Big Ball of Mud, an essay on why software systems end up being ones, and why that's to be expected given real world constraints. (h/ Andy Matuschak)

Very high-molecular weight hyaluronan in naked mole rats is thought of as one of the keys to them being almost immune to cancer. New study tests if cultivating mouse and human cells with that added substance has protective effects (Against senescence) and it does, even when it suppresses gene p53 which is a tumor suppressor.

How doctors broke the US healthcare system (ht/ Scott Alexander). Which is similar to how lawyers broke the US legal system.

New DARPA-like organization launched for the life sciences, Wellcome Leap.

Daniel Lakens and others launch a red team challenge: They will be paying five individuals to find flaws in a forthcoming paper. One more addition to the growing trend of paying for finding mistakes.

Magic Leap reinterpreted as a Theranos

Politecnico di Torino switched to fund all their researches for the same amount for three years. This sounds like, as per the Azoulay HHMI/NIH paper, it should lead to improved outcomes. But no, at least so far. They discuss pros and cons of both approaches. This is despite PoliTO's facaulty having become younger in that period. The sample here is different to Azoulay's: We have another country, another field (Engineering rather than life sciences), an entire university (Rather than elite researchers). Money is more in HHMI's case too: HHMI (43$k) vs PoliTO's (14k€).

Talking about the Azoulay paper, here's another paper pointing in the same direction.

Just because there is a meta-analysis, even when corrected for publication bias, doesn't mean the results are anywhere near correct.

Matthew McAteer on tech debt in ML

The Great Remotening, a thread

PLoS journals are implementing an "anti-scooping" policy

DARPA has been funding teams to replicate studies that come out of projects they fund (ht/ Gwern)

Stripe has started to buy negative CO2 emissions, and they have also made public the framework and materials used to assess the proposals.

Rodney Brooks on peer review

Peer review grew up in a world where there were many fewer people engaging in science than today. Typically an editor would know everyone in the world who had contributed to the field in the past, and would have enough time to understand the ideas of each new entrant to the field as they started to submit papers. It relied on personal connections and deep and thoughtful understanding.

That has changed just due to the scale of the scientific endeavor today, and is no longer possible in that form.

There is a clamor for double blind anonymous review, in the belief that that produces a level playing field. While in some sense that is true, it also reduces the capacity for the nurturing of new ideas. Clamorers need to be careful what they wish for–metaphorically it reduces them to competing in a speed trial, rather than being appreciated for virtuosity. What they get in return for zeroing the risk of being rejected on the basis of their past history or which institution they are from is that they are condemned to forever aiming their papers at the middle of a field of mediocrity, with little chance for achieving greatness.

Age reduction breakthrough claimed by doing parabiosis (Using a proprietary treatment derived from bloom plasma) in mice. A thread and a less optimistic thread. The main author of the paper, Harold Katcher believes -pace what is now consensus in aging- that aging is programmed and coordinated through molecules present in the blood, which drove him to do that particular study.

Steve Horvath, of epigenetic clocks fame and also one of the authors has a recent papers where he reviews the concept of epigenetic aging. The paper is quite interesting, some snippets like this one or:

When a comparison is made between methylation values of DNA of those below 35 and those above 55 years of age. The multi-tissue age predictor shows this difference to be on average, 0.032, which translates to 3.2% of the cell population. 1 This suggests that increase in epigenetic age is contributed by changes of methylation profiles in a very small percent of cells in a population.


The above association between clock CpGs, PRC targets,and development provides a smooth lead into the fifth fea-ture of the epigenetic clock, which is its applicability toprenatal biological samples and embryonic stem cells.The multi-tissue epigenetic clock is able to recognize andcorrectly predict ages of fetal tissues 38 and that of embry-onic stem cells (negative age, approximately 0.5 years). 1This is profound as it demonstrates that the epigenetic clock, which captures at least some degree of biologicalageing, begins ticking very early on before birth. The implications of this are two-fold. The first is that biological pro-cesses that constitute the ticking of the epigenetic clock,whatever they may be, are already in motion very soonafter conception. The second is that since the processes associated with ageing already begin before birth, it introduces the notion that the ageing process is an integral part of, and the consequence of the development of life.


while telomere attrition and senescent cells are undoubtedly important features of ageing, they do not constitute the epigenetic clock. Consolidating this conclusion is the multiple independent demonstrations that DNA methylation changes that accompany cellular senescence are distinct from those of epigenetic ageing


As listed above, many different human primary cells undergo epigenetic ageing in culture. This feature, however, does not extend to embryonic stem cells. Extensive passaging of stem cells up to even a hundred times is not accompanied by increase in epigenetic age.


An intuitive assumption of ageing is that it is not an intrinsic property of life, but an extrinsically induced feature, which is encapsulated in the term “wear and tear”. The fact that epigenetic ageing clock starts ticking very soon after the embryonic stem cell stage, prompts a re-assessment of this perspective. The evidence suggest that processes related to ageing are already afoot at the start of life. The involvement of DNA methylation changes to specific CpGs indicates that this is a very precise process that is inconsistent with entropy or randomness, which is the nature of damage. It is important to consider, however, that these changes are meant to develop the organism. Hence, the ageing process is a continuum which begins after the embryonic stem cells state through to death. Therefore, the essence of ageing might well lie in understanding why developmental processes inadvertently contribute to ageing of the organism. It is important to note that although wear and tear or damage-related events appear not to be the “prime-mover” of epigenetic ageing, they do nevertheless affect the rate of epigenetic ageing.


were stem cells to be isolated from tissues (free of transit- amplifying cells and fully differentiated cells) and analyzed, their DNA methylation profiles would indicate much younger epigenetic age than the tissue. This was indeed observed in a recent report showing that muscle stem cells isolated from mice were epigenetically much younger independently of the ages of the tissue/animal from which they were derived. 66 Likewise, small intestine and colon crypts, in which stem cells reside have younger epigenetic age than the upper portion of the tissue which are devoid of stem cells. 57 Although these do not by themselves constitute proof, it is nevertheless consistent with the notion that ticking of the epigenetic clock is constituted by methylation changes that accompany the differentiation of stem cells into non-stem cells


While the indications are strong that stem cell differentiation in the context of tissue development and homeostasis underlie epigenetic ageing, direct empirical evidence is still scarce. We would like to highlight a potential weakness of this hypothesis, which is that it does not address the fact that the number of hematopoietic stem cells increases with age, albeit with vastly reduced function, 72–75 while those of other tissues, such as muscle stem cells appear to decrease with age. 76–79 Whether this discrepancy is of significance is presently unclear. Hence, the above-mentioned involvement of a yet-to-be-identified cell type as being responsible for epigenetic ageing instead, must for now remain a viable alternative hypothesis.

Neuromatch, an algorithm to match scientists that should talk to each other

Taxes and innovation

An old review of various DARPA projects

Does the brain does something like backprop? Konrad Kording think so

Last Links I reported that a computer in Canada had been hacked to mine crypto. Seems it's not an isolated case.

Is it hard to incentivise more innovation in pharma just with money?

There are techniques that allow researchers to measure what RNAs are in a cell or tissue, and there are techniques to identify where they are. Doing both (Spatial transcriptomics) with high resolution is a hard problem. A recent paper combines expansion microscopy (Make the sample bigger) with in situ sequencing to achieve both goals.

Sam Bowman on competition policy in the US. Contra the common take that more enforcement is needed, Sam's view is that while there can be improvements, the common take is not justified from a consumer welfare standard.

Some evidence against the "F-35 is a super expensive failure" view

Solar is getting cheaper even faster than what optimist Ramez Naam predicted

Dr Paula Rowińska asks "What didn't I study!" Here's a thread on subjects I studied at university, in case you were curious.

Science is broken, a thread inspired by a diagram I made and tweeted.

Take two neurons out from a worm and you get 61% more median lifespan. Interesting discussion in the thread too about the role of E. Coli in experiments with C. Elegans; they are not just food for the worms and what they do (Here, scavenge hydrogen peroxide) can bias the results of the experiment.

The US army claims that in ~10 years we'll have quantum computers that work at room temperature.

What happens when scientists get scooped? Apparently scientists are more pessimistic than what the data suggests they ought to be.

A huge giant poster with all the ways to do single cell sequencing

Why are clinical trials so hard? A post by Derek Lowe and thread from Sarah Constantin

Alexey Guzey deprives himself of sleep, nothing bad happens other than feeling sleepy.

Why is blood made in our bones?

The Curse of the Golden Flower. A surrealist at times and incredibly colourful epic drama that first caught my attention for being in the Gambit Pileup page in Tvtropes