Underrated aspects of the “genetic singularity”
We now know that human traits are largely:
- additively composed of thousands of non-pleiotropic genomic variants,
- largely independent without noticeable tradeoffs between different traits at the margin, and
- increasingly predictable from genetic data as models improve and biobanks get larger.
For simplicity I will define the “genetic singularity” as the point when people become freely able to explore the high-dimensional space of human genetic variation without restriction, easily selecting or editing embryos with +5 standard deviation boosts to tens or hundreds of desirable traits. In my view, this is inevitable and is perhaps 1-2 decades out.
Why are clinical trials so expensive? Tales from the beast’s belly
Today I read, with great interest, a recently published STAT News feature by Matt Herper, Here’s why we’re not prepared for the next wave of biotech innovation. The basic thesis of this article is as follows: In the last decade, we have seen dramatic advances in molecular biology, which have enabled the development of a vast array of novel drug modalities and the successful treatment of previously undruggable diseases. The article mentions CAR-T, CRISPR-Cas9, COVID-19 vaccines, and drugs for cystic fibrosis; I myself also think of PCSK9 inhibitors, semaglutide, bispecific antibodies, and many others. However, the infrastructural requirements of modern clinical trials are now so high, at times reaching hundreds of thousands of dollars per patient, that they are limiting our ability to fully capitalize upon these technological developments.
Herper makes a very strong case for this argument, which I will not reiterate here. Instead, I will share some anecdotes about clinical trial development from my time working in biotech. Typically, one reads about corporate inefficiency in a very abstract manner. Specters of “regulation” or “middle management” and so on are invoked, but seldom do the details of particular scenarios emerge. I suspect this is in part because almost anyone who has a complete, birds-eye view of the whole scenario has already devoted so much of their life to their industry of choice that they have become willfully blind to its flaws. Unusually, I was a machine learning engineer who had the opportunity to watch our Phase I and II trials unfold from a good vantage point, and I hope the stories I share will be informative. Overall, they paint a picture of an industry which is severely lacking in human capital and fully captured by bureaucratic tendencies.
Limited evidence for neurotoxic effects of popper usage
“Poppers,” or inhaled alkyl nitrites, constitute a class of quasi-legal recreational drugs used to enhance sexual experience primarily through their vasodilatory effects. Thus far, the risks of alkyl nitrite inhalation remain poorly understood among the population of recreational users. Two concerns about potential neurotoxicity are often raised: first, comparison to other classes of inhaled organic solvents, and second, reference to a murine study by Cha et al. in 2016. These concerns do not appear to be well-founded. However, isopropyl nitrites specifically, rather than isobutyl or amyl nitrites, are known to cause adverse ophthalmic reactions and may pose a general neurotoxic risk. If isopropyl nitrites are avoided and recreational use is sufficiently limited, overall neurotoxic risk appears low.
A practical, low-cost supplementation regime of vitamins C, B2, and E before recreational use of alkyl nitrates as partial prophylaxis against adverse effects
“Poppers,” or inhaled alkyl nitrites, are commonly used recreationally to enhance sexual experience. Usage of inhaled nitrites is associated with both acute and chronic toxicity, but understanding of practical risk management strategies remains poor.1 Here, we examine one of the primary adverse effects of inhaled nitrites, methemoglobinemia. Drawing from an extensive assortment of published data, we propose that recreational users of poppers take oral antioxidant supplements (3 g vitamin C, 400 mg vitamin B2, and 800 mg vitamin E) two hours before anticipated usage. This supplementation regime has the potential to modestly ameliorate short-term methemoglobinemia associated with inhalation of alkyl nitrites.