himata4113
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.
|
> r58lf
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.
|
> > unknownfuture
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.
|
> > > liamwire
Dr. Richard Scolyer was at the forefront of
this, and died only recently after a long
battle against brain cancer at 59. His open
letter is well worth the
read.https://www.abc.net.au/news/2026-06-08/pr
ofessor-richard-sco...
|
> > jacinda
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.
|
> > vikramkr
That's understating the progress by a lot - many
cancers are a lot more survivable now than
previously with better chemo/radio/surgery +
immunotherapies + car-t etc etc
|
> > himata4113
I guess then a graph of deaths from disagnosed
cancer at various stages would be just as awe
inspiring. I'd settle for that as well.
|
> > > zevets
https://www.cancer.org/content/dam/cancer-org/
research/cance...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.
|
> > > > golem14
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)
|
> > > > > bbor
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.
|
> > > > > > consp
It is always interesting to point
out to people claiming it would be
better to not cure people that
over half of the people in the
room would be dead by the age of
5. That likely includes them.
|
> > > > > > lobocinza
Utilitarianism can justify that
kind of policy/behavior. It makes
economical sense, with your free
the burden of society it free
resources so people be more
productive, afford things, live
happier lifes (at least on the
material sense), have
children.Though I don't subscribe
to utilitarianism or the notion
that the value of an human being
can be reduced to its economical
aspects. It's not my moral
compass.
|
> > > > > > golem14
I think humour is the best
medicine. EG, why not kill all the
poor: https://youtu.be/s_4J4uor3JE
|
> > > > arbitrarywords
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.co
m/doi/10.3322/caac...
|
> > > > himata4113
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.
|
> > > > > parodysbird
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.
|
> > FunHearing3443
They are starting to ship this out across the
country. My uncle has pancreatic cancer and is
hoping to get a shipment in the next two months.
Apparently you discontinue chemo while on it
because it's so unnecessary at that point.
|
> > sydd
There are lots of other success stories too. For
example there is a reason why Keytruda is the most
valuable medicine globally -- it does amazing
things against melanoma and lung cancer
|
> > liveoneggs
I think some class of melanomas and small-cell
lung cancers went from 6 month survival to now
completely "cureable" using immunology drugs
|
> > > bglazer
You're probably thinking about non-small cell
lung cancers. Small cell lung cancer (SCLC) is
still absolutely devastating. The most
progress made on SCLC has just been getting
people to stop smoking, as its almost
exclusively a smoker's disease.Anyways, I
studied SCLC in grad school and saw lots of
scans of people with tumors from their heads
to their feet, and saw the enormous resources
dedicated to caring for SCLC patients and to
searching for a cure. It's hard to overstate
how profoundly evil the cigarette companies
were and still are. They got people (children)
addicted knowing what was coming for them,
knowing they were killing them in horrific
ways. Now we all get to pay for that in
funerals and tax dollars.
|
> da_chicken
It's difficult to do that because we don't even really
know how many cancers there are.Cancer is best
understood as a family of tens of thousands of
diseases. They're a whole range of different genetic
changes that can happen which result in similar
categories of symptoms and consequences. They can also
be incredibly complex, such as being the result of
hundreds of stacking genetic defects acquired over a
lifetime. There can be a thousand varieties of one
specific type of lung cancer, and they might all react
differently. Some of our solutions might work on a lot
of them, but others might only work on a handful. And
we're at the beginning of figuring all this out.CRISPR
may eventually allow us to genetically profile a
cancer and design highly targeted medications to cure
them, but we don't know yet how well it will work. It
may only work on a portion of them. It may have worse
outcomes than chemotherapy or radiation. It's nice to
think that we're going to find a magic solution to the
entire problem, but things almost never work that way.
I think we're going to be able to resolve a wide range
of issues, but I don't think it will really cure
cancer as a whole.
|
> > mhb
> Cancer is best understood as a family of tens of
thousands of diseasesThere's a site that lists the
AWS instance types, so maybe...
|
> rolph
you should probably look at oncogenes in
general.https://en.wikipedia.org/wiki/Oncogeneat 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_immun
ology
|
> flexagoon
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!)https://ourworldindata.org/cancer
|
> ricardobayes
All in all what a century to be alive in, 100 years
ago many people were living in mud huts globally (even
in rural Europe) and now we have CRISPR, self-driving
and hopefully UBI in a few years/decades. So much to
look forward to.
|
> TacticalCoder
> We might have "AI" ...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.
|
> itissid
#TIL multiple myeloma went from being a death sentence
in the 90's to quite manageable using a really old
compound called thalidomide[1]. Though it sad that it
was exploited for almost two decades to line the
pockets of a dozen rich
a*holes.[1](https://www.propublica.org/podcast/revlimi
d-cancer-drugs-fda...)
|
> aquafox
I think it's difficult to objectively quantify
"effectively solved". A good source with loads of
information about many diseases and their clinical
status is OpenTargets, e.g.
https://platform.opentargets.org/disease/EFO_0003860
|
> photochemsyn
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.
|
> Luckyemmet
Exactly.Now these are the kind of matters the world
should be more inclined to invest in.
|
> 4k0hz
Let the record reflect that I had this exact idea 2
years ago but never finished it, and remembered it
this morning.
|
> tyre
Have you asked Claude to pull this and graph it over
time? It could build a static site as well.
|
> > bitmasher9
Isn't this likely to lead to inaccurate data? I
wouldn't know enough about the domain to
fact-check Claude.
|
> > phyzome
Have you tried just mashing on the keyboard and
seeing if a great comment comes out?
|
bonsai_spool
Here's their preprint from a month ago, in case you can't
access the Nature paper:
https://www.biorxiv.org/content/10.64898/2026.05.08.723607
v1Nature -
https://www.nature.com/articles/s41586-026-10738-7
|
MontyCarloHall
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).[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
|
> AnimalMuppet
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.)
|
> > mikepurvis
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.
|
> > > MontyCarloHall
>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.[0]
https://www.youtube.com/watch?v=plVk4NVIUh8
|
> > > > mikepurvis
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)
|
> > > > > MontyCarloHall
Sure, but my point is that convergent
selective pressure across different
individuals' tumors is strong enough
that they independently arrive on the
same resistance mechanisms to a given
therapy, e.g. [0]. Just like if you
performed the same bacterial
antibiotic resistance experiment [1]
across multiple independent trials,
you'd repeatedly get the same
result.[0]
https://pmc.ncbi.nlm.nih.gov/articles/
PMC2538882/[1]
https://news.ycombinator.com/item?id=4
8505231#48507925
|
> > > strbean
> 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.The rare exception:
https://en.wikipedia.org/wiki/Clonally_transmi
ssible_cancer
|
> > > > mikepurvis
Well that's terrifying, TIL.
|
> > alexey-salmin
It's not very relevant here, but curiously some
cancers are, in fact, contagious organisms. The
most famous example is the devil facial tumour
disease. Luckily cases of transmissible cancer in
humans are extremely rare (if you count only
transmission of cancer itself and not the
cancerogenic agents).Another curious case of
"cancer being an organism" is the HeLa line
derived from cervical cancer cells taken from a
woman called Henrietta Lacks.
|
> > MontyCarloHall
Nonetheless, we see the exact same resistance
mechanisms to the same therapies recur across
individuals, e.g. [0]. Convergent evolution is a
harsh mistress.[0]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2538882/
|
> rolph
turn the stick around and grasp the other
end.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.
|
> cyberax
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.
|
> > MontyCarloHall
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.
|
> > > cyberax
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.
|
> > > > MontyCarloHall
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.[0]
https://pmc.ncbi.nlm.nih.gov/articles/PMC8
809250/
|
> > inglor_cz
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.
|
> > > cyberax
Tumor lysis syndrome is a thing, but it can be
managed. It's far better than the
alternative.The new therapies will also likely
be applied after surgical resection and/or
classic therapies to reduce the bulk of the
cancer.
|
> amluto
Surely a far simpler way to evolve resistance would be
a trivial mutation in the p53 transcript that the
guide RNA is looking for.
|
> > MontyCarloHall
In practice, you'd use multiple guides targeting
multiple mutations, so that the probability of
having/acquiring multiple resistance mutations
abrogating every guide from binding would be
infinitesimal.
|
> > > amluto
LNPs have limited capacity, and if the
CRISPR/Cas system they're using requires an
exact match, then any additional point
mutation or insertion or deletion in the
segment being matched would allow the cell to
survive. I suppose that approximately 3n extra
guide RNAs (where n is the length of the
matched sequence) could be added, but that
seems a bit messy.
|
> > > > MontyCarloHall
Including additional guides is negligible
with respect to the overall LNP capacity,
which can contain a few thousand
nucleotides. The CRISPR/Cas mRNA is about
5 kilobases total, and each guide is on
the order of 100 bases.
|
> strbean
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.
|
> > MontyCarloHall
>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.
|
> > > strbean
Interesting, thanks for the info!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
|
> > > > MontyCarloHall
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.
|
> > chasil
I'm no expert, but p53 is known as "the guardian
of the genome."If p53 is reactivated, the cancer
cell dies.https://en.wikipedia.org/wiki/P53Perhaps
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.
|
> > rolph
>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.
|
ordinaryradical
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.
|
> spligak
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.
|
> > Gethsemane
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!
|
> > > spligak
> Are there any plans to move to in vivo?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.
|
> > > spligak
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.
|
> > > > reenorap
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.
|
> > > > > smallnix
> I just wanted to reassure you that
the name sounds scary but the current
treatment appears to work wellEven a
charitable read is condescending. This
person just wrote they are in the
innermost research circles. I think
they are beyond the "scary name" -
needs reassurance phase.
|
> > > > btam
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.
|
> > > > > spligak
> How much overall has this costed
you?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.
|
> > > > > > p1esk
Do you feel that recent advances
in AI can speed up such rare
disease research?
|
> > > > darkwizard42
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.
|
> > > > andy_ppp
"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.
|
> > > > > CamperBob2
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/My
thos/Fable to discuss human biology,
and some of us object vociferously to
their premise, this is what we're
talking about.
|
> > > > > > gleenn
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?
|
> > > > junon
This is amazing. Thank you for sharing.
|
> > > > ticulatedspline
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.
|
> > > ordinaryradical
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.
|
> > > > spligak
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 diagnosisThe
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.
|
> > > p1esk
I'd also like to read about your experience.
|
> > > > spligak
Done! Wrote a bit more in a comment above.
Thank you for the interest.
|
> > acomjean
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.
|
> > GaggiX
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?
|
> > > spligak
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.
|
> > > > shevy-java
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.
|
> > > > > spligak
> I don't think that more than sloppy
accuracy is acceptable for any gene
therapyValid 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.
|
> > > > > cyberax
> 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.
|
> > > > > > spligak
> 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.
|
> > > > im3w1l
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.
|
> > > > > spligak
> I would deal with this by deciding
how many cells I want to kill each
dayYes, 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.
|
> > shevy-java
So how does Cas12a2 mitigate off-target effects?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?
|
> > > spligak
> 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.
|
> > rozap
This is wild, have you written about it publicly,
or can you expand on it here?
|
> > > spligak
I have now :) I replied to a sibling comment.
Thank you for the nudge to share.
|
> > manmal
May I ask, how much money you have spent so far on
this effort?
|
> ramraj07
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.
|
> tstactplsignore
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.
|
> roncesvalles
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).
|
> > Bjartr
Edit every cell? No.
Edit enough cells to impact health outcomes for a
meaningful period of time?
[Yes](https://www.youtube.com/watch?v=J3FcbFqSoQY)
|
> > > shevy-java
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.
|
> > projektfu
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.
|
> > asdff
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.
|
> WhitneyLand
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.
|
> > make3
it's revolutionary in genetic research, allows us
to observe cells with specific gene knockouts,
over activations, etc. it's just very hard to
deliver to a whole system
|
> fastball
Viral vector delivery is indeed harder to sell with
PopSci, what with movies like "I am Legend".
|
> > jvanderbot
Great first half of a movie, by the way. Up there
with Sunshine for "Sit down for a great hour-long
ambiance".I usually end Legend after the mannequin
trap, and end Sunshine after the transit of
mercury.
|
> tty456
You're confusing the beurocratic FDA stamp of approval
with safety and effectiveness. Those are not the same
thing.
|
> anovikov
Bingo! CRISPR has an advantage of being relatively
easy to describe to a layman, giving it a PR
advantage.
|
> > fragmede
So is the "idea" of microchips in vaccines. Should
we just give up and let everything else have the
PR advantage
|
> perlgeek
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.
|
> > shevy-java
Why does it take 20 years? Except, of course, that
it does not work nowhere near as well as it is
being promoted - aka hyped.mRNA vaccines are also
quite different. Do they modify the DNA? Of course
not. So that's already very different.
|
> > > ufmace
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.
|
> > > perlgeek
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?
|
> JumpCrisscross
Do mammals have a CRISPR analog?
|
> > spligak
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.
|
> jagged-chisel
"Virus" - that's why.
|
supertroop
Yes! I have a genetic disease that will take me out in my
70s and I'm really hoping CRISPR gets to it before I do!
|
> dreambuffer
I don't mean to sound insensitive, but don't most
people die around age 70-80?
|
> > aroman
Life expectancy in many countries is mid 80s.
|