I do not think that is true, at least in Europe where hundreds of millions of people use generic drugs every day. In Germany, in the UK and in Austria a doctor will amost always prescribe a generic when available and people will often buy a generic over the counter. While sometimes too conservative, the very reason why we need the FDA, the EMA, et al. is exactly to make sure that generics* work well—and they almost always do, one cannot use rare counter examples to disprove that. Do we have any hard data to suggest that generics are somehow unsafe?
* i.e. not some Indian blackmarket knock-off that isn’t FDA/EMA approved
Kamil Pabis
Karma: 52
With such highly subjective soft outcomes a lot depends on the way the question is phrased and interpreted (if self-reporting). Thus comparing different populations and studies is almost impossible without really carefully digging into the original publications and even then it is fraught with problems.
If I have a rash post-vaccine and I go to see my GP or pharamcist, am I seeking medical help and is this worrisome? If I get up and later realize that I need to lie down or else I will faint (vasovagal syncope, around one in ten people have some form of needle phobia), am I seeking medical help for a side-effect? Technically yes, but a saline injection would cause the same. If I have asthma or hayfever, issues with breathing, and later misattribute this to the vaccine, is this a side-effect? (around 1 in 10 people or so have asthma)
Finally, you cannot compare the serious side-effects in a trial (if this CDC figure really comes from a trial) with mild self-reported side-effects from Israel or American postmarketing surveillance. Trial participants will be monitored closely and will include a large number of at risk indiviudals (>60yo) so it is again a statistical artifact of data collection.
IMHO all the data is worthless without a very well-matched control group.
The sad fact is that we do not even understand mice very well. There is this old joke that can be paraphrased like this: if I were a mouse I could be cancer free and live forever, because it is so easy to cure these guys of diseases. As it turns out, however, this is not true. Within my field it was long gospel that caloric restriction (discovered some 100 years ago) can robustly extend mouse lifespan until studies in the last 20 years called this into question.
What the joke gets right is that we understand humans even less than mice. In fact, despite the controversies several interventions are relatively robust in mice when it comes to extending their life and health span (rapamycin, caloric restriction, growth hormone loss) while the evidence in humans is much weaker for these.
Delivering useful drugs, hopefully faster not slower than in the past, despite these issues will be an interesting challenge.
I guess this goes back to the issue of defining things and what you mean by hallmarks. If you define your hallmarks broadly enough they may include almost anything while being so vague that they are only useful for posters and ads. In the case of vague hallmarks you’d be right, if you fix them you’re all good. But even in this extreme case I do expect the number of vague hallmarks to grow a little bit over time as we learn more. In fact, to me they feel incomplete and ill-defined already.
Looking at the classic “The Hallmarks of Aging” paper (first published as López-Otín et al. 2013 I think) or Aubrey’s seven causes of aging I do feel like they are way too vague. Let’s take genomic instability as an example. Fix it and you make progress against aging. However, that is just an empty phrase like “repair the engine of the car”; that’s usually the reason why it stops in the middle of the highway. Which genome, mitochondria, nuclear? Which pathway do you target? Hundreds of genes involved in repair, hundreds of genes involved in prevention of DNA damage via the intricate ROS- and stress-sensing pathways. Which type of lesion to prevent? Damaged bases or strand breaks? Which type of existing damage to repair and remedy post facto? Actual mutations (not just temporary damage), small indels, aneuploidies, large deletions, inversions, translocations or more complex chromosomal rearrangements and clonally expanded cell populations? Don’t forget to fix chromatin organisation and epigenetic marks and all the inter-related extra-nuclear factors that promote genomic instability (could be inflammation, could be reduced autophagy, let’s speculate). Want to use nanobots instead? Be my guest, then you are solving advanced physics, engineering and AI problems.
Regarding incompleteness and definitions: Why did they choose to define telomere attrition as its own hallmark? First of all, this is an incredibily specific problem and secondly telomeres are part of the nuclear genome, i.e. they fit entirely within the scope of genomic instability. On the other hand, extracellular matrix aging is not part of The Hallmarks even though it has been suggested to be a life-limiting pathology since the early 20th century with good supporting evidence (think vascular aging).
As you can see these Hallmarks are a political, strategic and scientific compromise. (One can guess telomeres are on there because of the Nobel prize, public perception that they matter or some telomere researcher on the paper.)
However, I do see the appeal of these words, hallmarks, causes, even if their use in practise is limited.
My reply comes a bit late since I managed to write a long comment without clicking send and only noticed this now. I will address the errors I see in the TL;DR summary from the POV of a semi-professional biogerontologist:
The disease-based approach to aging this seems to favour is useful, but limited. In fact, if you genuinely want to extend both lifespan and healthspan this excessive focus on the disease-based approach would be inefficient because is inconsistent with everything we know about aging. I would go as far as to say that the disease-based approach may be actively harmful because it takes away resources from genuine aging research.
While aging probably has thousands of causes, or even more*, this does not preclude the existence of major causes that limit lifespan in the near term. This idea has been popularized by Aubrey de Grey a long time ago and now has reached the scientific mainstream with an emerging consensus about the Hallmarks of Aging (several key pathways and sequelae of aging). We also know that this view is decently well supported in mice and have known so since the late 1990s when Holly Brown-Borg and Andrzej Bartke introduced the Ames dwarf mouse to gerontology. If aging was strictly multifactorial and polygenetic there would be no hope to identify single genes that lead to pronounced lifespan extension, as they did with the long-lived Ames mouse, which is long-lived because of an underdeveloped pituitary and reduced growth hormone levels. This means one simple change to a single pathway can extend lifespan.
Of course, I am biased, since as a biogerontologist I think the biggest gains are to be had from targeting aging directly, although we can have a discussion how well the mouse data translates to humans. (Not well, IMHO, but it is the best we have.)
Sizable lifespan extension we have seen in mice has come, without exception, from interventions that target aging directly through the above discussed “hallmarks”. Just to give three famous examples of life extending treatments: We have Rapamycin, an inhibitor of the mTOR pathway, that became a plausible candidate after this pathway had been implicated in the aging of yeast. Then we have caloric restriction, which was discovered by accident and not by the disease-based approach, but is now known to target a global pathway that promotes tissue maintenance under nutrient stress. Finally, we also have senolytics, drugs that were developed to kill senescent cells, that had been linked with aging after decades of biogerontologic research.
In contrast, drugs like Aspirin, Simvastatin, Enalapril and many others were tested in mice with no clear biogerontologic rationale behind them and predictably failed to extend lifespan, even though they are obviously amazing from a disease-prevention point of view.
However, I do agree that biogerontology depends on the existence of a strong biomedical ecosystem. Rapamycin was initially discovered as an immunosuppressant and if not for that, it would have taken longer to find inhibitors of the mTOR pathway (but eventually it would have happened by standard medicinal chemistry). Working in the 1930s Clive McKay, the discoverer of caloric restriction, was perhaps more interested in the basic biology of starvation and malnutrition than finding treatments for aging, etc.
Nothing about age-related multimorbidity makes sense if it not viewed through the lens of biogerontology.
Notes
* for example, you may be able to get 10-30% of lifespan extension by targeting the top 10 causes of aging, then eventually as you want to extend lifespan more and more, other causes of aging would take the spotlight
Actually, they all do include it, but is is subsumed under stem cell aging, loss of cells and reduced regenerative capacity. Also to clarify what I would consider a misunderstanding. Not everything has to fit. There are probably infintely many causes of aging or at least quite a lot. Most of these fall into the rough categories or “hallmarks” we have come up with like reduced stem cell functioning or damage to biomolecules. Many of these causes are not relevant to immediate life extension which is why they can be ignored for now. Other categories or “hallmarks” will be discovered as we go along.
Having said that, dysfunction of the neurmuscular junction is probably the most important type of muscle aging, much more so than cell loss, and, being so complex, I do not think the hallmarks do it much justice. Many of the hallmarks are so vague as to be almost useless anyway.
Does not make that much intuitive sense to me because there are a lot of random mutations happening. If the first dose first (or first dose only) strategy reduces the size of the whole SARS-CoV-2 viriome, there will be fewer viruses and less genetic variation in total. More infections in total means more genetic diversity. More infections means that a vaccinated person will be exposed to more sources of infection, more virions, more different genomes over time, thus also increasing the likelihood of mutants able to escape the immunologic response.
Trying to organize my thoughts on progress a bit:
I do not think we lack a “philosophy of progress” as much as the OP. I would like to argue that progress is real and that there is decent literature on this topic that not enough people read. Moreover, the topic of progress is a good recruitment tool for EA and rationalism. I find it more exciting and powerful than the bleak nihilism offered by atheism, meek criticism of pseudoscience offered by “the skeptics” movements and the vague (but obviously not misguided) appeals to the noble human nature proffered by humanism.
The distinction between descriptive and prescriptive optimism raised in this thread is a very interesting one. Are these entirely distinct concepts, though? It would stand to reason that there is a virtuous circle where descriptive evidence of tangible progress promotes optimism and a desire to further improve the world – because it seems possible. Therefore, it would be great if the world were improving. If it isn’t, we shouldn’t lie about it, but still it better be improving given the industrial revolution and the internet and all the things we invented. If this has not improved the world, what else will? AI? Anarcho-primitivism and yoga?
Improvement and progress come in many forms and shapes. Progress will never be an entirely objective measure, but it also is not purely subjective. Human desires are hard coded in our DNA, as most animals we seek safety, health, freedom, stability, psychological fulfillment (think Maslow) etc. As also pointed out in this thread, Stephen Pinker has written several books about progress. He is perhaps the 20th century’s most prominent chronicler of progress. By and large, his books have made a good case that the world is improving and all the attacks on their contents I have seen were feeble at best. Homicides, press freedoms, democracy, armed conflict. No one can claim these aren’t markers of progress, nor that they haven’t improved markedly. Not yet mentioned, I do think the Oxford team around Our World In Data is continuing in a Pinkerian vein, but doing so live, around the clock.
Case in point, their current entry on Human Rights is a masterpiece of public education (1). Not only is it well presented, but it is also up to date referencing the work of Fariss (2019). This paper importantly argues that the democratic recession is an artifact of stricter human rights standards over time. Whether this is true or not is not even relevant. Temporary stagnation is entirely compatible with long term progress.
People tend to get way too caught up in one dimensional measures of progress. To some it is only ecology, so the world is dying. To some it is only press freedoms, so China is an evil empire, and the democratic recession is perhaps the biggest problem we face. Humans in practice, however, do not have such one-dimensional desires. And I mention China on purpose, because no discussion of progress in the 20th century would be complete without this country. Here, I highly recommend reading Joe Studwell. Briefly put, China exemplifies how and why the world is improving; also given its size recent shifts in China are major drivers of aggregate improvement in human welfare. (I am sorry to all the China haters). Roughly speaking, since reform and opening by Deng Xiaoping and his political allies, the country has lifted hundreds of millions out of poverty. Civil liberties have not deteriorated since this major reform (again please read reference 1). There is ongoing concern that they may be deteriorating; and one would have hoped for more progress, but no one can claim it isn’t a net improvement.
If we want to instill optimism, a “philosophy of progress”, Pinker and Our World in Data must become mandatory reading in high school and university. Please, share other similar books and sources if you know them. Already mentioned was Joe Studwell. I can also think of Yuval Harari’s Sapiens which is obviously Pinkerian but more accessible and shallow than “Better Angels of Our Nature”. Francis Fukuyama’s “The End of History” was already mentioned and I hope to read it some day. Could someone comment if the books is just popular with libertarians or if it really does have a libertarian slant? (I have mixed feelings about libertarian support for progress. Personally, I do feel like hybrid models have been exceedingly successful in the 20th century if you look at Scandinavia, Germany’s “Soziale Marktwirtschaft” or Asia.)
If you ask me, reasonable controversy does not exist on the topic whether the world has improved or not. Cautious optimism is objectively warranted. On the other hand, there are important issues that are still contested. Does it continue to improve? Who was left behind? Is the democratic recession real? How much progress happened at the cost of environmental damage? Why is inequality still increasing? How much was due to chance and will we fall back? What is the importance of existential risks? It very well may be the case that existential risks have increased while the world became better and safer in aggregate on the “classical” measures. All these are important debates.
1/ https://ourworldindata.org/human-rights
Yes, Human Rights Practices Are Improving Over Time. Farris (2019).