[HN Gopher] What can mRNA treat next?
___________________________________________________________________
What can mRNA treat next?
Author : elsewhen
Score : 234 points
Date : 2021-05-01 17:47 UTC (1 days ago)
(HTM) web link (qz.com)
(TXT) w3m dump (qz.com)
| createmyname wrote:
| and rossi thinks this way:
|
| "Immortality is not something that that will ever be achievable"
|
| well, noted.
| r3pl4y wrote:
| #ExplainLikeImFive
|
| Could somebody explain to me what a PVC (Personalized Cancer
| Vaccine) is? Like what is the personalized part in there? Is
| there really a realistic scenario in which we'll get some regular
| vaccination and then we'll be cancer free in the future?
| zaphod12 wrote:
| Ok, so cancer is essentially a blanket term for describing that
| you have a group of cells in your body doing uncontrollable
| runaway mitosis (replicating themselves). But the thing is that
| it's caused by hundreds of different mutations to your cells in
| thousands of combinations. So developing a single way to combat
| all of this is super hard. But if we can identify your
| particular set of mutations and train your body to attack cells
| with those, we can get rid of your cancer and prevent it from
| returning. There are a few strategies for this and it's how
| some of the most incredible cancer therapies of the last few
| years work...those are just only applicable to certain very
| specific mutations.
| [deleted]
| subpixel wrote:
| Tick-borne diseases are not all similar but many of them are
| very, very nasty and Lyme Disease is not the worst of them.
|
| I'd love for my kids to be able to play in the weeds and woods
| with abandon the way I did.
| hyko wrote:
| Started reading to find the answer, but gave up wading through
| the hagiography.
| Steuard wrote:
| It's an indictment of _something_ that we 've had this amazing
| new tool for vaccine production in existence for a decade but we
| never even tried to use it for that until COVID because "vaccines
| typically don't make much money" and "vaccines just aren't that
| exciting" scientifically: "it's nice and easy," to quote Rossi
| from the article.
|
| If it really does turn out that effective mRNA vaccines can be
| created in a straightforward way for a host of new diseases,
| that's ten years of deaths and misery that we as a society just
| allowed to happen unnecessarily. I don't know how to fix that:
| maybe the market-based incentive structures that work for acute
| disease treatments aren't a good fit for broad preventative
| public health measures like vaccines.
| inglor_cz wrote:
| We did not have this tool for a decade, it was still very much
| scientific work in progress, with a lot of practical problems
| to be solved. Those problems were only ironed out in 2017-2018.
|
| You can absolutely kill or at least maim a new medical
| technology if you push it on the market too far and a wave of
| serious side effects hits you. As an example: death of Jesse
| Gelsinger [0] delayed genetic therapies by several years,
| possibly a decade or more. Scientists were afraid to touch the
| tools that killed a young man and produced a public backlash.
|
| [0] https://en.wikipedia.org/wiki/Jesse_Gelsinger
| mchusma wrote:
| Or focus on lowering costs. We learned in the pandemic how
| fundamentally broken the FDA is. There is no reason that things
| can't be faster that "operation warp speed" all the time.
|
| Or re-focus the monetary models around either markets or
| patient outcomes. Right now, medicine is not a market, it's a
| strange game. The most money that can be made is finding a
| treatment that may provide a modest increased benefit over what
| is live, then sell it to medicare at "name your own price".
| This incentives high probability wins (which are typically
| things we already understand well).
| azinman2 wrote:
| > There is no reason that things can't be faster that
| "operation warp speed" all the time.
|
| Because money. Operation warp speed started mass
| manufacturing at the same time as clinical trials. 70% of
| drugs fail the 3rd stage of trials, so that would be a hugely
| wasteful endeavor to parallelize this when failure is the
| norm.
| akira2501 wrote:
| > There is no reason that things can't be faster that
| "operation warp speed" all the time.
|
| Safety? I'm not wild about new vaccines requiring emergency
| use authorization and indemnity for the manufacturer. It
| worked out fine for COVID, but this is not a model I would
| _want_ to replicate.
| i000 wrote:
| The authorization is eua not because of safety concerns but
| unknown long term efficacy > 1 year. Does this change your
| assessment?
| Ericson2314 wrote:
| By this model vaccines are sadly "too effective" on two
| counts:
|
| - They are preventative. Americans are scared that regular
| people walk into hospitals and debt peons walk out. We are
| too sickly and scared for preventative medicine, and like our
| infrastructure which is never maintained to the point of
| being in "good working order".
|
| - They are O(1) dose. The unity economics of once-and-done is
| bad. Better to sell something which makes a customer for
| life.
|
| It's really depressing.
| antibuddy wrote:
| This is not new at all. They tried to use mRNA vaccines for
| other diseases as well, but were never approved. This still
| holds true to this date.
|
| edit: An example would be Dengvaxia.
| greatpatton wrote:
| It seems that Dengvaxia is a live attenuated vaccine, what is
| the relationship with mRNA vaccine?
| antibuddy wrote:
| Yeah, you're right. Better examples are:
|
| Zika: https://clinicaltrials.gov/ct2/show/NCT04064905
|
| Influenza: https://pubmed.ncbi.nlm.nih.gov/31079849/
|
| Rabies: https://pubmed.ncbi.nlm.nih.gov/28754494/
| cjblomqvist wrote:
| I agree with your sentiment, but we also need to careful with
| hindsight bias (i.e. it's easy to pick the winners after the
| fact)! It's a tricky question!
| adeledeweylopez wrote:
| Sure, but when urgency suddenly became necessary, mRNA
| technology was pursued quickly, which indicates that we
| already knew it was promising.
| detaro wrote:
| A good chunk of that is that people had finally gotten a
| delivery mechanism to work in the past few years. The "for
| a decade" is misleading, because a decade ago it was an
| interesting idea nobody had gotten to work in a way that
| was useful. 2020 it was something with good promise and
| product development under way that could be sped up
| massively with more money and acceptance of it being a
| gamble.
| Ericson2314 wrote:
| This feels like a post-hoc rationalization to me. Of
| course it was less ready, and then more ready. But
| exactly how much of a gamble was it?
|
| The upside is immense even considering just existing
| diseases, but we are really bad at pricing things that
| improve the status quo vs prevent bad things.
|
| The theory, assuming a delivery mechanism is found, is
| rock solid---"if not when"---and I therefore wouldn't
| call it a gamble.
|
| On the other hand, I don't know enough about the biology
| to speak to the difficulty and uncertainty around
| delivery mechanisms. Can we get more info on that? I
| suspect it wasn't too uncertain, though "oh, we change
| this base pair a bit and the immune system doesn't care"
| does seem like a relatively unplanned discovery.
| Ericson2314 wrote:
| Hehe try jumping in the https://en.wikipedia.org/wiki/Post-
| Keynesian_economics rabbit hole, where perhaps the simplified
| jumping off point is "growth follows demand".
|
| That fact that we fund all this basic research, but then can
| hardly be bothered with the development part of "R&D" seems
| like a pretty strong anecdote in favor.
| altcognito wrote:
| I believe the correct packaging mechanism was only conceived in
| 2018.
| WanderPanda wrote:
| I thought about a scheme where the years of patent protection
| in a particular field where there has been lack of progress is
| adjusted upwards, creating incentives for r&d in that
| particular space. The same obviously should also go into the
| other direction
| Ericson2314 wrote:
| I think patents are just a poor way to fund this stuff in
| general. Better to do drug bounties in which case the
| financing trickiness is only about who funds the human
| trials.
|
| In more than medicine, there's a good argument that only
| monopolies can afford R&D (c.f. Bell Labs) and monopolies are
| also terrible, so I'm pretty down on leaving R&D to the
| private sector anyways. Remember we already publicly fund all
| the R, this just about the D.
|
| Also, ownership, and IP ownership in general, far from being
| the natural order of things, is an extremely weird and hard
| to price financial instrument. I don't see the point of
| forcing it, and trying to make it work with e.g. adjustable
| patent lengths. That just feels like an epicycle that's
| _very_ prone to regulatory capture.
| joshgev wrote:
| I see two big problems.
|
| The science funding climate, at least in the US (I don't really
| know what goes on elsewhere) is in a really sad state. Projects
| with a low probability of success are really hard to get funded
| but that is precisely what you need to come up with really
| novel things. Curiously, science funding bodies don't seem to
| think of things in a probabilistic way.
|
| The second issue is the same idea, but applied to industry.
| There is an activation energy that you need to surpass in order
| to make any business profitable. If we are talking about
| building a business around a brand new and unproven (in a
| business sense) technology like mRNA, the barrier is _huge_.
| You need entities with very deep pockets to accept year after
| year of losses before you can start getting a viable business
| producing cutting-edge products.
|
| In both cases I think intelligent use of government funds could
| be a big help. I am not big on socialism, but I have long held
| that this is one of the most important things a government can
| and should provide: subsidies for risky research and business
| endeavors, not to mention large-scale infrastructure projects.
| Ericson2314 wrote:
| We _do_ fund basic research decently well, but not
| development. That 's mostly in agreement of the above, but
| leads to a few differences.
|
| In particular, if we start funding the both research &
| development, the public sector starts taking on all risk, so
| there is 0 reason to reward the private sector with IP
| ownership. Do a drug bounty, and then public domain the IP. I
| would say have the state hold the IP and license it out with
| cost controls, but I think having medicare actually negotiate
| will do that well enough.
| bdonlan wrote:
| mRNA vaccines have been undergoing active research for decades,
| and in particular the lipid nanoparticle delivery mechanism
| used in both the Pfizer and Moderna vaccines was first used in
| 2018 in a (non-vaccine) drug called Onpattro[2]. Without this
| technology, Moderna in particular was having issues with
| excessive side effects as late as 2017[1].
|
| As such, the Covid-19 vaccines from Pfizer/BioNTech and Moderna
| could not have been developed pre-2018, and - absent a deadly
| pandemic that requires taking extreme measures (such as using
| very large trial groups) to hasten the timeline - normally
| vaccines undergo development over a period of many years[3] to
| collect sufficient data to ensure effectiveness and to ensure
| that the long-term side effects are well understood. Moderna in
| particular was, prior to the Covid-19 pandemic, working on
| developing vaccines to target cancer using mRNA technology[4].
| Had the pandemic not occurred, one would therefore not expect
| to have seen any approved therapies until the mid-to-late 2020s
| at the earliest (and probably later, given how often vaccines
| and other drugs fail in human trials).
|
| In short, the issue was not that pharmaceutical companies were
| disregarding the technology, so much as simply the last
| remaining breakthrough needed to be made - and now that mRNA
| vaccines have proven themselves to be safe and effective,
| there'll be no shortage of effort to apply them to new
| diseases.
|
| [1] - https://www.statnews.com/2017/01/10/moderna-trouble-mrna/
| [2] - https://www.statnews.com/2020/12/01/how-nanotechnology-
| helps... [3] -
| https://www.historyofvaccines.org/content/articles/vaccine-d...
| [4] - https://www.statnews.com/2017/01/10/moderna-trouble-mrna/
| rossmohax wrote:
| Why this article is so Rossi centered? Did he play key role in
| mRNA breakthrough?
| khendron wrote:
| Because the article is about him and the company he
| (co)founded.
| caturopath wrote:
| Because he/his company is the subject of the article?
|
| The headline doesn't make that all that clear, but everything
| about the article seems to.
| throwaway879 wrote:
| Do the concerns raised here have any merit?
|
| https://osf.io/epr24/
| throwaway879 wrote:
| Why would anyone down-vote a question asking if there is any
| merit to some concerns raised by a clinical researcher? The
| target audience is people working on mRNA vaccines who might be
| able to shed some light.
| ProjectArcturis wrote:
| There are a lot of folks excited about mRNA as a "programming
| language" for the body. And it kind of is, but it's more
| complicated than that. The critical thing is that mRNA is
| extremely immunogenic -- that is, it provokes a strong immune
| response. Makes sense, since evolutionarily when we had little
| particles delivering RNA strands to our cells, they we viruses.
|
| So, that's _great_ for vaccine production. Not so great for other
| diseases. Cystic fibrosis, for example, the body fails to make
| one specific protein. We (probably) can 't just program it to
| produce that protein, because it would also train the immune
| system to target that protein. The best non-vaccine targets are
| probably cancer, where you want to get the immune system revved
| up against a tumor.
| CorrectHorseBat wrote:
| I thought they solved that by replacing U by
| 1-methyl-3'-pseudouridylyl in mRNA vaccines? I can imagine it's
| not great for vaccines either, you want the immune system
| attack the spike the mRNA codes for, not destroy the mRNA
| before it can do it's thing.
|
| https://berthub.eu/articles/posts/reverse-engineering-source...
| pfdietz wrote:
| You also don't want to activate an innate response our bodies
| have when virus attack is detected: cells churn out enzymes
| that chop up RNA.
| JPLeRouzic wrote:
| > We (probably) can't just program it to produce that protein,
| because it would also train the immune system to target that
| protein.
|
| I am not a scientist but my understanding is that the immune
| system targets only what it is trained against. It doesn't
| target anything which is non-self without being trained
| beforehand.
|
| IMO if it was otherwise there would be no need for vaccine.
|
| So I think that it is quite feasible to make a cell to produce
| a new protein, for example Zolgensma [0] works that way: It
| creates a new gene (hence a new protein) to replace a deficient
| one.
|
| [0] https://en.wikipedia.org/wiki/Onasemnogene_abeparvovec
| fuckyah wrote:
| I wouldnt jump to conclusions, as we haven't seen the real
| impact of the vaccines yet. We still don't know if they
| actually prevent all-cause deaths. We also don't know anything
| about long term side effects.
| raverbashing wrote:
| > mRNA as a "programming language" for the body
|
| Kinda. Programming but more like a browser JS.
|
| You're not changing anything (your DNA) and whatever you're
| making is temporary and limited (especially because you can't
| have anything too complex or long as mRNA without that breaking
| up).
| gfodor wrote:
| Depending on your defect, CF can either under-produce CFTR,
| produce deficient CFTR, or produce no CFTR. I'd imagine each of
| these scenarios has different viability for mRNA theraputics.
| im3w1l wrote:
| What about hiv?
| simcop2387 wrote:
| HIV is a virus, so it would seem to be a good candidate for
| mRNA since you'd want to make it generate an aggressive and
| early response to the virus. I can't even guess though what
| challenges would arise given that HIV likes to target the
| immune system itself.
| unnouinceput wrote:
| This might shed some light:
|
| https://www.businessinsider.com/new-hiv-vaccine-could-be-
| mod...
| jcims wrote:
| Many cancers exhibit immunosuppressive qualities that allow them
| to co-exist in a healthy immune system. It seems possible that
| mRNA-based therapies could be used to interfere with those
| mechanisms (eg binding to PD-L1, etc).
|
| The delivery mechanism for the mRNA appears to be the primary
| innovation and I wonder if it would be possible to target it at
| specific cells. In the cancer context if you could differentially
| target the mRNA delivery to cancerous tissue, the 'payload' could
| be more generally cytotoxic but only affect tissue proximate to
| cancer cells.
|
| This seems like it's on the order of CRISPR for potential to
| change the landscape of medicine in the next 50 years.
| umanwizard wrote:
| Possibly naive question: if you can differentially target any
| particular thing to cancer cells specifically, why not just
| deliver poison to kill the cells directly? I.e. chemotherapy
| but without any of the nasty side effects.
| jcims wrote:
| Not naive at all. I didn't word my question well as my
| interest is broadly if this new technology gives us any more
| ability to differentiate the delivery, either by selecting
| for cancer cells or by only 'activating' within cells that
| are cancerous.
|
| In general there are a number of 'targeted' therapies being
| developed that don't specifically target the cancer cell, but
| try to make life more difficult for the cancer by broadly
| impacting a cell's ability to hide, replicate and
| accumulate...features that the rest of a healthy human tissue
| is less dependent upon.
| DanielBMarkham wrote:
| I agree. It's easy to overstate things, but over the next
| several decades I could easily see a computational personalized
| approach to fighting cancer: read the unique immunosuppressive
| markers, sort out what's tractable and what's not, then deliver
| a mRNA payload for that particular cancer for that particular
| person.
|
| For the incredibly small amount that I know, it looks like a
| game changer. (Like everything else, though, there's a long
| road from theory to practice. Implementation is going be very
| tough)
| perlgeek wrote:
| Makes you wonder what it would take to get such a process
| (that produces a new medicine for every individual)
| approved...
| IdoRA wrote:
| The FDA has recently issued draft guidance for such:
| https://endpts.com/for-tailored-single-person-antisense-
| olig...
| inglor_cz wrote:
| I think this is precisely what BioNTech has been doing with
| melanoma. Not in a few decades, they already had living
| patients with personalized vaccination against their own
| melanomas in 2019:
|
| https://www.nature.com/articles/d41586-019-03072-8
|
| If this immunotherapy gets developed further, the next
| generations of humanity may look at cancer in the same way
| that we look upon bacterial diseases: unpleasant, the threat
| of treatment resistance is there, but not the fearsome serial
| killer that they used to be.
| dhosek wrote:
| Although given how we've squandered (and continue to
| squander) antibiotics, future generations may view
| bacterial diseases the way past generations did.
| CodesInChaos wrote:
| > in the same way that we look upon bacterial diseases:
| unpleasant, the threat of treatment resistance is there
|
| Those treatment resistances are quite different. Resistant
| bacteria spread to other people, while cancer is almost
| always limited to a single patient. So it the treatment
| works for a certain fraction of cancers, it'll stay at that
| level, unlike bacteria which become increasingly resistant
| over time.
|
| (I guess that in the very long term that might not be true,
| since natural cancer resistance will offer less of an
| evolutionary advantage. But that assumes that humanity will
| remain in a similar state as currently, which seems
| unlikely.)
| inglor_cz wrote:
| I know, it is an imperfect analogy. But thank you for
| noticing and explaining my shortcut to other readers.
|
| Cancers are very patient-specific, and the main threat
| with immunotherapy is that the targeted cancer adapts
| quickly enough to escape the immune system again.
| jcims wrote:
| >Cancers are very patient-specific, and the main threat
| with immunotherapy is that the targeted cancer adapts
| quickly enough to escape the immune system again.
|
| (I'm just an interested party and don't have any formal
| training on the subject.) I'm sure there are technical
| terms for it, but from what I've read the lack of
| regulatory features in the replication process of cancer
| cells tends to accumulate more mutations and genetic
| damage through each generation. PARP-inhibitors, for
| example, help fight cancer by suppressing DNA repair
| enzymes and letting the cancer cells get into non-viable
| states more often than healthy tissue.
|
| In general though, this genetic entropy/volatility
| creates a scenario where adaptations can happen quite
| quickly.
| hirenj wrote:
| I was thinking about this very subject this morning, and I
| realised the mRNA stuff actually isn't the exciting part.
|
| It's the packaging in lipid particles that is much more
| interesting. We can get away with this approach for vaccines
| because we (largely) don't care where we deliver the payload
| to, just as long as we get mRNA to a cell where it can make the
| protein. Not sure about current formulation, but I read most
| LNPs end up in the liver from circulation.
|
| The next level of tech is targeting the particles, and then it
| gets as tricky as other contemporary techs, because you want
| your targeting mechanism on the prticles to be something
| resembling a receptor ligand (protein/carbohydrate).
|
| Manufacturing of those (and putting them on a lipid particle)
| is still a slog. If we figure out nice ways to do that (without
| reasonable purity) then it doesn't matter what is in the LNP
| (e.g put gold particles inside cancer targeting particles and
| zap your cancer cells dead).
| elcritch wrote:
| An alternative approach would be to learn enough to make mRNA
| "programs" that once inside a cell could determine cancerous
| vs healthy cells. There's been research on computations using
| DNA, and many natural pathways do similar "calculations",
| that it seems feasible to create a "if specific xyz
| protein/carbohydrate/etc in cell exceeds threshold trigger
| cell death pathways". Then injection in a tumor mass should
| be sufficient. The mRNA program might only need to be
| partially accurate to be more effective than many
| chemotherapy's.
| dukeofdoom wrote:
| hair loss?
| Xenoamorphous wrote:
| I know it's maybe pure vanity and I definitely wish to see
| cancer cured first but I think the psychological impact of hair
| loss, especially in young people (<25), is often
| underestimated.
| rocgf wrote:
| For better or worse, it's not the importance of a disease per
| se that drives innovation, it's money. So assuming that hair
| loss is the kind of problem that would get people to spend
| money, then we might see some progress here.
| lazide wrote:
| There are many possible ways to quantify importance? And
| many many stakeholders with often conflicting ideas,
| demands, and influence.
|
| If someone is spending money on something, they are voting
| that it is important FOR THEM - and more important than
| whatever else they would have done with the money.
|
| If politicians/government aren't spending money on
| something - despite saying it's important - that is a very
| clear signal that their words and their actions do not
| align. We have words for that too.
|
| If they don't even bother saying words about it, then that
| is a clear signal not enough pressure is being applied to
| make it even a pretend priority no?
| dehrmann wrote:
| Funny story: finasteride was used to treat enlarged prostates
| (and decrease risk of prostate cancer) before it was observed
| to reduce male-pattern balding as a side effect.
| fma wrote:
| I don't have experience in this field...but w/ hair, someone
| can get grafts which supposedly look better than plugs from
| decades ago?
| JohnWhigham wrote:
| It's still very costly, and carries a long recovery period.
| Your head will look quite gnarly. Of course we never see
| that because all the celebrities that do can afford to stay
| out of the public eye for extended periods.
| xKingfisher wrote:
| They still have a number of issues.
|
| * They're expensive (~4-8 dollars per follicle) with a
| single transplant being 1000-5000 follicles. Severely bald
| men may need multiple
|
| * There is a finite number of follicles that can be
| transplanted.
|
| * Permanent scarring in the donor zone.
|
| The ultimate treatment would be either hair cloning (still
| a ways out, very expensive) or a way to reactivate the
| dormant follicles. Presumably if you could solve the latter
| you would become very rich very quickly.
| thijsvandien wrote:
| I think you can easily make that <45 in case of men, and
| don't forget about women.
| ratsbane wrote:
| I think that DNA methylation is a big factor in hair loss as
| well as hair color changes. There are other disease processes
| which are also driven by DNA/RNA methylation, so a treatment
| for any of these might also lead to treatments for all of them.
| (And I don't really know what I'm talking about and I hope
| someone with more expertise can add to this)
| ecedeno wrote:
| Moderna has a public development pipeline. It shows they are
| working on, among other things, an HIV vaccine and
| vaccines/therapies for multiple types of cancer.
|
| https://www.modernatx.com/pipeline
| agumonkey wrote:
| brings an odd question, will we have to have artifical exposure
| to diseases just to ensure our immune system is capable ?
| coderaptor wrote:
| I'd also like to know where I can read further on discussions
| on this. My understanding is that it's the same for
| chickenpox - that lack of frequent natural exposure now
| requires artificial exposure with boosters to prevent
| shingles. Feels like vendor lock-in to me - often valuable
| but with some downsides that need to be evaluated on a case
| by case basis.
| roywiggins wrote:
| One theory about the 1918 flu us that it hit young people
| harder because older people had encountered a similar flu
| already, before the younger generation were born.
|
| But in general, being exposed to (say) seasonal flu every
| year might not help you at all when a new strain of pandemic
| flu shows up. The 1918 flu tore through young healthy people.
| staticassertion wrote:
| You mean a vaccine?
| blumomo wrote:
| HIV is a known virus for many decades. Now that mRNA was
| released in a rush, why would it suddenly cure HIV?
| toast0 wrote:
| Now that mRNA is productionized (or at least on the path
| towards it), and has been used in hundreds of millions of
| people without apparent major negative short term effects,
| the barrier is lower for other targets which no longer have
| to prove the whole technology is safe, effective, and
| producable.
|
| We have two examples of safe (so far), effective and mass
| produced mrna vaccines; so it's probably easier to get
| funding to research and test other targets. HIV is a popular
| target, although it's also very difficult.
| da_big_ghey wrote:
| how much money in cure HIV? largest endemic area is
| probably subsaharan Africa, not much in money there. In
| western nation it mostly is disease for gays or ocasional
| unlucky blood transfusion receive person [0]. i am not say
| that cure for it is bad - it is in obvious good - why did
| Moderna make choice for to research this cure in specific
| over other?
|
| https://www.cdc.gov/nchhstp/newsroom/docs/factsheets/cdc-
| msm...
| drzaiusapelord wrote:
| This is hate speech.
| tecleandor wrote:
| That's an answer right from the 80s and it's completely
| wrong and against the same statistics you link. In the US
| heterosexuals account for more than 25% of AIDS
| infections, not accounting bisexuals and undetermined
| infections.
| dinkleberg wrote:
| Do you ever read what you write before posting it and do
| a basic morality review?
|
| I'm sure there are many valid points to debate which
| diseases to go after next, but you only consider the
| money. I'm a capitalist and love making money, but come
| on!
|
| Questioning the choice to go after HIV because the
| primary people benefiting are too poor or gay? That is
| insanity.
| fnord77 wrote:
| mRNA vaccines are a product of 30 years of work. We got
| extremely lucky that covid hit when it did.
| aeyes wrote:
| BioNTech as well: https://biontech.de/science/pipeline
| est31 wrote:
| Plus a flu vaccine:
|
| > mRNA vaccines [...] generate a much stronger immune response
| than responses that are generated to the protein in a normal
| flu vaccine [...]
|
| > One limitation of the current flu vaccines is that they take
| about six months to develop, meaning scientists must choose
| which strains they think will be prevalent in the next flu
| season -- even before the current one is over. So by the time
| the vaccines are ready for distribution, a different strain may
| have emerged as the better target.
|
| > An mRNA flu vaccine, on the other hand, can be developed in
| about a month or so, giving researchers much more time to
| determine which strains to protect against.
|
| https://www.washingtonpost.com/health/2021/04/11/mrna-flu-sh...
|
| The flu vaccine seems to me to have a better chance of working
| than an HIV vaccine because we have been trying for decades to
| come up with one for HIV, without any success at all. I'm not
| saying that their attempts won't work either, but it's more of
| a bet than a flu vaccine. An iterative improvement on the
| existing flu vaccines would still be very helpful.
| lisper wrote:
| > by the time the vaccines are ready for distribution, a
| different strain may have emerged as the better target
|
| I have never understood this. How many strains are there? I
| thought there were only like 4 or so. Why don't they just do
| them all every year?
| cannaceo wrote:
| There are subtypes of each. Influenza A and B cause the
| seasonal flu. The subtypes are named by their hemagglutinin
| (H) and neuraminidase (N). E.g. H1N1, H5N9, etc.
| amluto wrote:
| And those subtypes themselves are constantly mutating.
| Look at actual WHO vaccine recommendations:
|
| https://www.who.int/influenza/vaccines/virus/recommendati
| ons...
| lisper wrote:
| OK, but that doesn't really answer my question.
|
| Turns out the answer can be found here:
|
| https://www.cdc.gov/flu/about/viruses/types.htm
|
| "There are four types of influenza viruses: A, B, C and
| D. Human influenza A and B viruses cause seasonal
| epidemics of disease (known as the flu season) almost
| every winter in the United States. Influenza A viruses
| are the only influenza viruses known to cause flu
| pandemics, i.e., global epidemics of flu disease. A
| pandemic can occur when a new and very different
| influenza A virus emerges that both infects people and
| has the ability to spread efficiently between people.
| Influenza type C infections generally cause mild illness
| and are not thought to cause human flu epidemics.
| Influenza D viruses primarily affect cattle and are not
| known to infect or cause illness in people."
|
| "Influenza A viruses are divided into subtypes based on
| two proteins on the surface of the virus: hemagglutinin
| (H) and neuraminidase (N). There are 18 different
| hemagglutinin subtypes and 11 different neuraminidase
| subtypes (H1 through H18 and N1 through N11,
| respectively). While there are potentially 198 different
| influenza A subtype combinations, only 131 subtypes have
| been detected in nature. Current subtypes of influenza A
| viruses that routinely circulate in people include:
| A(H1N1) and A(H3N2). Influenza A subtypes can be further
| broken down into different genetic "clades" and "sub-
| clades." See the "Influenza Viruses" graphic below for a
| visual depiction of these classifications."
|
| So the answer is: 198 possible strains, 131 that actually
| occur. That explains why they have to pick and choose.
| elcritch wrote:
| It seems they could pre-make vaccines for all 131 extant
| types and then mix the flu shots based on the current
| season. Though, likely that wouldn't be economical.
|
| It does raise the question of why they couldn't just put
| a bit of all 131 subtypes in the vaccine. Or if that'd
| overload the immune system, say, the X subtypes most
| likely to makeup say 99% of probable flu season strains.
| lazide wrote:
| They could - but up until recently no one cared enough,
| both for R&D spend and to get or mandate enough shots for
| it to work at it's stated goals.
|
| We've had people even recently refusing to give their
| kids polio, tetanus, or measles vaccines - and even 5
| minutes of honest research or questions to a doctor will
| make quite clear how bad an idea THAT is. Getting 100+
| flu vaccines, all which would have to go through a
| pipeline taking nearly a decade, when 'nothing bad has
| happened' on that topic for a hundred years?
|
| Ain't nobody going to pay for that.
|
| We'll see how the calculus is different soon. I for one
| would rather my tax dollars go towards figuring something
| like never having the flu again than blowing up some
| random middle eastern country a couple more times.
| jbjbjbjb wrote:
| There's got to be a large market for that given the
| entire elderly population is offered a flu shot every
| year. Doing that as a one off would be a huge cost
| saving.
| lazide wrote:
| Not sure it would pay for itself even in 100 years if you
| use that metric.
|
| $20 (likely current retail cost of a flu shot) x the 46
| million older adults in the US is a hair less than a
| billion a year. Making 131 or so effective flu vaccines
| and getting them through the process with the prior known
| and effective process? (including all the failed
| attempts)
|
| Hopefully we'd get some economies of scale, estimates
| [https://www.passporthealthusa.com/2018/02/how-much-does-
| it-c...] I found had it between 500m to 2.5billion and a
| decade each. So 65billion to 327billion.
|
| So between 65 to 327 years for positive ROI if that was
| your metric.
|
| If you're talking public good, it would be immeasurable
| for us and the world though, no question, and on the high
| end that's less than a third [https://www.google.com/amp/
| s/www.bbc.co.uk/news/world-473918...] of what we've spent
| in Afghanistan alone.
| nick_kline wrote:
| One more piece of this is they endlessly mutate, I don't
| think in reality there is a limit. Most mutations
| probably don't help the virus proliferate, might cause it
| to not be effective. Eventually the shape of a new one,
| what your body is looking for in it's remembered virus
| history will change enough that it can't be detected. We
| see this in real time with the cv19 variants. My mental
| model of this (I am in software so I welcome corrections
| to the applicability) is it's like antivirus in software
| - the bad guys making viruses keep trying new variations
| on old ones, switching what the protection software is
| looking for so they can get around detection methods, as
| well as trying to find new holes.
| entee wrote:
| I don't think that's quite right. Even if you have a flu
| strain with a particular name (H1N1) there are a number
| of variants within the H1 and/or N1 proteins that the
| vaccine will be targeted to as well, so the number is
| quite a bit larger than 198/131.
|
| It's not that hard to make a new vaccine, the process for
| flu is very accelerated because they're just a variation
| on the original theme which has been proven to be safe
| (though unclear on effective until AFTER the flu season
| hits). If you think about it, we make a new flu vaccine
| every year, and develop it in 6 months. Each one contains
| a few guesses as to which of the flus are going to be an
| issue, it's not just one antigen in the vaccine. Those
| guesses are just that, an informed prediction, which is
| why the vaccines tend to be fairly ineffective (40-60%)
| at preventing disease altogether, though perhaps better
| at preventing serious disease.
|
| Moderna is claiming to be quicker, so they'd have a more
| accurate read on what the REAL flu strain this year is
| going to be, and so it should be more efficacious. The
| key variable will be dosing. mRNA vaccines can only
| deliver a certain amount of mRNA so it might be
| impractical to deliver very many antigens at once. Also
| delivery issues, the current flu vaccine is super easy to
| make and deliver to patients, mRNA vaccines with their
| complicated cold chains aren't. Obviously it's not an
| impossible problem, but it's less convenient.
|
| Time will tell, it's certainly very promising!
|
| Helpful:
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619640/
| roywiggins wrote:
| It would be especially worth it to have approved mRNA flu
| vaccine in hand for the next pandemic flu. You'd might be
| able to actually vaccinate your way out of it.
| azinman2 wrote:
| They constantly mutate.
| stefantalpalaru wrote:
| > mRNA vaccines [...] generate a much stronger immune
| response than responses that are generated to the protein in
| a normal flu vaccine [...]
|
| That's probably due to the immunogenicity of those lipid
| nanoparticles used to encapsulate the mRNA (particularly the
| cationic lipid): https://www.biorxiv.org/content/10.1101/2021
| .03.04.430128v1....
| vmception wrote:
| It seems like with HIV they can simply sequence the prevalent
| evolutionary outcome in your body within a month and give
| your body the blueprint to destroy that version
|
| What typically happens with HIV is that the body kills most
| of it initially, but the remaining ones keep rapidly evolving
| until an iteration evades your immune response, this takes
| about 12 years. Seems like an mRNA vaccine could be done
| every 3 years for individuals and either completely eradicate
| the HIV presence in the body or do it once every 12 years for
| a reset
|
| Let me know if I fundamentally misunderstand something
| robbiep wrote:
| That's not quite true - HIV of course mutates but in-
| patient mutations are generally considered to have a
| negligible effect on outcomes/have a negligible effect as a
| driver of morbidity .
|
| What is the big driver of HIV is in the name, it's a
| Immunodeficiency virus - it kills CD4+ T cells and other
| cells of the immune system. At a certain point you don't
| have enough CD4+ T cells left and you lose your
| adaptive/cell-mediated immune system and then you're in big
| trouble. Essentially it's a war of attrition and unless
| you're part of some tiny proportion of people who have
| either a form of immunity against it or an immune system
| that for whatever reason is able to continue waging war on
| it then you will succumb
| [deleted]
| 2OEH8eoCRo0 wrote:
| What can companies do to ease the public's worry about mRNA
| vaccines?
|
| I work with a number of people who will not get an mRNA vaccine
| until they are better understood.
| ALittleLight wrote:
| The answer seems straightforward then. More research to better
| understand mRNA vaccines and their consequences plus an effort
| to communicate what is found in a way that is digestible for
| lay people.
| dehrmann wrote:
| Wait 5 years.
| ppf wrote:
| The next Covid-19 variant?
| perardi wrote:
| At the risk of responding to a throw-away comment:
|
| https://www.technologyreview.com/2021/01/13/1016098/moderna-...
|
| They can retool very, very quickly. The slight unknown is
| running another trial.
| rdlecler1 wrote:
| Greenlight Biosciences (one of our portfolio companies) is using
| RNA as a highly targeted-species-specific pesticide.
| DocTomoe wrote:
| This honestly is highly concerning - if that can be done for
| species, the next step could be to target ethnicity. I feel
| like this is one of those Oppenheimeresque moments in human
| history.
| lazide wrote:
| It's been tried and done before via chemical and biological
| methods (if you don't want to sleep for awhile, check out
| what has been declassified on THOSE topics and realize that
| is what they were OK releasing to the public!).
|
| The problem of course is that in deploying it, you'll
| inevitably kill a bunch of your own - no population is so
| consistent you won't kill a bunch of senior leaders who had
| parents 3 generations ago who were transracial or whatever
| and lied about it - and it will inevitably turn everyone in
| the world against you.
|
| Even states like NK or Iran need friends, and those friends
| would have enough casualties from anything like this there is
| no scenario I can imagine anyone would intentionally release
| something like that.
|
| Doesn't mean a mad scientist type would cook it up
| accidentally in the garage, but there are always real world
| constraints stopping wide spread (physics sometimes, often
| effectiveness limits or the like).
| parshua wrote:
| Why do you bring Iran or NK into this? Let's get it
| straight: Until now, the only counties who have actually
| tried genocide on industrial scale, have performed inhumane
| tests on live subjects of other cultures or used Nukes on
| civilian targets have been mostly western. Heck, they were
| literally wiping each other out right until 75 years ago.
| They are also the ones actively ganging up and invading
| others TODAY. What delusion suddenly caused you to think it
| is again 'others' who are trying to wipe you out?
| Asparagirl wrote:
| As a Jewish genealogist who got involved in direct-to-
| consumer genetic genealogy testing very early on (14+ years
| ago), this is one of my biggest fears. Genetic signatures for
| endogamous populations, in particular, are really easy to
| pick out of DNA samples. It's already openly discussed in
| Jewish DNA Facebook groups and blogs which chromosome
| segments tend to be Ashkenazi "pile up" regions, to separate
| true potential cousin matches from just plain endogamy. A bad
| actor, or nation-state, could easily do the reverse and look
| for those segments on purpose...
| lucb1e wrote:
| Because it's buried in some two thousand words:
|
| > helping cells produce tissue to heal from events such as
| cardiac arrest
|
| > beyond simple vaccines [...] mRNA therapeutics might be
| tailored to instruct a person's immune system to fight their
| specific type of cancer, or target protein deficiencies in
| specific organs, and without the toxic side effects of
| traditional medications.
|
| > "My personal moonshot is snake venom, and antivenoms for snake
| bites," he says. [...] "You inject it into a person, and within
| hours the protein that you wish is being expressed," he explains.
| The final product of such research, he imagines, would be an
| antidote that could work for the most lethal species of a
| specific area, delivered in a way that can be preserved for long
| times in very remote areas--for instance, a powder that can be
| stored for long periods of time and reconstituted quickly.
|
| This is literally all the info I found that is actually relevant
| to the interesting headline. The rest of the article is about
| this person's career and what funding vaccine companies got in
| 2020.
| lapalmian wrote:
| BioNTech's current development presentation:
| https://investors.biontech.de/static-files/53947c63-dd5c-44d...
|
| CureVac's pipeline can be found here on page 6:
| https://www.curevac.com/wp-content/uploads/2021/04/20210421-...
| lukeschlather wrote:
| Scientifically and medically, vaccines seem extraordinarily
| exciting as a simple tool that can permanently eliminate
| problems. Treatments sound very exciting if I were running a
| business, but scientifically less so.
|
| I'm really glad that we've developed these great mRNA vaccines,
| and I hope that a business drive for recurring revenue doesn't
| chase people back to merely looking for treatments.
| sk1459 wrote:
| Permanently? I thought the standard of performance has become
| "reducing symptoms, maybe, we think, we're not really sure.
| This is probably safe though"
| dehrmann wrote:
| Once drugs go off-patent, the subscription model is a lot less
| appealing. Even before then, allowing vaccines to sell for $200
| per dose (I'm just making up this number) would encourage
| vaccine production. But you're right that this is an example of
| markets not doing the right thing, so it might take government,
| or even insurance company subsidies on vaccine development.
| rsynnott wrote:
| That's not an outlandish number; retail price of the HPV
| vaccine in developed countries is about 200 euro a dose
| (though in practice usually paid by health services). They
| get a lot cheaper once out of patent, of course.
| Sommer wrote:
| Could there be mRNA applicability to food allergy treatments,
| peanut allergies in particular?
| GEBBL wrote:
| I am so excited for the prospect of mRNA treatments, especially
| in the field of auto immune conditions like multiple sclerosis.
| Those scientists are heroes.
| jcims wrote:
| If that's possible, curing type 1 diabetes would be on the
| horizon as well. There's some evidence that people with t1d
| have latent beta cells that could be reactivated to restore
| normal(ish?) insulin response. That would be incredible.
| vallard wrote:
| I really really hope so.
| mvanaltvorst wrote:
| Are there any online resources where I could learn more about
| what mRNA treatments could theoretically cure? Take Hashimoto's
| disease for example, a disease where your thyroid gland slowly
| gets destroyed by your immune system. If I understand
| correctly, mRNA could stop your thyroid gland from getting
| destroyed in the first place, but it cannot regenerate the
| thyroid gland if it has already been destroyed. Is that
| correct?
| henron wrote:
| My mental model is that in the next decade or so mRNA
| treatments could be effective if a disease can be treated
| through the expression of a small number of proteins. These
| proteins could either have a direct function or stimulate an
| immune response. I think your example works.
| mvanaltvorst wrote:
| What kind of proteins are important when you're looking at
| the immune system? Is there a protein that can attach to
| thyroid gland cells and signals to the body that it isn't a
| threat? Or is there some sort of memory of the immune
| system with non-threat cells, that mRNA could overwrite?
| I'm not a biologist, I'd love to read more about these
| specific inner workings without dissecting a whole
| undergraduate biology book.
| pseudosudoer wrote:
| I haven't read anything related to treating autoimmune diseases
| with mRNA, that would be quite exciting. Do you happen to have
| a reference for this?
|
| I have Ulcerative Colitis, which is a form of an autoimmune
| disease. A vaccine as a cure would be a game changer.
| azinman2 wrote:
| But I thought we don't really know what causes UC. Fungi?
| Bacteria? Genetic factors? Something else?
| sapsan wrote:
| Maybe something like that is relevant:
| https://science.sciencemag.org/content/371/6525/145. There's
| also a bit more context here:
| https://www.nature.com/articles/s41587-021-00880-0.
| usrusr wrote:
| How would the treating of auto immune work? In my understanding
| you can trick the immune system into putting yet anther protein
| on the "kill on sight" list, by forcing the protein's mRNA
| blueprints into the production pipeline of some cells and...
| waiting, assuming that the immune system does its thing. So far
| so good. But isn't an autoimmune problem an entry on the "kill
| list" that shouldn't be there? I understand how we can append
| to that list (through a fascinatingly elaborate stack of
| indirections), but how can we revoke an entry?
|
| Not questioning, just willing to learn.
| IAmGraydon wrote:
| https://khn.org/morning-breakout/biontech-reports-
| breakthrou...
| jonlucc wrote:
| I work in a pharma company, and I have been working with
| the animal model they use for this paper regularly for the
| past 4 or 5 years. I am not an mRNA therapy expert by any
| means, so I'll only comment on the results from the
| MOG35-55 and PLP EAE models.
|
| They have good disease induction in their control groups,
| their targeted mRNA therapy shows pretty remarkable
| efficacy, and they show they can diversify a little bit
| with respect to the target.
|
| These models are a little too "furry test tube" for me for
| this application. They work by injecting an antigen, either
| a short version of the myelin oligodendrocyte glycoprotein
| (MOG) peptide or the myelin proteolipid protein (PLP). The
| mouse makes antibodies against that antigen, and those
| antibodies also attack those antigens in their natural
| environments, leading to demyelination in the CNS. Well
| their mRNA for the MOG model makes more MOG peptide, giving
| the antibodies another target so they don't cause
| demyelination. In the human condition, there are multiple
| antibodies against multiple targets, so I'm not sure this
| is as relevant as they're suggesting, unless I'm missing
| something. I do want to add that this paper has a ton of
| work in it, and it looks pretty high quality as far as I
| can tell.
|
| None of this is to say there's no value here, I'm just not
| sure what target they would make an mRNA for to treat human
| MS based on this paper or how they'd identify and test that
| target to get FDA approval to move into trials.
| maxerickson wrote:
| They target signaling mechanisms that the immune system uses.
|
| I think I don't understand it very well, but it seems one
| approach is to have the vaccine cause cells involved in an
| auto immune disorder to put a bunch of 'friend' markers on
| their surface. So the technology is that they can trigger
| protein expression and the medical approach is to get cells
| to express proteins that lessen immune activity against the
| cell.
| bsanr2 wrote:
| Hopefully my height. Hello, 6 feet.
| CoastalCoder wrote:
| Probably a niche application. Most persons want exactly two.
| bsanr2 wrote:
| I dunno. The confluence of the interests of furries and Metal
| Gear/Deus Ex/Cyberpunk fans might make for a lucrative market
| leading into the widespread adoption of Anansization.
|
| Jokes aside, I'm surprised at the rather negative response.
| As a medical problem, you're looking at not just cosmetic
| applications, but also treatments for not-uncommon
| disfigurement or injury, and the phasing out of existing,
| quite brutal, leg-lengthening surgeries. Philosophically, you
| have the issue of bodily agency, and the opportunity to
| remove that particular source of interpersonal disparity and
| discontent. Scientifically, I'd think it an interesting
| problem, one that seemed as implacable as death, except that
| it isn't, because we have brute-force methods to circumvent
| the proscriptions of the natural process.
|
| Figured that would be something HN would be eager to chat
| about.
| danthedan wrote:
| this isn't reddit
| valarauko wrote:
| True, though most people also have more than the average
| number of feet.
| cigaser wrote:
| Well, it will treat everything. Soon it will be generic
| technology, accessible to any low-tier lab with "RNA printer".
| Any country will be able to download medication from internet.
| And in most places it is impossible to copyright naturally
| occurring RNA sequence.
| coldcode wrote:
| mRNA seems almost like a biological programming language; if you
| can determine how to build a protein that triggers the body's
| immune system to attack something you want to destroy it's just a
| matter of design and testing. I wonder if you could build a real
| language that you could use to design a sequence and automate the
| testing.
| dehrmann wrote:
| I still find describing anything in biology as a "programming
| language" to be a bit generous. It still feels more like
| fiddling with inputs to an ML model.
| arrosenberg wrote:
| You could, but keep in mind mRNA occurs in 3D and thermodynamic
| and kinetic forces play a huge role in biochemistry, so it's
| quite a bit more complicated than your average program.
| inglor_cz wrote:
| Well, that is why it comes 50 years later than, say,
| Kernighan and Ritchie standard of C.
|
| The know-how and hardware of today are just enough for the
| 1.0 of mRNA vaccines, so to say. How will the fourth or fifth
| generation look like, is probably beyond our imagination
| right now.
| [deleted]
| bqmjjx0kac wrote:
| Not quite what you're asking for, but check out CRN++ [0], a
| programming language built on chemical reaction networks (CRN).
|
| [0]: https://arxiv.org/abs/1809.07430
| intricatedetail wrote:
| I would love that the state sponsored research into chronic pain.
| Big pharma has no incentive to find cure, they want to push a
| suite of addictive pills that ruin lives or they spend money to
| block medical cannabis. Millions of people suffer with no way
| out.
|
| Edit: why people downvote the truth? I guess none of you suffered
| this and I hope you will not, but silencing a voice like that is
| inhumane.
| perardi wrote:
| Well...there is state sponsorship, via the NIH.
|
| https://www.nccih.nih.gov/nih-pain-research-center/research-...
|
| "Pain" is almost never the disease. _(OK, maybe CRPS.)_ There's
| a lot of things that cause pain, almost self-evidently, so it's
| not one particular thing to attack, unlike a virus.
|
| _(Also we are at 36 states now with medical marijuana, so I
| think the "pharma wants to block this" ship has sailed,
| especially when you consider big-hitters like California and
| New York have full recreational marijuana now.)_
| Steuard wrote:
| I didn't downvote, but if I had to guess, I suspect it's
| because your comment seems to have very little to do with the
| article (apart from the fact that the article is about medical
| research and you are advocating for a different sort of medical
| research). If there's a specific reason to think that mRNA
| could be used in treating chronic pain, including that could
| make your comment more obviously on-topic. (Not that your
| underlying point is a bad one! It's just hard to see how it
| fits in a discussion of this particular article.)
| missedthecue wrote:
| Gilead has made billions curing hepatitis c, so I think your
| theory is disproven.
| dcminter wrote:
| Probably because it's not really on topic.
|
| Worth reviewing the site guidelines here:
|
| https://news.ycombinator.com/newsguidelines.html
| cigaser wrote:
| Chronic pain is just a symptom. There could be million causes
| that needs to be treated first. And cannabis is just another
| form of "addictive pill", no better than opioids.
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