I think people have a hard time understanding what a wall aging is. My favourite aging fact is that if you live to be 100, your odds of reaching 110 are ~0.1% - 0.2%. Once you hit about 105, it becomes more likely than not that you will die within the year. Very few things are distributed like this. The biggest <item> is often a lot bigger than the second biggest <item>. Most cars die after about 15 years but the occasional car makes it for 50 years. But the longest lived person on earth only lived 1.5x the average developed world lifespan.
On the one hand this makes me appreciate the importance of understanding aging, on the other hand that field has a reputation as something of a train wreck. When I started graduate school, Situins were all the rage. Then that totally fizzled, not in a "failed to deliver" sense but in an "all of it was completely wrong sense." Failures of entire paradigms like that are more something I associate with sociology rather than biology. Then we went through a telomere length craze, where the length of your telomeres was supposed to indicate how much you had aged. The "epigenetic clocks" people talk about now undoubtedly have some validity but I'm not sure they will really explain aging so much as reflect it. Furthermore, all of these crazes seem to attract lots of inaccurate popular press, crooked supplement companies, etc. I wish we didn't suck at something this important. Perhaps it's just that there is nonsense in every field, but aging hasn't had enough real breakthroughs to drown out the nonsense.
I think we are making some good progress in aging. I go to biotech conferences frequently, and we should have pretty good treatments for muscle loss and cognitive function, by 2027, based on the clinical trial data I have seen, also clinical trials with already approved drugs are looking good.
Here are the muscle loss drugs, I think will be on the market by 2027.Azelaprag(Bioage labs) , enobosarm(Veru inc) LGD( Viking Therapeutics) and the most promising Galantamine + metformin( Rejuvenate biomed though we may have to wait until 2028 for that one as they are actually going straight into Sarcopenia, and not just GLP combo trials.
The cognitive drugs, I”m most excited about is Alzheon( Alz801) an oral pill with way less side effects then the anti bodies recently approved, and should be cheaper. They have a phase 3 readout this year. I am also optimistic about Cognito therapeutics, medical device, to treat Alzheimer’s and Parkinson.
We all start the same and end the same. It is only the middle we have some influence over. Medical advances don’t so much prolong life as they stop the middle from being cut short, or improve the quality of life in the middle.
Unless and until the life extension people find something that works, that is what we’ve got.
I wonder if there are tiny ways we can get creative on the margins with aging research. For instance, take people who had extremely delayed puberty in adolescence or some pituitary condition temporarily halting maturation. You could try to assess whether their rate of aging plays catch-up later on or whether their lifespan ends up a few years longer on average. Of course there are all the confounding variables, since those individuals presumably have other weird stuff going on. But maybe there's little clues to be found there. Full disclosure: I write as someone who had extremely delayed puberty, to the point of falling 8 years behind schedule (and still look about 10 years younger than my real age). Will it matter when I'm 80? Is lifespan capped at its upper limit by the aging we do along the whole journey, or only at the end when we're on the full decline?
About the telomere craze: one of my very early jobs, many years ago, was as an RA on a health psych study for this PhD student who later became one of the biggest names in the telomere movement. I followed with mild interest for a brief time after recognizing their name, but last time I checked telomere length had still not been studied across the lifespan, and it seems to be stuck at the proof-of-concept phase. I haven't really kept up with it though.
I haven't done enough research on this issue to make any meaningful argument, but if the mechanics described by Scott Alexander in this absolute horror piece are common; I can't imagine how many basic and intuitive studies have gone unrealized for purely bureaucratic reasons, and what the repercussions have been for medical progress generally.
This is a great overview for non-specialists. I think that one problem you encounter in science, in general, is the gulf between what I call the popular science fiction view of science (and technology) and the more quotidian reality of science (and technology). The popular view, among people who claim to pay attention to science and/or technology, is that we have seen, and will continue to see, rapid improvements in science/medicine/technology. The reality, at least within science and medicine, appears to be much more prosaic.
Is counting Number of Drugs really a good metric for success? As an analogy, the introduction of the microprocessor was a lot more important than any number of slightly new variants on shift registers, latches, etc.
I wonder what the trend line would look like if drugs were somehow importance-rated. Such an analysis would require subjective judgments, but better approximately right than precisely wrong.
Lifespan data is affected by a lot of other things...social dysfunction and drug addiction, access to care, auto accident rates..unless I'm missing something, not a pure indicator of medical progress. For the years of life saved numbers, how are these derived?...is it simply people with a particular level of a particular condition and how long they live, or is it calculated for specific drugs and other treatments?
This is why I didn’t just focus on lifespan data for US only, but from other countries too. Where the level of dysfunction is much lower. I also find the plot showing that we have been much better at improving lifespan at say 45 than at 80 convincing
The original question seems nonsensical to me. Every instance of cancer - every single one - is a completely new disease that developed in situ in the body where it lives. It’s kind of like asking “why haven’t biologists cured viruses?” Also, because the cancer is genetically very similar to the body it lives in (with a few important genetic differences which is what makes it cancer), there is the recurring question of how to kill the cancer without killing the person. I am not a researcher or medical professional - this is literally Cancer 101.
You know, one of my favorite presentations I ever saw was a genetic researcher explaining to a room full of patients and family members why progress towards gene therapy was so slow. He had parents laughing about a problem that is killing our children. More importantly, he had us understanding what the barriers really are. So how’s this for a question - why aren’t biologists doing a better job explaining how difficult - impossible - a universal cure for cancer actually is?
I do not think the idea is necessarily that we should have found a universal cure. More like, we could have already cured cancer by finding cures for all subsets of it or at least most of them
If medical progress per dollar is declining maybe we should allocate more dollars? The public doesn’t seem as engaged with this issue as they should be given the, you know, absolute relevance of medical progress to quality of life but is anyone is making the case to them for more public medical R&D? How much more is a question. Why not 10x? How is it that osteoarthritis is still a thing? And tinnitus. And chronic pain. And then there all the conditions I don’t have. Definitely on Team More Progress here.
Maybe more creative accounting approaches would help like more generous R&D credits? We saw with the child tax credit how this approach can be more palatable to people.
I’m confused by this argument. If some investment is seeing severely diminishing marginal returns, doesn’t it make more sense to invest in other areas if the goal is to increase lifespan? Off the top of my head, prevention, healthcare delivery, behavioral changes, and investments in public health care seem like they would all seem to be better investments on average.
Yeah I definitely agree there should be some investment. I just think *more* investment isn’t necessarily the solution in pharma when I reckon the large part of America’s underperformance in life expectancy is due to lifestyle / opioid addiction / diet / prevention (e.g. not getting annual checkups, colonoscopies, mammograms, etc).
I think perhaps this points to a reason why diseases that mainly reduce *quality* of life like certain of the arthritides, tinnitus and chronic pain are relatively neglected. Simply because they’re not killing people. Somehow the person-years of disability and misery are considered just part of life.
Public funding is what's holding back progress in medicine. Look at the meta-science field that keeps uncovering fraudulent research. It's all in publicly funded stuff and mostly in medicine, because the "public" (granting agency/foundation/charity committees) aren't checking the delivered papers for fraud or errors. They just assume that if they hand over money to academics what they get back is high quality, which is a recipe for being scammed over and over. Nor is there any interest in fixing thing. Nobody wants to be the guy in the room who stands up and says, no I don't think we should fund this cancer lab because they seem to be defrauding us.
I wonder what the main incentive to do fraudulent work is? It seems like such a big risk to take to progress one’s career. I agree this seems like a high impact problem.
I’d rather try to fix the granting process first than give up on public funding but the capacity available to do good work takes time to ramp up I imagine.
If internet sleuths can uncover all these cases of fraud it makes me think that governments need units that also perform this function.
Wealth, status, power. The same as always. You play it straight, you discover nothing and crash out. Now you have to hang your head in shame as you admit to friends and family that you're a failed scientist.
You tweak a few numbers here and there, suddenly the shame is replaced by fame. You are showered with money, given a lab named after yourself, a team. Now all your friends and family think you're a hero-genius. Soon you start to believe it yourself. It wasn't your fault the data didn't come out quite right on that last experiment, it must have been contamination by one of the postdoc dolts you got stuck with. Just need to keep going and everything will work out fine.
> It seems like such a big risk
The risk is nearly non-existent. There are hardly ever penalties or consequences. The labs I mentioned in my comment got away with it for over a decade and they have not been prosecuted. The median expected outcome of fraud is academic success, with a very small risk of being forced to retract a few papers (without being fired). That's why academia is saturated with fakery and bullshit. It's the winning move and people who don't play it wash out.
For me personally, the stand-out reason is the long feedback loops for clinical research in the areas that have been more resistant to progress. This was covered in your essay on (lack of) progress in cancer I think. Longevity research may be the most hindered in this regard. We can only see the benefits as people age so it is near certainty will all grow old before we see progress. Each new paradigm will require a new generation to observe a failure, and it may require several paradigm failures to achieve success. I suspect the failures in longeviety will be even more spectular than those in cancer or Alzheimer's disease. At least for single diseases we know what we are progressing towards - curing the disease - what would success against aging even look like?
Nevertheless, I am optimistic we will see progress. Let's just try to keep our expectations grounded.
Biology has also done a good job with cancer prevention. We have drugs for Hep C, vaccines for Hep B and HPV. The HPV vaccine probably won't have much effect on cervical cancer deaths in rich countries because they're very rare thanks to Pap smears, but it'll have a big effect in places like India, China and Africa. Given how obesity raises the risk of so many cancers, semaglutide will probably prevent a lot of cancers. A highly effective drug that makes either smoking or alcohol unappealing would also bring down the cancer rates, especially in lower income countries. But it will take years to see those declines, just like it took years to see the decline in lung cancer rates in rich countries.
I think there is a different way in which progress in medicine is much too slow -- and it's the extent to which it is slowed down but unreasonably high standards for safety and informed consent in studies.
As a member of the public, I want to maximize my expected quality adjusted life years and I'd be happy to exchange a bit less confidence that medications or procedures won't hurt me to increase the overall expectation. Unfortunately, the standard set for me to participate in medical trials is generally much higher than merely an expectation that the knowledge gained will exceed the cost to the participants.
Yes, the participants shouldn't be tricked into participating but I'd argue that it's every bit as morally wrong to deny them from altruistically choosing to do so (say I'm going to die in 6 months anyway and worst outcome is the trial goes badly and I die in 3) as it is to trick them into doing so.
Basically, our approach to medical advancement is to avoid the possibility that you can be blamed for hurting someone not to maximize the expected outcomes and that troubles me.
"The reason why I am (somewhat) bearish on medicine is that there are signs feedback loops are getting slower and also fewer in number. Clinical trials, the main avenue through which we can get results on whether drugs work in humans, are getting more expensive. The culprits are so numerous and so scattered across the medical world, that it’s hard to nominate just one: everything from HIPAA rules to Institutional Review Boards (IRBs) contribute to making the clinical trial machine a long and arduous slog. An increase in clinical trial costs will mean that for the same amount of money, there will simply be less of them and consequently, less feedback. There are some reasons for optimism too. The COVID pandemic showed us that some high-quality trials are much cheaper than others - the RECOVERY clinical trial in the UK that discovered steroids cut COVID-19 deaths by ⅓ was much cheaper than traditional trials. A challenge for policymakers will be learning from this experience and implementing RECOVERY-like strategies across a larger number of clinical trials."
While this argument has always seemed plausible to me in principle, I am skeptical that excessive regulation is the primary reason for slow medical progress. After all, if red tape were the primary hurdle, shouldn't there be countries with less onerous standards and a proportionally higher rate of medical innovation?
Why aren't we seeing a slew of medical innovations from China, for example? Maybe there's some general trend wherein medical regulations grow proportional to a country's wealth, essentially eating up any gains one would expect from a higher research budget? Does anyone know if this has been studied quantitatively somewhere?
Yes I think you need 2 things: 1) good ideas 2) ability to test and iterate. Red tape slows feedback loops but it doesn't mean that if you get rid of it you'll necessarily have good ideas
We should definitely be investing more in life extension. Progress in that area will automatically mean a huge decrease in age-related diseases. In recent years I have been a voice of caution among life extensionists. Now in my 60s, I would be surprised if major advances will come in time for me. That's why I urge people to see biostasis as longevity plan A.
While medicine is tackling one of the hardest problems we as humans can comprehend, I'd say medicine is severely underachieving for reasons that are common to all underachieving sciences:
- over-indexing on safety (e.g. see progress in aerospace 1970-2020),
- over-indexing on correlation over causal mechanisms (medicine is too satisfied with bad statistics over too small populations)
- not being incestuous enough (most discoveries are made when fields steal from other fields)
- clinical science (digitally speaking) is and is staying in the stone ages
What about trust issues? It's hard to precisely discuss progress in a field which has lost the trust of so many people, because it means the field can present things as progress but which will be rejected by a lot of the people it's meant to help.
A big part of increased life expectancies in the 20th century has nothing to do with medicine, it's all nutrition. But this has since tapped out and nutrition is now widely regarded as a joke science. I encounter way fewer people these days experimenting with diets - and actually that such experiments are called "fad diets" is a clue to the field's low repute.
Cast the field wider and the situation gets worse. What happened to Alzheimer's research? There seems little point to life extension research if you're just adding years of mental decline, yet recently it came out that the ß-amyloid hypothesis rested on a foundation of fraudulent papers published decades ago. How is it possible nobody noticed? For years we were told there was steady progress in Alzheimers, and when none of the drugs worked we were told it was a mystery why not.
But the biggest problem that's going to kill medical progress is mRNA. It's such a flexible technology that drugs research will come to rely on it heavily, as your example of melanoma makes clear. Yet biologists aren't honest about it. Even here, you give the conventional development narrative: many years of scientific struggle, a heroic female scientist, millions in VC investment, the near bankruptcy of Moderna due to mRNA (as a tech class) becoming toxic on repeat doses. But then you assert that they "got lucky", allowing the reader to infer that there was some scientific breakthrough that resolved the toxicity problem. No details are supplied, as always in this story, even though it should be the scientific climax.
The mRNA story is always told this way because in fact Moderna never did make a breakthrough. Instead, as STAT's coverage makes clear, after decades of research they admitted defeat. They just didn't know how to stop the body rejecting artificial mRNA lipids after they'd been seen more than once, and they'd run out of ideas too. Their fix was pivoting to vaccines, because - as everyone knows - vaccines are things you only take once <facepalm>. Moderna did get lucky, but not due to medical progress. They got lucky thanks to mass hysteria.
Give it a few more years and we're going to end up stuck in COVID nightmare land permanently, being told a narrative of progress in which brave and clever biologists have conquered every imaginable disease and the lack of any impact on the metrics is down solely to the benighted influence of awful right wing conspiracy theorists. Medicine, as a profession, is going to blame the sick. Just you wait and see.
As with the research side of it, my sense is that we are investing increasingly large amounts of money in actual medical care, with diminishing returns. The average 70 or 80 year old person hasn’t gained much, in terms of life expectancy, but sure as heck are spending a lot more money on their medical care.
yes that's actually true. Our World in Data has an article about investment in healthcare vs outcomes and it's not great.
But with medical research I think it's a bit different because we never know what might happen ... like, maybe it takes us 200 years of investment to find something to delay ageing and I think it would have been worth it
Is aging really one thing? I know, have known, a lot of old people and had a close connection to someone nursing very old people. It seems like what impairs and kills each person is their own personalised mix of chronic conditions. Presumably if each of these common chronic conditions was understood then a big part of aging might be demystified. Instead of “these drugs work in __% of people but we don’t know why”
Chronic conditions in the young are also the same process but “too soon” eg hypertension including gestational. If vascular and connective tissue, cell signalling, immunity, metabolism - if each individual area of malfunction were really drilled down into it would help a lot of young and middle aged people live better lives too.
Thinking of the studies where ADHD and later getting dementias are associated, or where cognitive performance in young nuns was predictive of later dementia. That’s among people with strictly mandated lifestyles - the same habits lol. There could be something going downhill in the brain from very early on.
I think people have a hard time understanding what a wall aging is. My favourite aging fact is that if you live to be 100, your odds of reaching 110 are ~0.1% - 0.2%. Once you hit about 105, it becomes more likely than not that you will die within the year. Very few things are distributed like this. The biggest <item> is often a lot bigger than the second biggest <item>. Most cars die after about 15 years but the occasional car makes it for 50 years. But the longest lived person on earth only lived 1.5x the average developed world lifespan.
On the one hand this makes me appreciate the importance of understanding aging, on the other hand that field has a reputation as something of a train wreck. When I started graduate school, Situins were all the rage. Then that totally fizzled, not in a "failed to deliver" sense but in an "all of it was completely wrong sense." Failures of entire paradigms like that are more something I associate with sociology rather than biology. Then we went through a telomere length craze, where the length of your telomeres was supposed to indicate how much you had aged. The "epigenetic clocks" people talk about now undoubtedly have some validity but I'm not sure they will really explain aging so much as reflect it. Furthermore, all of these crazes seem to attract lots of inaccurate popular press, crooked supplement companies, etc. I wish we didn't suck at something this important. Perhaps it's just that there is nonsense in every field, but aging hasn't had enough real breakthroughs to drown out the nonsense.
totally agree. I think the effect of this non sense is to drive out human capital
I think we are making some good progress in aging. I go to biotech conferences frequently, and we should have pretty good treatments for muscle loss and cognitive function, by 2027, based on the clinical trial data I have seen, also clinical trials with already approved drugs are looking good.
can you name names? wrp to companies, assets etc?
re muscle loss are you thinking of bimagrumab?
Here are the muscle loss drugs, I think will be on the market by 2027.Azelaprag(Bioage labs) , enobosarm(Veru inc) LGD( Viking Therapeutics) and the most promising Galantamine + metformin( Rejuvenate biomed though we may have to wait until 2028 for that one as they are actually going straight into Sarcopenia, and not just GLP combo trials.
Thank you!
The cognitive drugs, I”m most excited about is Alzheon( Alz801) an oral pill with way less side effects then the anti bodies recently approved, and should be cheaper. They have a phase 3 readout this year. I am also optimistic about Cognito therapeutics, medical device, to treat Alzheimer’s and Parkinson.
I fully agree.
We all start the same and end the same. It is only the middle we have some influence over. Medical advances don’t so much prolong life as they stop the middle from being cut short, or improve the quality of life in the middle.
Unless and until the life extension people find something that works, that is what we’ve got.
I wonder if there are tiny ways we can get creative on the margins with aging research. For instance, take people who had extremely delayed puberty in adolescence or some pituitary condition temporarily halting maturation. You could try to assess whether their rate of aging plays catch-up later on or whether their lifespan ends up a few years longer on average. Of course there are all the confounding variables, since those individuals presumably have other weird stuff going on. But maybe there's little clues to be found there. Full disclosure: I write as someone who had extremely delayed puberty, to the point of falling 8 years behind schedule (and still look about 10 years younger than my real age). Will it matter when I'm 80? Is lifespan capped at its upper limit by the aging we do along the whole journey, or only at the end when we're on the full decline?
About the telomere craze: one of my very early jobs, many years ago, was as an RA on a health psych study for this PhD student who later became one of the biggest names in the telomere movement. I followed with mild interest for a brief time after recognizing their name, but last time I checked telomere length had still not been studied across the lifespan, and it seems to be stuck at the proof-of-concept phase. I haven't really kept up with it though.
people are trying to exploit these rare populations. See supercentenarians. But also other peculiarities of development/ageing.
Re: telomeres. We have not established a causal relationship between telomere shortening and aging
I haven't done enough research on this issue to make any meaningful argument, but if the mechanics described by Scott Alexander in this absolute horror piece are common; I can't imagine how many basic and intuitive studies have gone unrealized for purely bureaucratic reasons, and what the repercussions have been for medical progress generally.
https://slatestarcodex.com/2017/08/29/my-irb-nightmare/
It's to prolonged and maddening to describe so I'll just leave the link.
Yes, some (but not all) of it can be attributed by the infuriating amount of red tape
This is a great overview for non-specialists. I think that one problem you encounter in science, in general, is the gulf between what I call the popular science fiction view of science (and technology) and the more quotidian reality of science (and technology). The popular view, among people who claim to pay attention to science and/or technology, is that we have seen, and will continue to see, rapid improvements in science/medicine/technology. The reality, at least within science and medicine, appears to be much more prosaic.
Tanks
Is counting Number of Drugs really a good metric for success? As an analogy, the introduction of the microprocessor was a lot more important than any number of slightly new variants on shift registers, latches, etc.
I wonder what the trend line would look like if drugs were somehow importance-rated. Such an analysis would require subjective judgments, but better approximately right than precisely wrong.
well that's what the lifespan data should tell you. But in the economist section they also do dollars spent for years of life saved
Lifespan data is affected by a lot of other things...social dysfunction and drug addiction, access to care, auto accident rates..unless I'm missing something, not a pure indicator of medical progress. For the years of life saved numbers, how are these derived?...is it simply people with a particular level of a particular condition and how long they live, or is it calculated for specific drugs and other treatments?
This is why I didn’t just focus on lifespan data for US only, but from other countries too. Where the level of dysfunction is much lower. I also find the plot showing that we have been much better at improving lifespan at say 45 than at 80 convincing
The original question seems nonsensical to me. Every instance of cancer - every single one - is a completely new disease that developed in situ in the body where it lives. It’s kind of like asking “why haven’t biologists cured viruses?” Also, because the cancer is genetically very similar to the body it lives in (with a few important genetic differences which is what makes it cancer), there is the recurring question of how to kill the cancer without killing the person. I am not a researcher or medical professional - this is literally Cancer 101.
You know, one of my favorite presentations I ever saw was a genetic researcher explaining to a room full of patients and family members why progress towards gene therapy was so slow. He had parents laughing about a problem that is killing our children. More importantly, he had us understanding what the barriers really are. So how’s this for a question - why aren’t biologists doing a better job explaining how difficult - impossible - a universal cure for cancer actually is?
I do not think the idea is necessarily that we should have found a universal cure. More like, we could have already cured cancer by finding cures for all subsets of it or at least most of them
I know some people believe in a universal cure, but I think even among who do not, they wonder why we have not made more progress
If medical progress per dollar is declining maybe we should allocate more dollars? The public doesn’t seem as engaged with this issue as they should be given the, you know, absolute relevance of medical progress to quality of life but is anyone is making the case to them for more public medical R&D? How much more is a question. Why not 10x? How is it that osteoarthritis is still a thing? And tinnitus. And chronic pain. And then there all the conditions I don’t have. Definitely on Team More Progress here.
yes. unfortunately, the push now is to pay less for drugs (see IRA proposals)
Maybe more creative accounting approaches would help like more generous R&D credits? We saw with the child tax credit how this approach can be more palatable to people.
Hmm I'm not sure I know what you mean can you expand
I’m no expert on pharmaceutical economics but something along these lines https://www.sciencedirect.com/science/article/abs/pii/S0048733324001021 as an alternative to simply maximizing corporate profits by not seeking bulk discounts.
I’m not in a position to assess the quality of this work but it seems quite relevant https://www.sciencedirect.com/science/article/abs/pii/S0167718722000261
I’m confused by this argument. If some investment is seeing severely diminishing marginal returns, doesn’t it make more sense to invest in other areas if the goal is to increase lifespan? Off the top of my head, prevention, healthcare delivery, behavioral changes, and investments in public health care seem like they would all seem to be better investments on average.
I guess so but I think we should invest for the future. 80 yrs ago we didn't know we would end up being able to cure *some* cancers
Yeah I definitely agree there should be some investment. I just think *more* investment isn’t necessarily the solution in pharma when I reckon the large part of America’s underperformance in life expectancy is due to lifestyle / opioid addiction / diet / prevention (e.g. not getting annual checkups, colonoscopies, mammograms, etc).
Oh yes Matt yglesias had a good article abt how life expectancy in us is low not cuz of healthcare but other factors
I think perhaps this points to a reason why diseases that mainly reduce *quality* of life like certain of the arthritides, tinnitus and chronic pain are relatively neglected. Simply because they’re not killing people. Somehow the person-years of disability and misery are considered just part of life.
Public funding is what's holding back progress in medicine. Look at the meta-science field that keeps uncovering fraudulent research. It's all in publicly funded stuff and mostly in medicine, because the "public" (granting agency/foundation/charity committees) aren't checking the delivered papers for fraud or errors. They just assume that if they hand over money to academics what they get back is high quality, which is a recipe for being scammed over and over. Nor is there any interest in fixing thing. Nobody wants to be the guy in the room who stands up and says, no I don't think we should fund this cancer lab because they seem to be defrauding us.
I wonder what the main incentive to do fraudulent work is? It seems like such a big risk to take to progress one’s career. I agree this seems like a high impact problem.
I’d rather try to fix the granting process first than give up on public funding but the capacity available to do good work takes time to ramp up I imagine.
If internet sleuths can uncover all these cases of fraud it makes me think that governments need units that also perform this function.
Wealth, status, power. The same as always. You play it straight, you discover nothing and crash out. Now you have to hang your head in shame as you admit to friends and family that you're a failed scientist.
You tweak a few numbers here and there, suddenly the shame is replaced by fame. You are showered with money, given a lab named after yourself, a team. Now all your friends and family think you're a hero-genius. Soon you start to believe it yourself. It wasn't your fault the data didn't come out quite right on that last experiment, it must have been contamination by one of the postdoc dolts you got stuck with. Just need to keep going and everything will work out fine.
> It seems like such a big risk
The risk is nearly non-existent. There are hardly ever penalties or consequences. The labs I mentioned in my comment got away with it for over a decade and they have not been prosecuted. The median expected outcome of fraud is academic success, with a very small risk of being forced to retract a few papers (without being fired). That's why academia is saturated with fakery and bullshit. It's the winning move and people who don't play it wash out.
For me personally, the stand-out reason is the long feedback loops for clinical research in the areas that have been more resistant to progress. This was covered in your essay on (lack of) progress in cancer I think. Longevity research may be the most hindered in this regard. We can only see the benefits as people age so it is near certainty will all grow old before we see progress. Each new paradigm will require a new generation to observe a failure, and it may require several paradigm failures to achieve success. I suspect the failures in longeviety will be even more spectular than those in cancer or Alzheimer's disease. At least for single diseases we know what we are progressing towards - curing the disease - what would success against aging even look like?
Nevertheless, I am optimistic we will see progress. Let's just try to keep our expectations grounded.
yes this is one of the biggest issues - it's not even clear what we need to measure wrp to aging
Biology has also done a good job with cancer prevention. We have drugs for Hep C, vaccines for Hep B and HPV. The HPV vaccine probably won't have much effect on cervical cancer deaths in rich countries because they're very rare thanks to Pap smears, but it'll have a big effect in places like India, China and Africa. Given how obesity raises the risk of so many cancers, semaglutide will probably prevent a lot of cancers. A highly effective drug that makes either smoking or alcohol unappealing would also bring down the cancer rates, especially in lower income countries. But it will take years to see those declines, just like it took years to see the decline in lung cancer rates in rich countries.
I think there is a different way in which progress in medicine is much too slow -- and it's the extent to which it is slowed down but unreasonably high standards for safety and informed consent in studies.
As a member of the public, I want to maximize my expected quality adjusted life years and I'd be happy to exchange a bit less confidence that medications or procedures won't hurt me to increase the overall expectation. Unfortunately, the standard set for me to participate in medical trials is generally much higher than merely an expectation that the knowledge gained will exceed the cost to the participants.
Yes, the participants shouldn't be tricked into participating but I'd argue that it's every bit as morally wrong to deny them from altruistically choosing to do so (say I'm going to die in 6 months anyway and worst outcome is the trial goes badly and I die in 3) as it is to trick them into doing so.
Basically, our approach to medical advancement is to avoid the possibility that you can be blamed for hurting someone not to maximize the expected outcomes and that troubles me.
Yes, I discussed this in my previous essay:
"The reason why I am (somewhat) bearish on medicine is that there are signs feedback loops are getting slower and also fewer in number. Clinical trials, the main avenue through which we can get results on whether drugs work in humans, are getting more expensive. The culprits are so numerous and so scattered across the medical world, that it’s hard to nominate just one: everything from HIPAA rules to Institutional Review Boards (IRBs) contribute to making the clinical trial machine a long and arduous slog. An increase in clinical trial costs will mean that for the same amount of money, there will simply be less of them and consequently, less feedback. There are some reasons for optimism too. The COVID pandemic showed us that some high-quality trials are much cheaper than others - the RECOVERY clinical trial in the UK that discovered steroids cut COVID-19 deaths by ⅓ was much cheaper than traditional trials. A challenge for policymakers will be learning from this experience and implementing RECOVERY-like strategies across a larger number of clinical trials."
Sorry, I sometimes lose track of who wrote what.
Np
While this argument has always seemed plausible to me in principle, I am skeptical that excessive regulation is the primary reason for slow medical progress. After all, if red tape were the primary hurdle, shouldn't there be countries with less onerous standards and a proportionally higher rate of medical innovation?
Why aren't we seeing a slew of medical innovations from China, for example? Maybe there's some general trend wherein medical regulations grow proportional to a country's wealth, essentially eating up any gains one would expect from a higher research budget? Does anyone know if this has been studied quantitatively somewhere?
Yes I think you need 2 things: 1) good ideas 2) ability to test and iterate. Red tape slows feedback loops but it doesn't mean that if you get rid of it you'll necessarily have good ideas
We should definitely be investing more in life extension. Progress in that area will automatically mean a huge decrease in age-related diseases. In recent years I have been a voice of caution among life extensionists. Now in my 60s, I would be surprised if major advances will come in time for me. That's why I urge people to see biostasis as longevity plan A.
https://biostasis.substack.com/p/biostasis-longevity-plan-a
Gl with Roots of Progress,did substack play any part in bringing like-minded ppl together
While medicine is tackling one of the hardest problems we as humans can comprehend, I'd say medicine is severely underachieving for reasons that are common to all underachieving sciences:
- over-indexing on safety (e.g. see progress in aerospace 1970-2020),
- over-indexing on correlation over causal mechanisms (medicine is too satisfied with bad statistics over too small populations)
- not being incestuous enough (most discoveries are made when fields steal from other fields)
- clinical science (digitally speaking) is and is staying in the stone ages
In short, medicine as it stands is insufficiently acceleratable - https://venuvasudevan.substack.com/p/acceleratable-science.I look forward to seeing of this can change things - https://twitter.com/jacobkimmel/status/1829550511768674401
What about trust issues? It's hard to precisely discuss progress in a field which has lost the trust of so many people, because it means the field can present things as progress but which will be rejected by a lot of the people it's meant to help.
A big part of increased life expectancies in the 20th century has nothing to do with medicine, it's all nutrition. But this has since tapped out and nutrition is now widely regarded as a joke science. I encounter way fewer people these days experimenting with diets - and actually that such experiments are called "fad diets" is a clue to the field's low repute.
Cast the field wider and the situation gets worse. What happened to Alzheimer's research? There seems little point to life extension research if you're just adding years of mental decline, yet recently it came out that the ß-amyloid hypothesis rested on a foundation of fraudulent papers published decades ago. How is it possible nobody noticed? For years we were told there was steady progress in Alzheimers, and when none of the drugs worked we were told it was a mystery why not.
But the biggest problem that's going to kill medical progress is mRNA. It's such a flexible technology that drugs research will come to rely on it heavily, as your example of melanoma makes clear. Yet biologists aren't honest about it. Even here, you give the conventional development narrative: many years of scientific struggle, a heroic female scientist, millions in VC investment, the near bankruptcy of Moderna due to mRNA (as a tech class) becoming toxic on repeat doses. But then you assert that they "got lucky", allowing the reader to infer that there was some scientific breakthrough that resolved the toxicity problem. No details are supplied, as always in this story, even though it should be the scientific climax.
The mRNA story is always told this way because in fact Moderna never did make a breakthrough. Instead, as STAT's coverage makes clear, after decades of research they admitted defeat. They just didn't know how to stop the body rejecting artificial mRNA lipids after they'd been seen more than once, and they'd run out of ideas too. Their fix was pivoting to vaccines, because - as everyone knows - vaccines are things you only take once <facepalm>. Moderna did get lucky, but not due to medical progress. They got lucky thanks to mass hysteria.
Give it a few more years and we're going to end up stuck in COVID nightmare land permanently, being told a narrative of progress in which brave and clever biologists have conquered every imaginable disease and the lack of any impact on the metrics is down solely to the benighted influence of awful right wing conspiracy theorists. Medicine, as a profession, is going to blame the sick. Just you wait and see.
I'd appreciate second opinions from people more knowledgeable in biology than me about this mRNA claim...
As with the research side of it, my sense is that we are investing increasingly large amounts of money in actual medical care, with diminishing returns. The average 70 or 80 year old person hasn’t gained much, in terms of life expectancy, but sure as heck are spending a lot more money on their medical care.
yes that's actually true. Our World in Data has an article about investment in healthcare vs outcomes and it's not great.
But with medical research I think it's a bit different because we never know what might happen ... like, maybe it takes us 200 years of investment to find something to delay ageing and I think it would have been worth it
Gl with Roots of Progress,did substack play any part in bringing like-minded ppl together
GI?
Good luck
Thanks! Oh yeah. Substack is great for thst
Is aging really one thing? I know, have known, a lot of old people and had a close connection to someone nursing very old people. It seems like what impairs and kills each person is their own personalised mix of chronic conditions. Presumably if each of these common chronic conditions was understood then a big part of aging might be demystified. Instead of “these drugs work in __% of people but we don’t know why”
Chronic conditions in the young are also the same process but “too soon” eg hypertension including gestational. If vascular and connective tissue, cell signalling, immunity, metabolism - if each individual area of malfunction were really drilled down into it would help a lot of young and middle aged people live better lives too.
Thinking of the studies where ADHD and later getting dementias are associated, or where cognitive performance in young nuns was predictive of later dementia. That’s among people with strictly mandated lifestyles - the same habits lol. There could be something going downhill in the brain from very early on.