Of Mice and Men…
Our mice are broken…
Eric Weinstein
Wellcome back again. This post will be a bit different because I’ll be posting an English version of it (hey, it’s here!), for a number of reasons. The most important one being the the implications of this post ought to reach as far as possible.
NOTE TO THE ENGLISH VERSION: As will surely be noticed by reading this post, English is not my native tongue but I’ve decided nonetheless to write a version of the original Spanish entry due to the capital nature of the topic. Please bear with my many imperfections in the use of the language.
How did this post come to be?
This post hatched after watching the conversation between both Weinstein brothers in Eric’s (the elder brother) Youtube Page. Here you can find a link to the video. A word of advice: this is a long format podcast in which long conversations over relevant topics are held. The idea behind the long format is being able to address difficult topics while honouring the spirit of freedom of speech and even allowing for error, what makes the format in my view even more compelling. In the first hour, the conversation basically is a “clever clogs” version for “big brother sets the field for a lesson for young brother, while handing him some hard lessons for life. During the second hour is mainly Bret doing the talking after falling for his brother’s trap. We see how the biologist is forced to relate what happened to a breakthrough he made some 20 years ago. It is not only the nature of said breakthrough but the circumstances around it. The finding was finally published here. If you want to listen to/watch the whole conversation, which I strongly suggest, cut momentarily with the reading and resume it once you’ve watched the video…
The Portal
The Portal is a Podcast by polymath Eric Weinstein, mathematician by career, Ashkenazi Jew (if I got it well from the comments) and proper incarnation of the concept “eclectic”, considering his range of knowledge and interests. The purpose of this Podcast is to deal with complex issues and stagnation points in human progress, so that we found “portals” that take us to a new age. Just the approaching itself serves as an “intellectual erection, more so when one listens to the host’s vast pool of knowledge and the interesting conversation with his no less interesting guests. The conversation with Sam Harris, for instance explores conjectures such as how to ease the way for learning abstract concepts for people somehow handicapped for symbolic reasoning. Highly recommended.
Conspiracy theory
I’m not a conspiracy theorist, but I do consider myself gifted with some critical mindset. I think that any person that reads this post and comes from a scientific background, specially a biomedical one, needs to go through a deep retrospective process about the safety of many drugs but also about the lost opportunities aborted due to an excess risk in tumorigenesis in murine models. We’ll come to that next.
The article
In their paper, Bret Weinstein and Deborah Ciszek elaborate a hypothesis that should have shaken the foundations of biomedical research at the beginning of the present century but that has fallen into oblivion for some reason. Ahead comes my disclaimer, as I’m no biologist and as is well mentioned by Bret Weinstein in the podcast “medical types” lack the minimum background with respect to the Evolutionary Theory, which in turn conditions many times a simplistic vision of a field that is governed by complex systems mechanisms, as is Human Biology.
At the beginning of the paper, the authors try to synthesise the two existing approaches used to explain senescence , by which our cells lose their juvenile vigour, become more damage-susceptible, that in turn become less fit to repair, all of which ensues a global scale modification in the organism that triggers what we usually call “old age”.
Side note: as a physician “ignorant” of the biological details, I simply loved the topological description/interpretation being done about the physiology of tissue repair. The authors mention that one of the aspects that keep tissue integrity is the individual cells keeping track of their spatial references. They know where their neighbours are and get repaired using the information about their environment. When too much damage is accrued, a sort of void ensues. This void can no longer be filled with native cells, and this sets the stage for the substitution of parenchimal tissue with non (differently) functioning tissue, such as glia or fibroblasts. Since my embryology courses back in 1998 I’ve never given so much consideration to the role of space in homeostasis, and it’s a shame.
The authors offer us a small reminder of what telomeres are, that is, the terminal structures in our chromosomes. They are non-codifying chromosome chunks that contain repetitive guanine-rich 6-part nucleotides. They get shorter by each cell division. Next, Weinstein and Ciscek explain the plausible relationship between telomeres and senescence, both according to the function of these structures and to what happens in diseases associated with premature tissue ageing, where short telomeres are found. It is noteworthy also, that in these diseases cancer is usually less frequent.
If short telomeres are linked to premature ageing, abnormally long telomeres should be linked to a greater risk for cancer, because if a purely random effects causality would be considered for neoplasm formation, the accrued risk of cancer should grow with the potential total number of cell divisions. This is not entirely accurate, as is shown in a review paper by Barret et al, but if adjusted by the specific tumours that are more common in childhood and the ones that usually happen in adulthood, an association can be found.
The authors define the concept of antagonistic pleiotropism based on the telomeric functions, citing authorities in Evolutionary Biology such as Williams. To better understand the concept, it would be useful to decompose its originating terms. I first learnt the meaning of pleiotropism from the definition of cytokines lectured by my first boss, Dr. Francisco Santolaria, great internist and another polymath. Of the he said that their actions were “redundant and pleiotropic”. Pleiotropism, he then said was the situation in which an agent can have diverse effects over diverse targets. We’ve got the first concept now. We could define antagonism as an agent opposing another one or the action that counters another one.
In Evolutionary Biology, antagonistic pleiotropism happens when a the selection fora character that bestows significant advantages in ones stage of life has a counterweight at the other end of life. For our case, telomeres grant the capacity for regeneration and damage recovery that improves the chances of the individual of reaching reproductive age. The cost can be, among others, a higher cancer incidence past juvenile stage. In environments where lethality is high (due to predators, parasites, infections, competitors), it pays off to have a better fitness for reaching the minimal reproductive age. The costs of the potential tumour are comparatively low, due to the low chance of survival until the clinical onset of the cancer. The authors do a much better job of explaining this, but I’m sure you are getting the idea…
The crux of the matter
The paper’s climax comes when the authors, having solidly planted the foundations of telomerical length’s biological implications point directly to the standard procedure of producing common mice mus musculus in the lab. It mainly consists of a highly controlled environment where infections, predators and competition for reproduction simply do not exist. Moreover, there is no prospect of experiencing senescence, since animals are «withdrawn» from line at age = 8 months. All of this has created a strong selective pressure in favour of ever greater telomeric lengths. Until the arrival of this paper, the scientific community agreed on the fact that «mice have abnormally long telomeres». It was an epiphany-like moment in Bret Weinstein’s life that took him to posit that maybe only lab mice had long telomeres. If you truly want to see how lowly and dirty the world of science can be, please do watch the video.
The fact is that, indeed, telomeres are only longer in mus musculus used as experimental animals and bred as I mentioned above. Wild individuals have «normal» telomeres, that is, shorter in an order of magnitude than those used for research. This hypothesis was confirmed in a different laboratory than Dr. Weinstein at the time. First revelation. What’s the implication? Abnormally long telomeres give the individual, as explained above, a remarkable resistance to damage, a greater capacity for tissue regeneration AT THE EXPENSE (antagonic pleiotropism), of greater susceptibility to develop cancer in mature stages of life. Stages that these individuals never reach, being «retired» at 8 months. It is well known that when laboratory mus musculus are examined in necropsies, the findings often reveal very juvenile organs in terms of histology, and a higher proportion of tumors.
Let’s repeat the question: What is the implication?
Side note: human drugs development process
To truly understand the scope of this research, we need to take into account what the process of developing a drug that ends up being used in humans looks like. This summary is brief out of necessity, and more entries on this point may come in the future, especially after I have fully digested the consequences of Weinstein’s paper. Here we go:
- Target search studies. This stage is relatively new, with Imatinib as a pioneer. Once a biomolecule or metabolic pathway and its effects are identified, computer studies (in silico) and in vitro assays are performed, enabling the next step.
- In vivo studies in experimental animals. This is where our rodent friends come in. The basic pharmacological characteristics of the molecule to be studied are explored in some studies, while in others (proof-of-concept studies) the drug is shown (or not) to have the effect(s) predicted in the previous phase.
- Clinical trials Phase 1 and Phase 2. From this point on, we move to experimentation in human beings. These human studies explore the pharmacological effects and tolerable doses of the substance to be studied.
- Clinical trial Phase 3. The study drug is tested against placebo or against the existing standard for the disease in question. In the first case, the drug is required to be more effective and less toxic than placebo, while the second requires «non inferiority», which is a slightly more complex concept, and may merit a critical diatribe of the current stagnation in the development of new drugs. Be as it may, the concept of «non-inferiority” means that the new product is comparable to the standard. These studies have limited monitoring time and close control of multiple variables that could influence the capacity for full observation of beneficial and adverse effects. The association strength found for either outcome is likely to be strong, since a large number of factors are very strictly controlled. Usually, drugs enter the market after a large enough number of patients have undergone a Phase 3 Trial.
- Phase 4 or post-commercialization trials. These are of a different nature but basically have to do with pharmacovigilance on the one hand, and taking advantage on the other. On the one hand, adverse events that have not been described in the previous phases are collected (in this entry we can get an idea of the reason). On the other hand, new effects, uses and indications for «old molecules» are sought, which in itself is not bad, as has been the case with antimalarials as immune system modulating drugs.
What then, are the implications of this paper?
The paper’s most striking consequence is, as the initial quote says, that «our mice are broken.» They may not be fulfilling their primary role, which is merely to assume a comparable model to humans to assess the safety of drugs, in terms (antagonistical pleiotropism) of their direct/accumulated toxicity on the one hand and their ability to induce the appearance of tumors on the other.
These mice are intrinsically resistant to degradation and tissue damage against physical, chemical and biological aggression, in exchange for an increased risk of cancer. The long-term toxic effects will never be observed in these animals, which in addition to being resistant to them, do not live long enough to «age with any chronic treatment». This causes the toxic effect of various drugs to be underestimated, especially in tissues of low regeneration capacity such as cardiovascular system, nervous system or joint tissue (rofecoxib, rosuvastatin, imatibib…).
Their high propensity for the appearance of tumors, on the other hand, makes it easier to overestimate the actual capacity of carcinogenesis that a potentially useful drug may have in the human species. Thus, hundreds of substances may have gone down the sink, that might otherwise be playing a useful role today.
Said in the language of formal logic: the conclusions we are drawing from our murine models for pharmacological development may well be based on the Law of Syllogism.
Second revelation, more general in order. Science is supposed to use models on which it makes inferences to approach reality. Such models should become all the more akin to reality as technological development increases. The detection of an error in the model should call on the scientific community to make an effort to disseminate that error and, more importantly, to amend it and produce a model that comes a little closer to reality. What is not welcome is that such a finding is communicated to the scientific community and rejected WITHOUT REVIEW in a reputable magazine (see/hear the video/podcast, really), as the authors mention with sublime elegance at the end of the article. The consequence is that we have been approving me toos for 20 years, or only discreetly relevant substances and passing up opportunities to progress in our pharmacological arsenal.
The million dollar question
Why has this paper been cited only for 16 subsequent works, according to Pubmed?
A call to action:
Do you write a Blog? Comment on this paper. Do you use social media? Comment, or link this Blog entry if you will. Speak to your friends, family, and why not, to your physician. Spread the word and let’s shake things up a little. Let’s fix our mice!