Does anyone know a website where I can see/read of how many cancers (and their variants) we've effectively solved, have drugs to negate their effects, have experimental drugs for and uncurable cancers? I think that graph would be awe inspiring looking at the past decade of advancements.
What's more crazy is that we're slowly going from millenia, to decades, to likely years in the near future from being presented a biological problem and achieving the next milestone in solving it. We might have "AI", but we also have brilliant minds right now that are speeding up development to a pace that would be unimaginable just few years ago.
It's not as great as you might think, despite all the stories you see like this one. That's because most of the stories are in cells (this one) or mice.
The big success story, about 20 years old now, is testicular cancer. You can have metastatic testicular cancer with tumors all over your body (like Lance Armstrong had) and they can cure it. They use platinum based chemotherapy and it's not really well understood why it works for testicular cancer, but not others.
The story with childhood leukemias is similar. They figured out how to combine a bunch of chemotherapy to get the cure rate up pretty high. Leukemia in a child used to be (1990s) 90% fatal, it's like 10% now.
Besides those, most of the advances in the past few decades come from early detection/ surgery or just prevention (stop smoking).
There is some hope though. When people first started studying cancers at the molecular level, one of the first things they noticed was how often a gene called Ras was mutated in different cancers. It turns out that designing a drug for Ras was really hard, but it finally got done, it's called daraxonrasib. They just released phase III human trials with this drug in pancreatic cancer a week or two ago and it destroyed the standard of care (Chemotherapy), but that is saying people who were dying in 1-2 months were still alive after 5-6 months.
The former senator Ben Sasse was diagnosed with metastatic pancreatic cancer last December. Historically, that's like 5% survival rate for 5 years. He is on daraxonrasib. We will see how it works out.
I wouldn't understate advances in Melanoma treatment. Immunotherapies have absolutely changed the game in that space. It's not a curable cancer (few are) but it's far more treatable.
Well, depending on how cynical you are. I'm sure there are those that are happy to let the 'senecent' people die of cancer and have a younger population and healthier population pyramid.
Getting older, I'm not subscribing to that, but it sometimes feels like the RFKjr -style interventions are calculated. Then again, this theory makes zero sense when dismantling herd status for measles (I don't think 'natural measles survivors' are genetically 'better' than the rest of us)
Wow, I’ve joked about the prospect so frequently that realizing it has a real Twitter subculture hit me hard. Describing people like that… it’s akin to derisively referring to “the dysfunctional” part of society, to pick on my own disability. The parallels to the Nazi’s ableism are pretty hard to ignore :(
But on a lighter note: is there any belief more certain to spoil?? My god. Don’t underestimate the moral worth of futureYou, folks. I guess delighting in their assured regret is a bit of a guilty pleasure, but it helps!
RE:RFK, I think you’re indeed overestimating their intentionality. They intuitively feel that measles wouldn’t affect them because they’re stronger, and would do their best to dance around that belief if pressed beyond their comfort zone of cherry-picked facts.
But really, they’d much prefer to just not think about that part altogether IMO; ‘MAHA’ is much more about hypernaturalism & tradwives than it is about public health. This is all just annoying scaffolding to them.
Looking through that, they seem to leave out what would be the most interesting comparison - expectancy adjusted for stage at detection against time?
Edit Claude suggests the problem is bordering on intractable, but table 7 in this link is probably as good as it gets https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac...
Oh wow, not as impressive as I thought, but I guess we are looking at broad categories rather than specific types and variants. But overall the trend is down on ever cancer since around a decade ago. Was expecting a sharper drop around 1-2 decades ago, but things just take time when it comes to experimenting with human lives. Will be interesting to revisit this in another decade when a lot of the treatments finally leave the experimental stage.
Unfortunately, we actually don't make the kind of general widely applicable gains in treatment that people believe we have. We're not in a much different place for major cancers than we were 30 years ago, and I don't see much value in assuming we will just suddenly improve.
Amen to childhood leukemia rates improving being awe-inspiring. I had a friend I rode the bus with around 2001 who was diagnosed with leukemia and didn't make it. They let us know over the PA system at school. I suspect these days she would have survived.
Not exactly what you're looking for, but OWID has a bunch of great visualizations about cancer, including ones that really show the progress we've made (and how much we've yet to make!)
at the simplest level, the particular gene, and particular perturberance, sets the "type" of cancer.
there will most often be additional genetic abnormalities giving nuance to the character of the oncotype.
the tumour is originated from a cell type of specific differentiation, and developmental potency, further widening the pool of possible cancer type.
immunotype of cancer also sets the relationship between cancer and the body.
the cells of the body are setup for a functional death and replacement so when you try to rescue a particular cell [or cohort] you are fighting against how the grand scheme of tissue maintenance operates.
unless you have concern for a particular long lived cell, it is best to destroy the tumour cell, and let the next cells in line replace them.
it is still a multifacet strategy being developed, inhibit the genetic properties of the tumour, and target the immunotype for destruction.
Basically everything that was invented up to 3 years ago was invented without the help of "AI". And that includes "AI" itself, for we, humans, invented that too.
The foundational problem with cancer is that multicellular organisms rely on tight control of the cell division cycle and there are hundreds of ways that can go off kilter. The record of understanding and treatment is impressive, certainly, but the correct mental model is more ‘think of all the problems that can go wrong with a rocket launch - from contaminated fuel to software glitches’ than ‘here’s a list of cancers of different cell and organ types’.
Just as attacking such problems with rocket launches involves hundreds of different approaches, that’s the situation for cancer. I’d also point out that this is why it was really not trivial to identify microbial and viral causes of disease in the 19th century - especially since we now know that certain kinds of infectious disease can themselves result in cancer initiation. It’s definitely a hard set of problems.
I would also add, there was a concerted effort by industry to promote ‘inherent genetic malfunction’ as the cause of cancer in the late 1990s and early 2000s, but the reality is that exposure to industrial carcinogens tracks closely with a wide variety of cancers (skin, digestive tract, etc.). This was a very deceptive and dishonest approach to avoiding regulation.
The idea of using CRISPR/Cas to detect tumor-specific mutations that aren't necessarily oncogenic and then kill the cell is not a new one [0, 1, 2]. However, previous studies used Cas9, which just damages the DNA at the target site; this uses Cas12a2, which is far more destructive because it shreds the chromatin in the cell once activated by detecting the target sequence.
As with any cancer treatment, it's likely the tumor will evolve resistance. My guess is that cells will find ways to reject the lipid nanoparticles used to deliver the CRISPR/Cas mRNA and associated guide sequence(s), either via modifications to the cell surface (preventing LNP uptake) or via changes to endosomal/lysosomal pathways (causing the mRNA payload to get degraded before it has a chance to be translated into protein).
evolution isnt about generating a response to a challenge, its about differential success.
those cells [oncocytes] that have properties conferring resistance carry it as un-utilized baggage, those without said properties make a living without that fetter.
the selective factor comes into play when payloaded LNP [in this case] facillitates destruction of "nonresistant" oncocytes and spare the "resistant"
the resistance is not generated in response to the challenge, it is already present, and confers survivorship in the face of the administration of the drug.
But cancer isn't an organism. Cancer cells in any specific individual may evolve that way, but "human cancers" as a group will not. (The only way they could is by evolving human DNA, but "survival of the fittest" pushes the opposite direction for that.)
Indeed, there's no "be a better/stronger cancer and spread more effectively to more hosts" the way there is with bacteria or a virus. It's not like the flu where we need a new shot every winter because every winter is a new flu.
Once we solve the cancers we know about, they're solved forever, with the one caveat that more people will live longer, so that will increase the window for eventually still ending up dying to one of the cancers that happens to have a non-evolved built in resistance to this or that treatment. Which is a great deal of course, especially if it's a treatment that sounds way less destructive of QoL than chemo, radiation, etc.
>there's no "be a better/stronger cancer and spread more effectively to more hosts"
No, but there is "be a better/stronger cancer cell and don't succumb to whatever therapy is killing its neighboring cells." It's exactly akin to how dosing isolated populations of bacteria with antibiotics selects for individual cells that are resistant, which then multiply and dominate [0], just like a tumor.
Right, but that's within a single host isn't it? Like patient A gets that mutation and succumbs, that sucks, but the stronger cancer cells don't them jump to patient B the way antibiotic-resistant bacteria do.
(barring the transmissible cancers article that your sibling comment linked to, but that's not the common case)
Nonetheless, we see the exact same resistance mechanisms to the same therapies recur across individuals, e.g. [0]. Convergent evolution is a harsh mistress.
There are some ideas about making it triggerable. So first you load the cells with a protein that is ready to start shredding but is inactive. Then you trigger it with a second compound.
This would shorten the timeframe for cells to mutate and acquire resistance mechanisms, but would not address the issue of cells with preexisting (epi)genetic resistance mechanisms that would then be promptly selected for.
Yes, and if you shorten the timeframe enough, there's a chance that it can clear all the cancerous cells. You also ideally would use multiple variations of the therapy to further reduce the chance of a pre-existing escape mutation.
That's how we deal with HIV. No single HIV therapy (so far) is effective enough to suppress the virus all by itself, but a combination of them provides a barrier that is too high for mutations to jump.
Agreed. Assuming it's ultimately proven to work in vivo, I think the endgame of this therapy is multiple guides targeting multiple mutations along with multiple delivery mechanisms (a formulation-diverse cocktail of LNPs + eVLPs [0]?). Sure, tech like [0] is futuristic and fanciful, but so is the tech of the OP, and both will probably reach in vivo maturity around the same time.
This will also cause problems because too many cells die at once. See the comments in other threads; killing the entire cancer at once is very hard on the body.
Depending on how the LNPs are designed, would resistance also potentially cripple the cancer cells? Like, it stops surfacing some cholesterol receptor because the drug is being delivered by LNPs that target that receptor, and now the cell is starved for cholesterol?
I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
>would resistance also potentially cripple the cancer cells?<
this is the concept of genetic baggage, and metabolic budget.
there is only so much energy to a cell, and scant amounts to "waste" on preservation of something that is not used. in the long term, carrying unused properties are disadvantageous, and reduce reproductive output [replication]
the result is "unfettered" oncocytes outgrow those with baggage, and occlude access to resource. if there is no challange that reduces population of nonresistant cells, the resistance will be minimized and extinct in the face of large disparity of success.
>Depending on how the LNPs are designed, would resistance also potentially cripple the cancer cells?
Yes, if the LNP could be engineered to target an essential surface receptor, which is still a very tough problem. It would also not solve the issue of the payload successfully entering the cell but being subsequently degraded.
>I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
This is essentially how treatment for chronic lymphocytic leukemia happens (hence why it's called "chronic"). People with CLL can stay on BTK inhibitors for decades, often until they die of other natural causes.
Another question: how does this approach compare to trying to repair the pathogenic variants in the cancer? I asked here about that approach recently and the response was mainly about delivery difficulties: https://news.ycombinator.com/item?id=48285386
Even with 100% delivery efficacy, editing efficacy is nowhere near 100%. CRISPR/Cas editors will reliably detect the target sequence but will not reliably edit it in order to repair the mutant allele, whereas CRISPR/Cas12a2 will activate and destroy chromatin ~100% of the time when it detects the target.
As is often the case, it's a lot easier to indiscriminately destroy than precisely (re)build.
That doesn't seem to be true, the global expectancy is 73 and only a dozen of the wealthiest countries are mid 80s. I wouldn't be worried about dying at 70, but maybe I'm built of tougher stuff.
You say my claim is not true then proceed to acknowledge it is true. To be clear about the fact: about 1/4 of all countries have a life expectancy >80, and as you said, more than a dozen in mid-80s.
CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV and 7 for Lentivirus.
Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR.
I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real future. It just didn’t get the same news cycle, for whatever reason.
You're correct about CRISPR Cas9. The off-target affects are difficult to manage.
The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell.
The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.
Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.
Have you written about your experience anywhere? It would be interesting to see how you approached the research sector as a layperson. Are there any plans to move to in vivo? Best of luck with your research!
I haven't written about it publicly, but I can elaborate here. I don't mind answering further questions about it even if you believe they'd make me uncomfortable - they won't.
I've come to terms with what's happening to my body and that I may not benefit from my efforts.
Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem cells (HSCs) acquired this mutation and they produce busted downstream products.
Most notably, one of those downstream products are hyper-lobulated megakaryocytes that spew inflammatory cytokines into my bone marrow and destroy the bone marrow niche over time. The destruction happens specifically because the inflammation mobilizes stromal cells and they erroneously produce scar tissue (fibrosis) all along the walls of the good, spongy marrow. There are other sources of damage but this is the one path most aligned to abbreviated survival and transformation into AML.
In effect, my bone marrow is rusting and very slowly failing. The failure could speed up with the acquisition of additional mutations or any other systemic inflammatory condition.
Anyway, 3 years ago my first retail hematologist told me "it's rare, you're fine, take aspirin and go home."
I couldn't accept that - this seemed bad. I decided that if I wanted to know the truth I needed to physically stand in front of the foremost expert in the world on the topic and ask them "what is the state-of-the-art?"
I came to this conclusion after about a year of reading all the most well-cited academic papers about AML, Myelofibrosis, and Essential Thrombocythemia. In particular, anything that mentioned MPL. There are virtually no papers mentioning MPL.
To put that in perspective: 500,000 patients in the US deal with the broad disease category. 5% of those are MPL, and 40% of those are the -K variant. So 10,000 people - which means anything targeting it would be well into orphan drug designation territory. I'd need to find a pretty niche researcher.
So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.
I listen carefully to them, ask dumb questions, connect dots across research. I rehomed my care to an academic research hospital specializing in MPN research, and started funding research on the condition it includes my specific MPL mutation. Researchers happily oblige.
Cas12a2 was the keynote topic at this year's meeting and there was _very little_ dissent.
My aunt had the same disease you mention and was on medications since the 90s. She lead a healthy life with no real side effects from her medication and she passed away last year in her 80s. To be perfectly honest, she did die of the disease, because her medication stopped working and her bone marrow was all scarred. But up until a year before she passed away she was very active and healthy. Once the medication stopped working, she went steadily downhill until she passed away.
Hopefully you get great progress on your research but I just wanted to reassure you that the name sounds scary but the current treatment appears to work well and hopefully gives you enough runway to find your cure.
"When have you most successfully hacked a non-computer system to your advantage?" Amazing resourcefulness, you should consider applying to YC if you haven't! And I hope you manage to find a solution to your problem it sounds very promising.
And by the way, when Anthropic (sic) tells you that it's too dangerous to allow GPT-2/GPT-3/GPT-4/GPT-5/Sonnet/Opus/Mythos/Fable to discuss human biology, and some of us object vociferously to their premise, this is what we're talking about.
I haven't heard anyone specifically state their justification for blocking bio research along I can only assume it's to prevent manufacturing bio weapons or virii?
Incredible story, just pure resourcefulness and grit in following this through. I know it sucks to have this disease, but kudos for how you approached this.
This is so impressive - kudos to you. Thanks for sharing and being open to questions.
How much overall has this costed you? Do you think that a middle-class person could afford to do what you did?
> So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.
Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.
For this project, seed capital low six figures. I am collaborating with family and friends, non-profits, and using doubling mechanisms available to me to at work to fund the very early speculative bench research. This is where we are and its sustainable today.
Once we have the basic tech worth scaling up - to raise the first round of capital, I estimate $1-2m with a wider friends & family and angel investor round. This will be early de-risking research and delivery mechanism testing.
Beyond that I can see a path to a ~$20m round to further de-risk any assets that come out of these speculative efforts, but I haven't gotten this far.
In rare disease therapeutics the challenge isn't raw capital, it's finding the _right_ capital that understands how assets like these get de-risked and can tolerate the shape of the upside. Anything CRISPR-based is usually not a chronic therapeutic, so that disqualifies most of big pharma. Acute, curative technology like this requires informed capital.
> Do you think that a middle-class person could afford to do what you did?
Yes.
In the rare disease field even a small amount of capital attracts enough attention to have meaningful conversation with bench researchers. If you're willing to travel to the niche conferences, ask dumb questions, grind out the studying, and approach the speakers after their sessions.
Researchers respect people who do their homework and mobilize to meet them. They want (need) to hear from patients and caregivers - so they tend to listen very carefully.
Fun fact: I've had multiple researchers ask me for samples of my bone marrow. Has only happened in-person :)
> Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.
I don't know, it's been going on for a while. I can speculate: they're discussing pre-publication data, some of which had come out of their labs only hours prior to their presentation. It's completely unfiltered. I think there's real risk of some of the things that are shown being sensationalized or taken out of context.
The audience is trained and practiced in keeping a sober, skeptical lens on everything they see - so it's more about the debate and tear-down of the early data for the betterment of the niche.
There's zero attempt to hide anything, it's just a forum for collegial debate.
wow, very interesting I can't say I've really ever heard of anyone financing research themselves, hope things work out and maybe a treatment arrives in time for you.
As an aside if you end up cryogenically freezing yourself for a future treatment don't forget to actually cure your boneitis when they thaw you out.
Yes! That's the next step. There wasn't a mouse model for my variant so they're building that, too. But in vivo testing should be underway this calendar year.
Seconding this comment. I would love to read a write-up about your experience and how you’ve been trying to work on solutions for yourself. Stories like these are valuable to the field and inspiring to other folks dealing with a tough diagnosis.
Thank you. I want to make sure you see the comment above - I think it was your comment that nudged me into writing it :) Happy to answer any other questions, here or over email (in my user profile).
> other folks dealing with a tough diagnosis
The toughest part has been the spiritual journey. Loneliness unlike anything I've experienced. I felt forgotten without the opportunity to be known in the first place. I was happy - and emotional - to learn I wasn't alone. It took me 2 years, but I've found my people.
We did whole genome crispr designs at my last university job. Can confirm that off target effects are an issue with cas9. Pattern matching across the genome to see if a design is unique takes some time. These were interesting pipelines to work on.
It’s only a matter of time before the next better thing shows up.
I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?
There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other.
The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet.
The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse.
As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
Lipid nanoparticles are quite old as-is. How do you target cells specifically?
> If you get really good at delivery, you can destroy A LOT of cells very quickly.
You can destroy cells quickly. Ok. So the question is: how do you detect specifically only cancer cells via lipid nanoparticles? That was already a problem years ago with Herceptin. The rationale that is always used is that "we need to do something" for certain aggressive cancers. It has never been a super-effective technique, despite all the promo of how monoclonal antibodies are so accurate.
> As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
That's already the status quo in the whole cancer field. I don't think that more than sloppy accuracy is acceptable for any gene therapy - and the off-target cleaving of CRISPR has always been the number #1 problem here.
> I don't think that more than sloppy accuracy is acceptable for any gene therapy
Valid critiques of Cas12a2 must acknowledge the mechanistic differences between Cas9 and Cas12a2. There is no research to suggest Cas12a2 is "sloppy" and significant research that demonstrates it is not "sloppy."
I appreciate the skepticism but I would encourage you to study the actual mechanism discussed in the paper.
> So the question is: how do you detect specifically only cancer cells via lipid nanoparticles?
You don't. Healthy cells will also get these nanoparticles, but without the triggering DNA sequence, the mRNA payload will remain inert and eventually will be degraded.
> Healthy cells will also get these nanoparticles, but without the triggering DNA sequence, the mRNA payload will remain inert and eventually will be degraded.
Naively, I would deal with this by deciding how many cells I want to kill each day and then figure out a dosing schedule that achieves that. Or maybe it's better to do one dose every few days. But yeah either way.
> I would deal with this by deciding how many cells I want to kill each day
Yes, this is an approach. This starts to exceed my understanding of the problems the teams are facing - but there are concerns about the efficacy of Cas12a2-based approaches fading. Not because the cells adapt, but because your immune system starts acting funny in the presence of the payload.
I don't recall the specifics but there seems to be a window of opportunity for these things.
If it were to work, gene therapy as-is would be possible. Which it is not,
not even for those overpriced therapies. I have no doubt that sooner or later
it will happen, as the problem space is finite, not infinite, but I simply
don't see the correlation here.
> The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.
So what does this change exactly? Humans defined it as "undruggable conditions". You can reason this is an improvement, but I still see it in failure-territory. If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.
> I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.
How does "answering questions" offset the technology being inferior right now?
> So how does Cas12a2 mitigate off-target effects?
Others in this thread may be able to give a better analogy, but I'll try:
Cas9 is like open heart surgery on millions of cells all at once. We know the specific outcome we want - a surgical replacement of a sliver of a sequence - but just like open heart surgery, it's an inexact operation. Cas9 tolerates mismatches which categorically allows off-target matching. It also operates on DNA, so any off-target effects reprogram the cell's primary source code.
We want the Cas9 "patient" cell to survive.
In contrast, Cas12a2 is key-locked self-destruction switch. It targets single-stranded RNA transcripts with a specific guide protein. So the specificity is two-fold: the guide protein doesn't tolerate mismatches, and its operating on a _downstream byproduct_ of the DNA. When the key (guide protein) matches, it unleashes total destruction within the cell.
We want the Cas12a2 "patient" cell to die.
> If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.
Correct on the first point. If it were to work, gene therapy could be more common. I do not know how to make it affordable, yet. In the models I've built to commercialize this I estimate a Cas12a2 treatment would cost approximately as much as a bone marrow transplant.
> How does "answering questions" offset the technology being inferior right now?
In fairness, asking and seeking answers to questions is all I have right now. There is no cure to my disease so the upside - no matter how futile you may perceive it to be - to me, is infinite.
If I can solve it I may get a few more years with my daughter. If I can't, I can show her how to live fighting for an answer that may never come.
You're not wrong, you and I just have different perspectives on the upside.
Devils advocate, I also vehemently shat on RNAi therapeutics a decade back. We do have RNAi therapies in market now though. I do think Crispr will find its place similarly.
This comment doesn't understand why CRISPR is such a big deal in science. While Cas-as-a-therapeutic is easy for the public to understand, and therefore often emphasized in popular science, the primary use of CRISPR Cas systems is in modifying genes in the lab.
Tens of thousands of papers have made important scientific advances using it successfully and CRISPR-Cas methods are used routinely throughout almost all of biology.
This is like calling PCR "overhyped" because PCR-based infectious disease diagnostics are limited.
I would guess you did not first write “CRISPR is an overhyped approach”, then after careful reflection decide, I don’t think that quite captures the intensity, better go with “extremely overhyped”.
The comparison is kind of a category error. One is a DNA editing technique and the others are deliver platforms. I recall the hype mostly being how revolutionary it could be, not comparing it on a timeline to specific technologies that are at different levels of the stack.
CRIPSR was a game-changer for genetics research. A lot of gene knockout studies use CRISPR. However, it was always weirdly overhyped for clinical use from the beginning and this was obvious to anyone with a genetics background.
The public in general doesn't have a good understanding of basic genetics and I blame high school science curriculums for not covering it well enough. Too much time is wasted on Mendelian genetics without covering the Central Dogma.
You basically cannot "edit" your somatic DNA in a meaningful wholesale way since every single cell in your body has a copy of the DNA, and it's a foolish endeavor. What you can conceivably edit to good effect is your germline DNA, stem cell DNA, or modify mRNA expression (e.g. retinoids; yes putting retinol/adapalene cream on your face is "gene therapy"), or introduce foreign mRNA for your translation machinery to co-opt (e.g. mRNA vaccines).
I disagree that it's "gene therapy" to affect the natural regulation of mRNA production. If that were true then the term "gene therapy" loses its meaning, as just about everything changes the expression of mRNA. You can probably do so somewhere just by thinking really hard about it.
Expressing mRNA that doesn't exist in the genome, that would be gene therapy. Or just a virus.
This approach can work for some genetic diseases such as blindness based on some cells in the retina or partial blindness. For others this is not really a cure. If you want to cure people with progeria, does curing 20% of the cells really help? Perhaps 100% is not necessary, but it would seem strange to cure only some cells but not others. You'd have a mosaic of cells where some would work and others don't. Cells interact; timing also plays a role in development. I don't really see that aiming for anything but a very high number of cells cured, can work.
It was a game changer in terms of making things cheaper and a little easier. However the actual functionality was still possible with other methods. Zinc finger nucleases for example. Knockdown via RNAi is often still done because a knockout target may be inviable, and it is pretty cheap and easy to knockdown in most model systems.
CRISPR is foremost a research tool. Calling it "extremely overhyped" without restricting it medical treatment seems disingenuous.
The CRISPR-Cas9 gene-editing tool was developed in 2012, so I don't find it surprising that merely 14 years later, there's only one approved treatment. From discovery to approval, drug development often takes 10-15 years, and often much longer for novel techniques. So I'd say it too early to call it overhyped for treatments.
Finally, I think we'll see a lot of treatments that don't use CRISPR-Cas9, but related gene editing techniques, but it'll take another 10 to 20 years.
Take a look at https://en.wikipedia.org/wiki/MRNA_vaccine#History for how long another novel technique has been in development before it became really widespread with the mrna-based covid-19 vaccines.
One of the reasons is, you don't get really good data on how something works until you start running clinical trials for it. It's all very time-consuming - having to plan how the trial is going to work, getting approval for it, finding subjects who meet the criteria (here, a specific type of cancer at a specific stage probably) and sites near them willing to work with you, manufacturing and shipping the treatments, and only then can you start gathering data. If it didn't work, you gotta start over, And it all costs a boatload of money too.
Let's see... first of all, 14 years ago was the discovery of the base mechanism, not of specific treatments. So specific treatments need to be developed, delivery systems need to be developed, side effects reduced. Then you need safety tests and efficacy tests.
> mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different.
And yet it took more than 30 years after the first mRNA experiments to develop a successful vaccine. Why it should be so much faster for CRISPR & Co?
Background on this question: CRISPR-Cas is a naturally occurring process in bacteria that is used to adapt to viral attacks. We've coopted the system for use in mammals.
As far as I know a few labs in this space are operating under the basic question, "why haven't viruses killed everything by now?"
So this category of research is more or less the answer.
> Do mammals have a CRISPR analog?
Not exactly. There are things like https://en.wikipedia.org/wiki/Ribonuclease_L that nuke cells and are stimulated by interferons. This might be why interferon injections are common chronic therapeutics for diseases in this space.
The closest thing we have is probably whatever adaptability B or T cells can muster on their own? I'm sure someone lurking in the comments has a better answer.
I hope this finally works out. I remember almost exactly ten years ago I got excited about one of these proposed cancer cures, tried to talk about it at lunch with my coworkers, and they laughed at me for believing.
I'm pretty optimistic. I think it's a threshold question where we need a number of basic technologies to all get over certain bars before the floodgates start to open.
Over the past 1-2 decades there has been unbelievable progress at the basic technology level but most people are unimpressed because they haven't translated yet due to not individually being sufficient to cause an explosion of progress. IMO, we're starting to see it finally as so many different technologies have gotten so cheap, fast, and good.
So we're waiting for the Apple of the medical world to take a bunch of preexisting things to be applied together in a way that makes the whole much more valuable than the pieces. Or we need all of the individual lions to come together to make the Voltron?
I think realistically we're waiting for someone in the top 10-20 richest people in the world to get cancer (or a close relative etc) who will then throw billions at research to try and fix the problem.
We spend upwards of $15B a year globally on cancer research. About half of that is funded by government and charities, half by pharmaceutical companies.
If spending billions was the main trick, we’d know it already.
Usually it takes about a decade for most medical inventions to work their way through medical bureaucracy[0], so I'd say that 10 years ago we were at the stage of watching Matthew Broderick war-dialling with an acoustic coupler and reading Usborne Books telling us that criminals of the future would work from home, and today we're in the exciting early days of dialup, AltaVista, and GeoCities[1].
[0] The covid vaccines collectively were faster only due to the fact that when money is no object you can parallelise a lot of options and can pipeline the testing stages rather than waiting for full review and another funding round before progressing to the next stage
[1] Where they-don't-tile-but-we-did-it-anyway animated gif backgrounds are the metaphor for home kits to make random things bioluminescent: https://www.the-odin.com/gfp-bacteria/
Depends where in the history of the web you count it as such. For me it was more like the late 2010s when that happened, so 20 years. And of course vanity surgery is already a thing, so it may have already happened to an extent with medicine?
10-20 years for an Alastair Reynolds' style Indoctrinal Virus? I hope not, but I can totally see it happening eventually.
I'm not sure what this comment is trying to say. Theranos was a company build from the ground up on fraud. Apple, for all its faults, is provably at the forefront of technology used in personal computing devices.
And theranos did that too? Theranos, a medical company, was an affordable luxury (??) brand that makes sleek hardware? In fact the hardware was not sleek at all, since it didn't function.
The floodgates open = the market will see that at least some of that can actually work and make money => they will pour funding => new approaches built on that funding will start working, too?
Real in vivo genetic engineering isn't going away and will indeed be a powerful tool to face cancer. Any particular effort is doubtful because this is a journey measured in decades. It is not the same story as any one particular wonder drug fizzling out to nothing, it is a class of tools that is maturing into the realm of early therapeutic deployment.
What stands out to me is how cancer therapy keeps moving from broad destruction (chemo/radiation) toward increasingly precise identification of malignant cells. The challenge no longer seems to be "can we kill cancer cells?" but "can we reliably identify only cancer cells and reach all of them?" This paper looks like another step in that direction.
I'm not sure what this comment means - we could always kill cancer cells, and the challenge has always been "how can we ONLY kill the cancer?" We've been burning cancer, cutting cancer out, and drugging cancer cells for decades or centuries depending on the method. What is changing is not the type of challenge, but the precision of our tools - and even then, it remains to be seen if we actually can get the precision while improving the lives of the patients.
In order to kill all cancer cells in the body, it probably needs to be delivered to every single cell in the organism, and scan the nucleus of that cell. Viruses usually don't infect every single cell, just a small percentage.
So one needs to figure out a delivery method that is efficient enough, and that doesn't elicit an immune response. But I guess one can analyze the cancer in the lab and figure out which receptors it expresses, and then bind to those? We could have a toolkit of different delivery methods, tailored for each patient's cancer.
Cancer treatments are really scary things. There are all sorts of impacts that we have no idea about when using drugs that fundamentally attack pieces of our own body.
My partner of many years had one of the nastiest cancers around, one with no targeted treatments. She went through an experimental combination of existing
drugs. Some of the side effects included:
* Her heart stopping during a drug infusion. This happened multiple times over the 18 months of treatment.
* Disseminated fungal infections.
* Sepis because holes were developing in her GI tract.
This is just a sampler of the horrible effects.
This was a good response. Other patients just died from the drug combination.
This is what going slowly looks like in the world of cancer treatment.
We relax ‘do no harm’ quite a bit when the alternative is certain death. People like to try stuff in order to hang on to hope. Towards the end I became convinced that she made the wrong choice to do aggressive interventions. Quality of life was very bad.
On the other hand, she gave it her all trying to survive. Hopefully that was satisfying for her.
The point of going slowly is that we make sure something works, even if it has these bad side affects. Do we try experimental drugs with worse effects so that we can find effective ones faster? There are brave souls out there who will participate in clinical trials or experimental exceptions
Typically what happens is that the new treatments with bad side effects are given to the sickest patients (who have exhausted all other mechanisms), rather than to the bravest souls with less dire current circumstances.
This makes some sense in terms of compassion and matching new experimental techniques with patients with no hope, but it skews the results highly negative because the patients are already very close to death's door. It does not provide an accurate signal for what the results would be if we gave them to less sick people.
I don't think any of this can be changed without large-scale social acceptance of greater risk in clinical trials and significant support from the government.
> It does not provide an accurate signal for what the results would be if we gave them to less sick people.
It provides an excellent signal because we want to prove that these drugs are doing something that the standard of care is unable to.
There's this sense that medicine is easy and some evil cabal are limiting health to their cronies. Most medications never get to trial for their intended indications, and most fail trials. There's no reason to believe oncology medications are somehow uniquely unlikely to go through this well-described process of failure.
That's a good article with a good point. As a caregiver impatiently waiting for Daraxonrasib, I can at least acknowledge that the institutional machinery is going as fast as it can. I've litterally witnessed a trial patient in the first cohort of a drug (that went no further) be rushed from infusion to the hospital; the trial process cannot be sped up from its current state without endangering lives.
My father's been using it since April. It's a little cumbersome and only improves overall survival rates by about two months over chemo alone, but we're hoping that it helps him remain relatively healthy until Daraxonrasib becomes available.
> Much like other CRISPR therapies, delivery is a critical challenge, i.e., getting the large genome-cutting enzyme to all the targeted cells efficiently.
makes me think this is in vitro so far. So, years to decades away from being available for actual treatment in humans. Still good news.
Basically the issue is often that gene therapies end up in the liver since its the livers job to detoxify, but that may cause a dangerous immune response if the immune system notices it in the liver and attacks the organ, since the person could die from the damage.
I’m assuming this has been tried, but why doesn’t nano-encapsulated mRNA (that then makes the CRISPR sequences in cells) or whatever the peptide injectors do solve the problem?
You can target an individual by injecting that very individual with something lethal.
If that's not what you want, you'd need something like a virus to spread it. But then you have to ask yourself: what if that virus mutates? The specialization to certain gene markers is an evolutionary disadvantage, so evolution will tend to make it lose that restriction. Ooops.
Old concern, but it really doesn't work that way. Genetics don't respect human ideas like "nationalities" or "borders" - the targeting you can get by selecting on singular DNA variants is coarse enough to make ICBMs look like precision weapons.
Like many things of this nature, people keep bringing it up because it sounds Very Scary and Very Dystopian - not because it's worth giving an actual fuck about.
If it's year 2126, and you have this kind of tech floating around, and you aren't equipping the entire population with artificial immune systems capable of dealing with known and unknown biological threats? You've done something wrong.
What economic / political model would cause the society to prioritize this over adtech? It seems so unsettling that brilliant human minds are trying hard, every day, to figure out how to make it impossible to bypass watching ads on YouTube, instead of helping cure cancer.
> would cause the society to prioritize this over adtech?
Private pharmaceutical R&D spending in the U.S. is around $100bn per year [1]. NIH spends another $50bn a year on biomedical research [2].
That eclipses total investments into adtech per se, which generously counted shouldn’t exceed $50 to 60bn. (And that only by counting like a third to a half of Google, Amazon, et cetera R&D and capital spending as adtech.) More precisely counted, it probably doesn’t exceed $10bn.
One of the primary challenges of drug and device economics is the long lead time between capital deployment and returns. One of the selling points of tech is speed to Market.
Factors that would make it more attractive our lower interest rates, higher returns, or faster development.
All of these are theoretically possible to adjust, but the last is most feasible to do in a tailor-made way through FDA review and approval reform. An ambitious example would be allowing conditional Market approval after Phase 2 and treating phase 3 deliverables as post-market commitments.
Advancing the revenue curve two to three years while maintaining the same patent expiration dates can dramatically change the ROI of a pharmaceutical development program.
Beyond this, even conditional Market allowance allows firms to better gauge Market interest and validate Financial investment models sooner.
Similarly, there's also some really low hanging fruit in this area to help manufacturers get to Market faster. For example, the FDA approval of trade names and label content is one of the last steps in Market authorization. Moving this earlier in the process would help products itself sooner and start producing Revenue sooner. Imagine having your billion dollar annual revenue shift out a quarter because the FDA wanted some last minute change to how a cartoon belly button looks in the instructions for use.
The bargaining dynamics are stacked against biology researchers at every stage of their career, from needing years and years of unrelated performance to be admitted to terribly expensive programs before they can begin to do experiments, to requiring costly equipment and resources to work, to needing to work with a small number of very powerful companies.
As a result, life science researchers are more price-taking than proce-setting when it comes to their wages / salary. If money is the motivator, then the market as-is isn’t addressing this one.
I said it elsewhere but I'll say it here - we need one of the top 10 richest people in the world - the Bezos, the Musks etc - to suddenly get very interested at a personal level about cancer treatment.
Bezos and several other billionaires stuck a load of money into Altos Labs, an organization that studies aging and longevity.
Cancer prevention is downstream from that, as cancer frequency grows exponentially with age. If you can truly rejuvenate a person, you will also reduce their risk of cancer.
And when you can measure how effective those ads are in changing human behavior; it's easier for businesses to spend there. As an American, I would love it if pharmaceutical companies couldn't market to consumers. It would free up money for research or lower prices.
I don't think an economic model would work. Only a political one would work where the government would redirect a lot of funds towards this, making it a lucrative profession.
Adtech works because there is a lot of money in it. There is a lot of money in it because people seek quick entertainment, and we have a LOT of people driving the demand.
Now compare that to cancer research. There's no short term gratification about it.
There's a fair bit of frequency illusion involved here. A lot of brilliant human minds aren't, in fact, working on ad tech, and a lot of the people working on ad tech aren't, in fact, that brilliant (as evidenced by them working adversarially against their own fellow humans, for one).
There's a wide world outside big tech, Silicon Valley, and software in general. It only tends to be a bit less visible online.
Not sure why you're getting downvoted, it's quite an interesting (and important!) question.
Also wonder, outside of politics and economics, whether there's a social and cultural component that can contribute. TV shows, movies, books, and other forms of media that put science and scientists in the spotlight in a positive light can be tremendously inspirational.
>brilliant human minds are trying hard, every day, to figure out how to make it impossible to bypass watching ads on YouTube, instead of helping cure cancer.
And even more brilliant minds are defeating it, every day. I have doubts about how useful they would be in a research lab.
Same problem with chemo and radiation. A tumor may start off with a single cancerous mutation, but by the time it spreads there may be several. Once the cell repair machinery has been broken, the cancer cells are prone for more mutations.
Chemo, radiation, and CRISPR will kill everything it can reach that is susceptible. That leaves everything that was unreachable or resistant behind to start growing again.
Kill cancer cells is easy. Killing ONLY cancer cells is very hard.
This is why I hate patents. If CRISPR were put behind a paywall, none of this would have happened. Everything having to be about profit is getting tiring.
> This is why I hate patents. If CRISPR were put behind a paywall, none of this would have happened. Everything having to be about profit is getting tiring.
CRISPR was the cause of a huge patent case and likely led to a change in US patent law because of the impracticability of deciding who did something first in the laboratory.
It continues to influence research as some nations took a while to decide how they would resolve their own researchers' CRISPR claims with respect to MIT/UC Berkeley.
And yet... all the research has continued apace.
Edit: the CRISPR patent cases are continuing even today
So how do drugs like this get fast tracked so that people who are in danger of dying can exercise their freedom and opt into experimental treatments very easily
First thing to remember: cancer drugs attack human cells. Because of this they can very unexpected and traumatic side-effects.
Because of this initial trials consume lots of medical staff to deal with the potential side effects. Normal side effects for cancer treatments include:
* Your gut lining dissolves, your shit leaks into your body cavity, and you get sepsis.
* Your heart stops during the infusion.
* Cumulative poisoning that nobody understands. (E.g. some agents have lifetime limits, and if you go beyond that, then you die. Guess how we found out.)
* Your immune system, and you get things like disseminated fungal infections.
The danger of side-effects like this requires a medical team largely dedicated to the experimental patients.
This puts a limit on how many patients you can put into a trial. I'm under the impression that cancer trials are pretty much always full.
Over on reddit people were debating whether cancer should be cured since it disproportionately affects rich people and it made me realise how far reddit has fallen. It's just a botnet now to manipulate elections.
I'm certain that is not a mainsteam opinion on reddit, but by its nature you will be able to find arbitrarily stupid opinions in individual echo chambers
After we launched our startup, we had all sorts of folks reach out to sell their GTM services. I went with one group from Vietnam that would make engagement bait Reddit questions with some accounts, and advertise our product in the comments section with others. It was expensive but it worked
Do you think (or care) about the ethics of this sort of behavior? Do you consider it unethical and if you do, under what conditions would you decide to do it anyway?
Reddit is a huge danger to society. There's no doubt that subs about specific non political (and non popular) topics are hugely beneficial, the overall damage the echo chambers do still outweigh these benefits.
The way the voting system works at Reddit encourages group think and bubbles. All it takes is five more down votes than up votes and a comment or post essentially disappears from view. It's a design that actively avoids debate.
That's a huge misreading. Hiding comments in the UI empirically does not suppress discussion, if anything it actually attracts engagement. Lots of people are seeking the "wrong" to "correct" it.
Suppressed debate is almost universally due to biased/captured moderation teams aggressively using bans.
You're wrong, because if your karma fall below a certain number, your comments wont show up anymore. I can show you if you like.
People shouldn't be blocked from commenting because their karma goes negative. Spamming, hateful talk, etc should be a completely different system. Just because what you say is unpopular (in one place mind you) doesn't mean your words should be hidden.
The flip side is that "fuck cancer" is a shibboleth there, to the point where a headline, "[Bad person] has contracted cancer" has every comment thread starting with "First, fuck cancer."
I would imagine the charitable characterization of that discussion is much closer to “awesome, this will mean the Peter Thiels and Elon Musks of the world will live to 150 while both me and my children will be dead long before this trickles down to regular people” vs. “we shouldn’t cure cancer”.
What's more crazy is that we're slowly going from millenia, to decades, to likely years in the near future from being presented a biological problem and achieving the next milestone in solving it. We might have "AI", but we also have brilliant minds right now that are speeding up development to a pace that would be unimaginable just few years ago.
The big success story, about 20 years old now, is testicular cancer. You can have metastatic testicular cancer with tumors all over your body (like Lance Armstrong had) and they can cure it. They use platinum based chemotherapy and it's not really well understood why it works for testicular cancer, but not others.
The story with childhood leukemias is similar. They figured out how to combine a bunch of chemotherapy to get the cure rate up pretty high. Leukemia in a child used to be (1990s) 90% fatal, it's like 10% now.
Besides those, most of the advances in the past few decades come from early detection/ surgery or just prevention (stop smoking).
There is some hope though. When people first started studying cancers at the molecular level, one of the first things they noticed was how often a gene called Ras was mutated in different cancers. It turns out that designing a drug for Ras was really hard, but it finally got done, it's called daraxonrasib. They just released phase III human trials with this drug in pancreatic cancer a week or two ago and it destroyed the standard of care (Chemotherapy), but that is saying people who were dying in 1-2 months were still alive after 5-6 months.
The former senator Ben Sasse was diagnosed with metastatic pancreatic cancer last December. Historically, that's like 5% survival rate for 5 years. He is on daraxonrasib. We will see how it works out.
Page 2 has the figure. Getting people to not smoke has been the most effective treatment in our lifetime.
Public health is a really big deal, and RFK et al are a disaster for the nation.
Getting older, I'm not subscribing to that, but it sometimes feels like the RFKjr -style interventions are calculated. Then again, this theory makes zero sense when dismantling herd status for measles (I don't think 'natural measles survivors' are genetically 'better' than the rest of us)
But on a lighter note: is there any belief more certain to spoil?? My god. Don’t underestimate the moral worth of futureYou, folks. I guess delighting in their assured regret is a bit of a guilty pleasure, but it helps!
RE:RFK, I think you’re indeed overestimating their intentionality. They intuitively feel that measles wouldn’t affect them because they’re stronger, and would do their best to dance around that belief if pressed beyond their comfort zone of cherry-picked facts.
But really, they’d much prefer to just not think about that part altogether IMO; ‘MAHA’ is much more about hypernaturalism & tradwives than it is about public health. This is all just annoying scaffolding to them.
https://ourworldindata.org/cancer
https://en.wikipedia.org/wiki/Oncogene
at the simplest level, the particular gene, and particular perturberance, sets the "type" of cancer.
there will most often be additional genetic abnormalities giving nuance to the character of the oncotype.
the tumour is originated from a cell type of specific differentiation, and developmental potency, further widening the pool of possible cancer type.
immunotype of cancer also sets the relationship between cancer and the body.
the cells of the body are setup for a functional death and replacement so when you try to rescue a particular cell [or cohort] you are fighting against how the grand scheme of tissue maintenance operates.
unless you have concern for a particular long lived cell, it is best to destroy the tumour cell, and let the next cells in line replace them.
it is still a multifacet strategy being developed, inhibit the genetic properties of the tumour, and target the immunotype for destruction.
https://en.wikipedia.org/wiki/Cancer_immunology
Basically everything that was invented up to 3 years ago was invented without the help of "AI". And that includes "AI" itself, for we, humans, invented that too.
So yup, humans can be quite resourceful.
Just as attacking such problems with rocket launches involves hundreds of different approaches, that’s the situation for cancer. I’d also point out that this is why it was really not trivial to identify microbial and viral causes of disease in the 19th century - especially since we now know that certain kinds of infectious disease can themselves result in cancer initiation. It’s definitely a hard set of problems.
I would also add, there was a concerted effort by industry to promote ‘inherent genetic malfunction’ as the cause of cancer in the late 1990s and early 2000s, but the reality is that exposure to industrial carcinogens tracks closely with a wide variety of cancers (skin, digestive tract, etc.). This was a very deceptive and dishonest approach to avoiding regulation.
Nature - https://www.nature.com/articles/s41586-026-10738-7
As with any cancer treatment, it's likely the tumor will evolve resistance. My guess is that cells will find ways to reject the lipid nanoparticles used to deliver the CRISPR/Cas mRNA and associated guide sequence(s), either via modifications to the cell surface (preventing LNP uptake) or via changes to endosomal/lysosomal pathways (causing the mRNA payload to get degraded before it has a chance to be translated into protein).
[0] https://pubmed.ncbi.nlm.nih.gov/28575452/
[1] https://www.nature.com/articles/s41598-018-30205-2
[2] https://www.nature.com/articles/s41467-020-18875-x
evolution isnt about generating a response to a challenge, its about differential success.
those cells [oncocytes] that have properties conferring resistance carry it as un-utilized baggage, those without said properties make a living without that fetter.
the selective factor comes into play when payloaded LNP [in this case] facillitates destruction of "nonresistant" oncocytes and spare the "resistant"
the resistance is not generated in response to the challenge, it is already present, and confers survivorship in the face of the administration of the drug.
Once we solve the cancers we know about, they're solved forever, with the one caveat that more people will live longer, so that will increase the window for eventually still ending up dying to one of the cancers that happens to have a non-evolved built in resistance to this or that treatment. Which is a great deal of course, especially if it's a treatment that sounds way less destructive of QoL than chemo, radiation, etc.
No, but there is "be a better/stronger cancer cell and don't succumb to whatever therapy is killing its neighboring cells." It's exactly akin to how dosing isolated populations of bacteria with antibiotics selects for individual cells that are resistant, which then multiply and dominate [0], just like a tumor.
[0] https://www.youtube.com/watch?v=plVk4NVIUh8
(barring the transmissible cancers article that your sibling comment linked to, but that's not the common case)
The rare exception: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer
[0] https://pmc.ncbi.nlm.nih.gov/articles/PMC2538882/
That's how we deal with HIV. No single HIV therapy (so far) is effective enough to suppress the virus all by itself, but a combination of them provides a barrier that is too high for mutations to jump.
[0] https://pmc.ncbi.nlm.nih.gov/articles/PMC8809250/
The new therapies will also likely be applied after surgical resection and/or classic therapies to reduce the bulk of the cancer.
I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
If p53 is reactivated, the cancer cell dies.
https://en.wikipedia.org/wiki/P53
Perhaps a different mutation that disables p53 could evade the pattern match.
This article is all about p53.
Edit: This section of the wiki best explains this critical cellular component...
p53 regulates cell cycle progression, apoptosis, and genomic stability through multiple mechanisms:
-Activates DNA repair proteins in response to DNA damage, suggesting a potential role in aging.
-Arrests the cell cycle at the G1/S checkpoint upon DNA damage, allowing time for repair before progression.
-Initiates apoptosis if the damage is beyond repair.
-Essential for the senescence response triggered by short telomeres.
this is the concept of genetic baggage, and metabolic budget.
there is only so much energy to a cell, and scant amounts to "waste" on preservation of something that is not used. in the long term, carrying unused properties are disadvantageous, and reduce reproductive output [replication]
the result is "unfettered" oncocytes outgrow those with baggage, and occlude access to resource. if there is no challange that reduces population of nonresistant cells, the resistance will be minimized and extinct in the face of large disparity of success.
Yes, if the LNP could be engineered to target an essential surface receptor, which is still a very tough problem. It would also not solve the issue of the payload successfully entering the cell but being subsequently degraded.
>I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
This is essentially how treatment for chronic lymphocytic leukemia happens (hence why it's called "chronic"). People with CLL can stay on BTK inhibitors for decades, often until they die of other natural causes.
Another question: how does this approach compare to trying to repair the pathogenic variants in the cancer? I asked here about that approach recently and the response was mainly about delivery difficulties: https://news.ycombinator.com/item?id=48285386
As is often the case, it's a lot easier to indiscriminately destroy than precisely (re)build.
Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR.
I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real future. It just didn’t get the same news cycle, for whatever reason.
The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell.
The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.
Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.
I've come to terms with what's happening to my body and that I may not benefit from my efforts.
Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem cells (HSCs) acquired this mutation and they produce busted downstream products.
Most notably, one of those downstream products are hyper-lobulated megakaryocytes that spew inflammatory cytokines into my bone marrow and destroy the bone marrow niche over time. The destruction happens specifically because the inflammation mobilizes stromal cells and they erroneously produce scar tissue (fibrosis) all along the walls of the good, spongy marrow. There are other sources of damage but this is the one path most aligned to abbreviated survival and transformation into AML.
In effect, my bone marrow is rusting and very slowly failing. The failure could speed up with the acquisition of additional mutations or any other systemic inflammatory condition.
Anyway, 3 years ago my first retail hematologist told me "it's rare, you're fine, take aspirin and go home."
I couldn't accept that - this seemed bad. I decided that if I wanted to know the truth I needed to physically stand in front of the foremost expert in the world on the topic and ask them "what is the state-of-the-art?"
I came to this conclusion after about a year of reading all the most well-cited academic papers about AML, Myelofibrosis, and Essential Thrombocythemia. In particular, anything that mentioned MPL. There are virtually no papers mentioning MPL.
To put that in perspective: 500,000 patients in the US deal with the broad disease category. 5% of those are MPL, and 40% of those are the -K variant. So 10,000 people - which means anything targeting it would be well into orphan drug designation territory. I'd need to find a pretty niche researcher.
So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.
I listen carefully to them, ask dumb questions, connect dots across research. I rehomed my care to an academic research hospital specializing in MPN research, and started funding research on the condition it includes my specific MPL mutation. Researchers happily oblige.
Cas12a2 was the keynote topic at this year's meeting and there was _very little_ dissent.
Hopefully you get great progress on your research but I just wanted to reassure you that the name sounds scary but the current treatment appears to work well and hopefully gives you enough runway to find your cure.
How much overall has this costed you? Do you think that a middle-class person could afford to do what you did?
> So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.
Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.
For this project, seed capital low six figures. I am collaborating with family and friends, non-profits, and using doubling mechanisms available to me to at work to fund the very early speculative bench research. This is where we are and its sustainable today.
Once we have the basic tech worth scaling up - to raise the first round of capital, I estimate $1-2m with a wider friends & family and angel investor round. This will be early de-risking research and delivery mechanism testing.
Beyond that I can see a path to a ~$20m round to further de-risk any assets that come out of these speculative efforts, but I haven't gotten this far.
In rare disease therapeutics the challenge isn't raw capital, it's finding the _right_ capital that understands how assets like these get de-risked and can tolerate the shape of the upside. Anything CRISPR-based is usually not a chronic therapeutic, so that disqualifies most of big pharma. Acute, curative technology like this requires informed capital.
> Do you think that a middle-class person could afford to do what you did?
Yes.
In the rare disease field even a small amount of capital attracts enough attention to have meaningful conversation with bench researchers. If you're willing to travel to the niche conferences, ask dumb questions, grind out the studying, and approach the speakers after their sessions.
Researchers respect people who do their homework and mobilize to meet them. They want (need) to hear from patients and caregivers - so they tend to listen very carefully.
Fun fact: I've had multiple researchers ask me for samples of my bone marrow. Has only happened in-person :)
> Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.
I don't know, it's been going on for a while. I can speculate: they're discussing pre-publication data, some of which had come out of their labs only hours prior to their presentation. It's completely unfiltered. I think there's real risk of some of the things that are shown being sensationalized or taken out of context.
The audience is trained and practiced in keeping a sober, skeptical lens on everything they see - so it's more about the debate and tear-down of the early data for the betterment of the niche.
There's zero attempt to hide anything, it's just a forum for collegial debate.
As an aside if you end up cryogenically freezing yourself for a future treatment don't forget to actually cure your boneitis when they thaw you out.
Yes! That's the next step. There wasn't a mouse model for my variant so they're building that, too. But in vivo testing should be underway this calendar year.
> other folks dealing with a tough diagnosis
The toughest part has been the spiritual journey. Loneliness unlike anything I've experienced. I felt forgotten without the opportunity to be known in the first place. I was happy - and emotional - to learn I wasn't alone. It took me 2 years, but I've found my people.
It’s only a matter of time before the next better thing shows up.
The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet.
The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse.
As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
> If you get really good at delivery, you can destroy A LOT of cells very quickly.
You can destroy cells quickly. Ok. So the question is: how do you detect specifically only cancer cells via lipid nanoparticles? That was already a problem years ago with Herceptin. The rationale that is always used is that "we need to do something" for certain aggressive cancers. It has never been a super-effective technique, despite all the promo of how monoclonal antibodies are so accurate.
> As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.
That's already the status quo in the whole cancer field. I don't think that more than sloppy accuracy is acceptable for any gene therapy - and the off-target cleaving of CRISPR has always been the number #1 problem here.
Valid critiques of Cas12a2 must acknowledge the mechanistic differences between Cas9 and Cas12a2. There is no research to suggest Cas12a2 is "sloppy" and significant research that demonstrates it is not "sloppy."
I appreciate the skepticism but I would encourage you to study the actual mechanism discussed in the paper.
You don't. Healthy cells will also get these nanoparticles, but without the triggering DNA sequence, the mRNA payload will remain inert and eventually will be degraded.
This is my understanding as well.
Yes, this is an approach. This starts to exceed my understanding of the problems the teams are facing - but there are concerns about the efficacy of Cas12a2-based approaches fading. Not because the cells adapt, but because your immune system starts acting funny in the presence of the payload.
I don't recall the specifics but there seems to be a window of opportunity for these things.
If it were to work, gene therapy as-is would be possible. Which it is not, not even for those overpriced therapies. I have no doubt that sooner or later it will happen, as the problem space is finite, not infinite, but I simply don't see the correlation here.
> The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.
So what does this change exactly? Humans defined it as "undruggable conditions". You can reason this is an improvement, but I still see it in failure-territory. If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.
> I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.
How does "answering questions" offset the technology being inferior right now?
Others in this thread may be able to give a better analogy, but I'll try:
Cas9 is like open heart surgery on millions of cells all at once. We know the specific outcome we want - a surgical replacement of a sliver of a sequence - but just like open heart surgery, it's an inexact operation. Cas9 tolerates mismatches which categorically allows off-target matching. It also operates on DNA, so any off-target effects reprogram the cell's primary source code.
We want the Cas9 "patient" cell to survive.
In contrast, Cas12a2 is key-locked self-destruction switch. It targets single-stranded RNA transcripts with a specific guide protein. So the specificity is two-fold: the guide protein doesn't tolerate mismatches, and its operating on a _downstream byproduct_ of the DNA. When the key (guide protein) matches, it unleashes total destruction within the cell.
We want the Cas12a2 "patient" cell to die.
> If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.
Correct on the first point. If it were to work, gene therapy could be more common. I do not know how to make it affordable, yet. In the models I've built to commercialize this I estimate a Cas12a2 treatment would cost approximately as much as a bone marrow transplant.
> How does "answering questions" offset the technology being inferior right now?
In fairness, asking and seeking answers to questions is all I have right now. There is no cure to my disease so the upside - no matter how futile you may perceive it to be - to me, is infinite.
If I can solve it I may get a few more years with my daughter. If I can't, I can show her how to live fighting for an answer that may never come.
You're not wrong, you and I just have different perspectives on the upside.
Tens of thousands of papers have made important scientific advances using it successfully and CRISPR-Cas methods are used routinely throughout almost all of biology.
This is like calling PCR "overhyped" because PCR-based infectious disease diagnostics are limited.
The comparison is kind of a category error. One is a DNA editing technique and the others are deliver platforms. I recall the hype mostly being how revolutionary it could be, not comparing it on a timeline to specific technologies that are at different levels of the stack.
The public in general doesn't have a good understanding of basic genetics and I blame high school science curriculums for not covering it well enough. Too much time is wasted on Mendelian genetics without covering the Central Dogma.
You basically cannot "edit" your somatic DNA in a meaningful wholesale way since every single cell in your body has a copy of the DNA, and it's a foolish endeavor. What you can conceivably edit to good effect is your germline DNA, stem cell DNA, or modify mRNA expression (e.g. retinoids; yes putting retinol/adapalene cream on your face is "gene therapy"), or introduce foreign mRNA for your translation machinery to co-opt (e.g. mRNA vaccines).
Expressing mRNA that doesn't exist in the genome, that would be gene therapy. Or just a virus.
I usually end Legend after the mannequin trap, and end Sunshine after the transit of mercury.
The CRISPR-Cas9 gene-editing tool was developed in 2012, so I don't find it surprising that merely 14 years later, there's only one approved treatment. From discovery to approval, drug development often takes 10-15 years, and often much longer for novel techniques. So I'd say it too early to call it overhyped for treatments.
Finally, I think we'll see a lot of treatments that don't use CRISPR-Cas9, but related gene editing techniques, but it'll take another 10 to 20 years.
Take a look at https://en.wikipedia.org/wiki/MRNA_vaccine#History for how long another novel technique has been in development before it became really widespread with the mrna-based covid-19 vaccines.
mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different.
> mRNA vaccines are also quite different. Do they modify the DNA? Of course not. So that's already very different.
And yet it took more than 30 years after the first mRNA experiments to develop a successful vaccine. Why it should be so much faster for CRISPR & Co?
As far as I know a few labs in this space are operating under the basic question, "why haven't viruses killed everything by now?"
So this category of research is more or less the answer.
> Do mammals have a CRISPR analog?
Not exactly. There are things like https://en.wikipedia.org/wiki/Ribonuclease_L that nuke cells and are stimulated by interferons. This might be why interferon injections are common chronic therapeutics for diseases in this space.
The closest thing we have is probably whatever adaptability B or T cells can muster on their own? I'm sure someone lurking in the comments has a better answer.
https://www.nature.com/articles/s41586-026-10466-y
Over the past 1-2 decades there has been unbelievable progress at the basic technology level but most people are unimpressed because they haven't translated yet due to not individually being sufficient to cause an explosion of progress. IMO, we're starting to see it finally as so many different technologies have gotten so cheap, fast, and good.
If spending billions was the main trick, we’d know it already.
[0] The covid vaccines collectively were faster only due to the fact that when money is no object you can parallelise a lot of options and can pipeline the testing stages rather than waiting for full review and another funding round before progressing to the next stage
[1] Where they-don't-tile-but-we-did-it-anyway animated gif backgrounds are the metaphor for home kits to make random things bioluminescent: https://www.the-odin.com/gfp-bacteria/
10-20 years for an Alastair Reynolds' style Indoctrinal Virus? I hope not, but I can totally see it happening eventually.
- Theranos was at the forefront of medical technology
- Apple is a fraudulent company to the core
So one needs to figure out a delivery method that is efficient enough, and that doesn't elicit an immune response. But I guess one can analyze the cancer in the lab and figure out which receptors it expresses, and then bind to those? We could have a toolkit of different delivery methods, tailored for each patient's cancer.
The post on AI and and cures for cancer is https://www.writingruxandrabio.com/p/a-response-to-dario-amo... .
My partner of many years had one of the nastiest cancers around, one with no targeted treatments. She went through an experimental combination of existing drugs. Some of the side effects included:
This is just a sampler of the horrible effects.This was a good response. Other patients just died from the drug combination.
This is what going slowly looks like in the world of cancer treatment.
We relax ‘do no harm’ quite a bit when the alternative is certain death. People like to try stuff in order to hang on to hope. Towards the end I became convinced that she made the wrong choice to do aggressive interventions. Quality of life was very bad.
On the other hand, she gave it her all trying to survive. Hopefully that was satisfying for her.
This makes some sense in terms of compassion and matching new experimental techniques with patients with no hope, but it skews the results highly negative because the patients are already very close to death's door. It does not provide an accurate signal for what the results would be if we gave them to less sick people.
I don't think any of this can be changed without large-scale social acceptance of greater risk in clinical trials and significant support from the government.
It provides an excellent signal because we want to prove that these drugs are doing something that the standard of care is unable to.
There's this sense that medicine is easy and some evil cabal are limiting health to their cronies. Most medications never get to trial for their intended indications, and most fail trials. There's no reason to believe oncology medications are somehow uniquely unlikely to go through this well-described process of failure.
Same here. Are you and your care recipient familiar with the Optune Pax device that the FDA approved in February?
https://www.fda.gov/news-events/press-announcements/fda-appr...
My father's been using it since April. It's a little cumbersome and only improves overall survival rates by about two months over chemo alone, but we're hoping that it helps him remain relatively healthy until Daraxonrasib becomes available.
> Much like other CRISPR therapies, delivery is a critical challenge, i.e., getting the large genome-cutting enzyme to all the targeted cells efficiently.
makes me think this is in vitro so far. So, years to decades away from being available for actual treatment in humans. Still good news.
If that's not what you want, you'd need something like a virus to spread it. But then you have to ask yourself: what if that virus mutates? The specialization to certain gene markers is an evolutionary disadvantage, so evolution will tend to make it lose that restriction. Ooops.
Like many things of this nature, people keep bringing it up because it sounds Very Scary and Very Dystopian - not because it's worth giving an actual fuck about.
Private pharmaceutical R&D spending in the U.S. is around $100bn per year [1]. NIH spends another $50bn a year on biomedical research [2].
That eclipses total investments into adtech per se, which generously counted shouldn’t exceed $50 to 60bn. (And that only by counting like a third to a half of Google, Amazon, et cetera R&D and capital spending as adtech.) More precisely counted, it probably doesn’t exceed $10bn.
[1] https://phrma.org/blog/phrma-member-companies-rd-investments...
[2] https://www.science.org/content/article/final-nih-budget-202...
Factors that would make it more attractive our lower interest rates, higher returns, or faster development.
All of these are theoretically possible to adjust, but the last is most feasible to do in a tailor-made way through FDA review and approval reform. An ambitious example would be allowing conditional Market approval after Phase 2 and treating phase 3 deliverables as post-market commitments.
Advancing the revenue curve two to three years while maintaining the same patent expiration dates can dramatically change the ROI of a pharmaceutical development program.
Beyond this, even conditional Market allowance allows firms to better gauge Market interest and validate Financial investment models sooner.
Similarly, there's also some really low hanging fruit in this area to help manufacturers get to Market faster. For example, the FDA approval of trade names and label content is one of the last steps in Market authorization. Moving this earlier in the process would help products itself sooner and start producing Revenue sooner. Imagine having your billion dollar annual revenue shift out a quarter because the FDA wanted some last minute change to how a cartoon belly button looks in the instructions for use.
As a result, life science researchers are more price-taking than proce-setting when it comes to their wages / salary. If money is the motivator, then the market as-is isn’t addressing this one.
Then the money will flow.
Cancer prevention is downstream from that, as cancer frequency grows exponentially with age. If you can truly rejuvenate a person, you will also reduce their risk of cancer.
Adtech works because there is a lot of money in it. There is a lot of money in it because people seek quick entertainment, and we have a LOT of people driving the demand.
Now compare that to cancer research. There's no short term gratification about it.
There's a wide world outside big tech, Silicon Valley, and software in general. It only tends to be a bit less visible online.
Also wonder, outside of politics and economics, whether there's a social and cultural component that can contribute. TV shows, movies, books, and other forms of media that put science and scientists in the spotlight in a positive light can be tremendously inspirational.
And even more brilliant minds are defeating it, every day. I have doubts about how useful they would be in a research lab.
Chemo, radiation, and CRISPR will kill everything it can reach that is susceptible. That leaves everything that was unreachable or resistant behind to start growing again.
Kill cancer cells is easy. Killing ONLY cancer cells is very hard.
CRISPR was the cause of a huge patent case and likely led to a change in US patent law because of the impracticability of deciding who did something first in the laboratory.
It continues to influence research as some nations took a while to decide how they would resolve their own researchers' CRISPR claims with respect to MIT/UC Berkeley.
And yet... all the research has continued apace.
Edit: the CRISPR patent cases are continuing even today
https://news.berkeley.edu/2025/05/12/federal-appeals-court-s...
https://www.broadinstitute.org/crispr/journalists-statement-...
Because of this initial trials consume lots of medical staff to deal with the potential side effects. Normal side effects for cancer treatments include:
The danger of side-effects like this requires a medical team largely dedicated to the experimental patients.This puts a limit on how many patients you can put into a trial. I'm under the impression that cancer trials are pretty much always full.
Suppressed debate is almost universally due to biased/captured moderation teams aggressively using bans.
People shouldn't be blocked from commenting because their karma goes negative. Spamming, hateful talk, etc should be a completely different system. Just because what you say is unpopular (in one place mind you) doesn't mean your words should be hidden.
>children
stepchildren, perhaps.