease is a good fit if you can just inject the therapy into a localized region (say, the eye, or an organ) and the treatment works for a reasonably long period of time (months+). Typically another requirement is that the target is a defective gene where the phenotype can be repaired through addition of a "corrected" form of the gene, without the defective gene needing to be removed. This is the case in X-linked retinitis pigmentosa, where the genetic cause of the disease has been understood for some time, it's relatively simple underlying mechanism (so we think), and you can deliver the medicine to the retina with periodic injections.
Treating a disease where you have to remove an inserted retrovirus from a large number of freely circulating or "hidden" cells (which is the case in HIV) is far more challenging- you need a way to recognize the cells of interest, access all of them, and get 100% transversion. All without causing negative side effects.
We learned early on that one of the difficulties in eliminating HIV is that it hides in the nervous system and can reemerge at any time. This article show promise in that it can reduce HIV viral load during active shedding. I think it is less likely that it could ever eliminate HIV entirely (i.e. cure)
I do agree, but that is just the good news. In other news although we can harbor optimistic thoughts for scientists, medical professionals, lawmakers and maybe even politicians all around the globe to do the "right" thing to preserve human life in a currently recognizable form, but there is not a force on heaven or earth that is going to stop parents from trying to give their children every advantage.
> In other news although we can harbor optimistic thoughts for scientists, medical professionals, lawmakers and maybe even politicians all around the globe to do the "right" thing to preserve human life in a currently recognizable form
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.
Despite academic/political/military/banking/corporate alignment against fundamental morals,
"right" appears to be in agreement with nature/natural selection. The States had a more "right" society founded om constitutional and civil rights that was a big part of its climb from an English colony to the world power in less than 150 years after the constitution was written.
The reason people probably have strong convictions about right or wrong is most likely because of nature, not despite it. Groups that had this genetic trait built tribes, societies that had greater success in the long term.
In the short term, individuals, or even groups of individuals, can be successful by acting amorally, but this comes as a cost to their group's long term success--the cancer analogy.
Right now there is limited competition between groups in the world. Most of what we should be competing against is the coming extinction event when something else out there gets a whiff of all the artificial elctromagnetic radiation. Probably the reason we hear so little in the cosmos is because it is not a very competitive strategy.
> academic/political/military/banking/corporate alignment against fundamental morals
"fundamental morals"? What are those and where the hell do you get them from?
> The reason people probably have strong convictions about right or wrong is most likely because of nature, not despite it. Groups that had this genetic trait built tribes, societies that had greater success in the long term.
Actually, couldn't agree more. But people do have _different_ convictions about right or wrong.
I would wager >95% of people agree on these. I've never met someone who didn't have an understanding of fundamental morals, except for a few people whom I consider to be a psychopaths.
I really would bet that most of us dont need an education to know that killing children for pleasure is wrong and disgusting. However, we might be split on whether spanking your children as punoshment is wrong. I think people understand the difference.
> I really would bet that most of us dont need an education to know that killing children for pleasure is wrong and disgusting.
Can I remind you that abortion is legal and funded by the state in most of the first world?
It's not that I have a personal opinion on the matter (I find it too complex to develop a definite opinion), but it does come pretty close to what you're describing.
It's not. An egg moments After fertilization experiencing suffering requires quite a bit of inagination, while we all can agree a child can suffer. Where we draw the line between that is obviously somewhat up for debate (and no one in their right mind is saying we should kill born babies for pleasure).
I dont believe for a second that let's say you did something you knew to be evil, such as kill a child for convenience, and were hypothetically asked about this in an after life: "why did you do it, you knew it was evil," that you'd be able to say honestly that you didn't actually know that.
As far as I am aware anything is possible, but suffering and happiness seem to be real.
> we can harbor optimistic thoughts for scientists, medical professionals, lawmakers and maybe even politicians all around the globe to do the "right" thing to preserve human life in a currently recognizable form
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.
>although we can harbor optimistic thoughts for scientists, medical professionals, lawmakers and maybe even politicians all around the globe to do the "right" thing to preserve human life in a currently recognizable form
That race is already over. Technology over the last century has changed our realities so much that we can never hope to go back.
Penicillin probably saved at least tens of millions of lives, and other antibiotics even more. Yes, some strains of bacteria are developing resistance, but even today antibiotics are saving many many lives every day.
Interesting idea. So you would first infect voluntarily with a custom virus that targets the bacteria by using CRISPR to remove the DNA strand of the resistance, then simply use the usual antibiotics to kill it.
Fortunately in the late 19th century so did the prospect of Moon exploration and arrogated human knowledge in our pockets. But it's pretty standard now
That was the plan from the start, no? I was pretty disappointed to learn that most drug research is essentially mass testing all kinds of molecular agents that happen to show some beneficial effect for a problem at hand. It seems just too simple a method.
That is rapidly changing to a more targeted approach.
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.
Isn't the only way to mutate to avoid CRISPR to change your genes enough that CRISPR can't identify you? If so, doesn't that mean we just find the new genetic signature and generate a variation that targets it?
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.
Well, as CRISPR was originally found as a kind of immune system, there do exist a number of anti-anti-Cas9 systems against that evolved alongside it. There are a number of small inhibitors of Cas9 [1] (which themselves could be used to tune Cas9 in therapeutics). However up-taking such a defense is admittedly an unlike route for a virus like HIV to take to evolve resistance to a CRISPR-based therapy.
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.
"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). "
Unless I'm grossly misunderstanding how CRISPR works, there's no conceptual reason why you couldn't target multiple sequences at the same time, with a cocktail method. That is, rather than trying a single overly broad match, you could go for (say) ten highly-specific targets at the same time. A particular HIV virion would then have to differ in all ten regions to avoid getting chopped up.
Just spitballing here:
Google tells me that HIV has a mutation rate of about 4E-3 per base.
Let's say you choose target sequences ten bases long (I don't know what the maximum practical length for the technology is, nor the minimum length you'd need to reliably tell HIV from human, and Google isn't any immediate help there).
The probability that there will be a mutation in that sequence is then about 0.04. However, if you target ten sequences simultaneously, the probability that all ten would be mutated is (0.04)^10 ~= 1e-14.
That's likely more than good enough to assure that there weren't any resistant mutants around (if by some chance there are...lather, rinse, repeat).
This is hand-waving, to be sure. If you have better numbers, plug them in.
I think ∼3E−5 per base per replication. Might be a more useful number [1].
If you use 10mers, that only gives you 1048576. I'd be almost certain that >90% of those sequences also exist in the human genome. So your target isn't specific enough (take out stuff you need as the parent suggested).
So you need to use a longer sequence, perhaps 25bp. Maybe there's a stable region or set of regions you can target (in which case the high overall mutation rate doesn't matter). Or a cocktail of sequences, specific to the global HIV population (I doubt this, HIV mutates more in a single individual than Flu does in the global population).
But if not, then you first need to figure out what the viral population in this individual looks like. So you sequence a subset of population, and come up with a 25mer or set of 25mers that target this population.
That might be a lot of sequences (significant problem). Which you then need to get synthesized (will take weeks).
Now. It's taken days to run your sequencing experiment, and weeks to get your CRISPR stuff synthesized. In this time the viral population has been generating 10E11 new virions per day. You're population has moved on, and almost certainly contains members which don't have your previous cocktail of 25mers in them and will survive the treatment.
Because HIV mutates so much, there was some interesting work I saw a while back on guiding the evolution of the population. You'd use drugs which don't wipe out the infection, but push the population toward specific genotypes. Specifically those which you have good treatments for, in the hope that you can wipe out most of the population at once.
"Maybe there's a stable region or set of regions you can target (in which case the high overall mutation rate doesn't matter). Or a cocktail of sequences, specific to the global HIV population (I doubt this, HIV mutates more in a single individual than Flu does in the global population)."
Hmm... I would bet that there is a cocktail of sequences such that if they are not conserved, the virus effectively becomes no longer HIV (no longer infectious, no longer capable of producing symptoms...).
HIV is obviously not a human being, right? Find every sequence where it differs, target them all. :-)
> 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.
I wonder if several narrow CRISPR payloads simultaneously would achieve the same effect since any survivors would need n many mutations simultaneously.
It seems this would be the question when using CRISPR against any virus. Right now one would have to use gene drive to 'amplify' CRISPR and apply it in a living, adult organism (as I understand it). Perhaps some "similar" feedback machanism could be used against quickly mutating viral pathogens?
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.
Can a mod change the title to reflect the findings? The original title is "In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models" and should be kept. That way maybe some people wouldn't just reflex-upvote and actually at least read the abstract...
"Eliminates" is a very loaded term in viral therapy. This paper doesn't show elimination of virus, it shows that the integrated viral genome can be excised in -some- cells by administration of adeno-associated virus harboring the CRISPR system.
In 2013 a very highly-placed Goldman Sachs exec, a friend of a friend, told me his AMFAR contacts predicted a 'genetics-based cure' in a 3-4 years instead of the 10 years they publicly projected. The rationale was donations would stop if people knew how close they were to a cure.
I think by cure they mean eradicate the virus, rather than suppress it. Most people can live relatively normal lives by keeping their viral load low, but this involves taking expensive medications every day for the rest of one's life. The drugs are things like protease inhibitors, modified DNA bases, etc. that muck up the virus' replication machinery so that it cannot make more copies.
The goal of a lot of researchers is basically an HIV antimicrobial that kills the virus in the same way you might treat pneumonia, so that maintenance therapy is not needed.
I think people also forget that it's not as simple as taking a pill and all is good. All medications carry side effects and risks. Even Tylenol can cause major problems like hearing loss down the line. As I recall, the life expectancy of this cohort is close but still below the general population. This difference is probably a reflection of a lower quality of life, which don't ultimately take their toll for a long time. There's also the ongoing risk that the drugs may fail to work at some point or that the patients may not be a good candidate for them or there may be interactions interfering with other treatments.
This, coupled with immunotherapy which boosts efficacy of our own defense mechanisms - for example, NK cell doping via LY49D/DAP12 - is quite exciting.
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.
Craig Venter, the first genome sequenced and first promoter of shotgun sequencing, disses CRISPR. He claims its not reliable enough. Nor can you prevent from altering unexpected parts of the genome.
I dont know how much is not-invented-here and how accurate he is.
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.
You post the classic cautionary comment but reviewing your sources, none of them at all seem relevant:
"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".
Broadly, it's using an animal that is sufficiently like a human that it probably behaves similarly in whatever way is important for the study.
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.
It's any animal (mice, in this case) with a set of characteristics you keep constant between trials. It could be mice of the same age or weight or that have a specific gene or have the same diet.
As exciting as this is, we already know how people have used the decreased danger of HIV infection to become careless about other types of STIs. Given that our antibiotics are losing their ability to treat many common STIs, an HIV cure without some advancement in antibiotics will be swapping one epidemic for a series of others.
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.
I'm not sure the point of your statement -- even if we accept that "an HIV cure without some advancement in antibiotics will be swapping one epidemic for a series of others", what's our alternative? Not moving forward with the HIV cure?
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?
You are right to warn of the risk. But people will party. Else people wouldnt be.
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 agree. By the numbers, most STIs aren't dramatic or fatal in the way HIV is, but rather "annoying little infections", though they can still affect the quality of the rest of one's life in a profoundly negative way. But they don't get much press.
Isn't this treatment good news for everyone with a persistent viral infection? Shouldn't we be able to reverse a large class of viruses with similar methods?
I find it difficult to adhere to the meaning of guidelines like this, because I don't know exactly what they intend. For example, I would say what I did in a face-to-face conversation, and I don't think I'm being gratuitously negative.
I haven't obviously broken that rule. Is it even a classic flame war topic? I've seen more flame wars about vim vs. emacs than I have about this issue, at least how I framed it.
What your comment (and followup) shows is that you think some other people's behaviour makes them deserve HIV. That's an utterly intolerable position, and especially so in this community. Nobody deserves HIV.
It's awesome that this is possible. Right now HIV infections are basically a minor nuisance, provided you're taking the appropriate medication, but this bodes well for future treatment of viral infections.
People who don't have access to truvada definitely aren't going to be getting cutting-edge gene therapy any time soon. And how many people died of type I diabetes in 2015?
> Even with your caveat, the fact that more than 1 million people died from HIV in 2015
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.
>Right now HIV infections are basically a minor nuisance, provided you're taking the appropriate medication
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.
Well, that just sets the market clearing price of the cure. The sum of money paid to acquire any cure is going to be anchored by the current cost of treatment. And certainly anyone who would pay $400k for a lifetime of "shitty treatment" is going to want to pay at least that much for the miracle cure.
> Right now HIV infections are basically a minor nuisance
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.
Sure if you live in the developed world and have insurance that covers Truvada or have a plan with a deductible at or under ~$3K you can get PrEP for free (With the free copay card that covers $3600/yr). But I've got friends who have higher deductibles and can't cover the difference and the card is only good in the US:
> The Gilead Advancing Access® co-pay coupon card (“Card”) can be used only by eligible residents of the U.S., Puerto Rico, or U.S. territories at participating eligible retail, specialty, or mail-order pharmacies in the U.S., Puerto Rico, or U.S. territories. Product must originate in the U.S., Puerto Rico, or U.S. territories. You must be 18 years or older to use the Card for yourself or a minor.
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/