Lab Mice Telomeres Do Not Break Them as Disease Models

Bret Weinstein was interviewed on the Joe Rogan show and Bret claimed that the breeding protocols and telomeres of lab mice are broken. Bret claims that this problem is so severe that it calls into question the safety and correctness of decades of pharmaceutical studies.

Bret wrote a paper on that in 2002 which is totally broken.

Aubrey reviewed the paper.

The statements labeled (1) through (4) of the abstract are fine, and so is the first sentence of statement (5). However the rest of statement (5) is totally backwards: it would predict that humans have longer telomeres than mice, for example. (It’s true that wild mice have shorter telomeres than lab mice, but they are no shorter than human telomeres.)

There are three fundamental errors:

1. Their first mistake is forgetting that cancer is one aspect of senescence, so the level of selection against senescence acts in the same direction against both cancer suppression and tissue regeneration. Basically, if there is lots of extrinsic mortality then there is weak selection BOTH against cancer AND against other aspects of senescence; the antagonistic pleiotropy is between them on the one side and the selection for rapid growth and reproduction on the other since that latter is stronger for such species. (Note that fast growth is not synonymous with good regenerative capacity.)

2. The second mistake they make is forgetting that the telomere length thing is not a spectrum, it’s binary: either telomeres are kept as short as they can be in a given cell type and still function as telomeres at all, i.e. prevent the double-strand break machinery from joining chromosomes together end-to-end, or they are not kept short at all (i.e. telomerase is expressed promiscuously). The reason this is binary is that body size determines how many cell divisions cancer needs to undergo before it is fatal, and small animals can be killed by cancers that are so small that they didn’t need to turn on telomerase to get there, hence “telomerase thrift” doesn’t work as an anti-cancer defense.

3. The third mistake they make is assuming that being bred in captivity exerts strong selection against reproductive senescence. It does not because facilities like Jackson Labs don’t keep all their mice until then – they sacrifice mice once they’ve had enough offspring. So there is an abundant selection for rapid growth to reach sexual maturity, but that actually HASTENS reproductive senescence, same as it hastens the rest of senescence.

If the Weinstein hypothesis were correct, we would see long telomeres in decades-old strains of rat too, which we do not. The whole thesis is built on a failure to take into account the sophistication of the ways in which cells can use telomerase to stay in the sweet spot between cancer and lack of regeneration.

Nextbigfuture would point out that mice studies are only the start of drug validation. There can be dog and primate clinical trials. Human clinical trials are performed in three phases. Drugs safety is tracked while they are being used.

There are many limitations to lab mice for disease study.

Highlights of Bret Weinstein interview with Joe Rogan on the Segment on Lab Mice

This is only a summary of the transcript. There are many phrases missing or sentences that were paraphrased.

00:02 [Bret was a graduate student studying bats in I was interested in evolutionary trade-offs] [George Williams a great evolutionary biologist noted the evolution of senescence. From our genome a tiny fraction of genes help when you are young and hurt you when you are older]
01:37 this was called the antagonistic pleiotropy theory of senescence

02:24 we knew that this hypothesis was right but what we had never found sample genes

02:44 [Bret calls this the missing pleiotropy]

04:25 [Bret believes telomeresare the missing pleiotropy]. Bret believes telomeres prevents cancer when you are young but makes you age when you are older

05:48 lab mice have extremely long telomeres but are short-lived. Only US lab mice. Europe mice have different lengths based on supplier

07:05 [Bret talked to Carol Greider who’s now won a Nobel Prize]
07:42 [her graduate student Mike Heymann worked with Bret]
07:54 [Wilder mice had short telomeres than lab mice]

08:18 the mice that are being used to study physiology are broken and we are blinding ourselves. these mice who have been altered and we should not use them as models

08:51 animals in drug safety testing

09:33 is it going to shorten your 80 or 90-year life by 10 or 20 years that it will shorten a mouse’s life long enough to
09:47 environment by favoring the radical elongation of its telomeres then it has the ability to replace its tissues indefinitely a toxin that will harm you by killing tissue may not harm that Mouse

10:01 in fact it may actually help it because these mice are very cancer-prone so when we give a toxin that will damage you to a mouse that is highly resistant to tissue damage you may slow down it tumors and in fact we’ve seen this a
10:21 result of not toxic (when it might be toxic) it actually makes the mice live a little longer

11:06 the world of scientists working on the question was unwilling to respond to the discovery that their model organism had this fatal flaw that was going to predispose us to see certain things and not other things in the laboratory
11:24 environment the governmental commission that was charged with studying the Vioxx scandal which I believe was likely the result of something like this in its 300-page report doesn’t mention mice it

11:38 [Vioxx scandal :a drug for arthritis that gave people strokes]

13:25 [Bret claimed : researchers screwed up on using flawed lab mice. They blew off Bret’s warnings]

14:42 [Bret claims – there is a problem with many drug tests and many research papers]

14:59 been taken care of or even more curious is the argument well everybody knows that the mice are bad models which is insane because this telomere actually
graduate student was an instance which frankly woke me up to the fact that my colleagues even when human life was at on the line we’re going to pretend they didn’t know what was going on it’s quite

16:07 put out my hypothesis and Carol Greider who later pretended she didn’t know what I was talking about published the empirical work that revealed that indeed lab mice are unusual in having long telomeres after that work was out

16:21 there’s no excuse for not investigating what the consequences were I cannot
16:30 culture of science has become so rotten that this sort of thing is maybe standard operating procedure just protecting their ass and protecting the ass of those who give them jobs and … medicine chest not safe.

Summary

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