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:
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...
International Compilation of Human Research Standards (2017 edition)
- Office for Human Research Protections, U.S. Department of Health and Human Services
(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.
It is not CRISPR-related, but part of the same interview. It was really inspiring.
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.
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.
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
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.
"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.
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.
As far as I am aware anything is possible, but suffering and happiness seem to be real.
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 , and 95% from standard anti-retrovirals , 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.
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.
Edit: fixed fat-fingering the calculator.
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.
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. :-)
There appears to be at least one conserved protein. However there's a lot of scope for different underlying sequences due to synonymous codons.
Depending on how long a fragment you need to target, that could end up being a lot of sequences, and unpractical.
I wonder if several narrow CRISPR payloads simultaneously would achieve the same effect since any survivors would need n many mutations simultaneously.
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
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.
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
Great example is thalidiomide.
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.
"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.
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.
The account is 303 days old, and this its only post.
> Please avoid introducing classic flamewar topics unless you have something genuinely new to say about them.
> Degenerate behavior can't be punished with AIDS anymore.
I think that's important context for their original post, which is why I'm posting it although it was flagged and downvoted to death.
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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