The first steps are (probably) to come up with an estimate of both material and labor costs for all 3 of the above options. The labor costs might be mostly nullified if you can find altruistic biologists, or biologists that are status-seeking and have sufficient confidence that the transposon hypothesis is true. Or if a motivated person who isn’t a biologist takes a crack at it.
The Transgenic Core guarantees that at least 300 fertilized mouse eggs will be microinjected with CRISPR/Cas9 reagents. Microinjected eggs will be transferred to pseudoopregnant female mice. Tail tip biopsies will be provided to the Investigator’s laboratory for genotyping. Mouse pups will be transferred to the investigator at weaning.
This is the service for C57BL/6 (C57 black 6) mice, the mice most commonly used as disease models, and the best-selling mice from mouse-breeding laboratories. For another $1,100, UMich will also “build CRISPR/Cas9 reagents to target a specific location in the mouse or rat genome”. So, for $7,000, one can get a founder population of transgenic mice, targeting any genome location the customer desires. Another transgenic mouse service from UMich, also for $5,800, guarantees at least 3 transgenic founder mice will be produced. ‘Founder’ implies that the actual experimental subjects will be the children of the transgenic mice you get, so you’d need to head down to PetStop and buy a few dozen hamster cages, some rodent chow, and a mouse-breeding manual.
Jackson Labs, the primary provider of experimental mice, sells C57BL/6 mice for $90 per mouse at 25 weeks old, and at $430 per mouse at 90 weeks old, with cost per mouse growing roughly linearly in between. At 25 weeks old, that’s $2,700 for 30 mice (enough for a pilot study’s control group).
There’s also the cost of shipping and handling live mice, which will vary depending on where the experiment is conducted. There are probably a bunch of auxiliary costs I haven’t considered yet as well. My main point is, as far as the Crispr route goes at least, I don’t anticipate material costs over $50,000, meaning an unofficial pilot study is probably quite doable by a small group of motivated individuals / one crazy person in a shed / crowdfunding.
In terms of experimental endpoints, would this mainly just be an experiment to see how long the mice live? If so, that does seem like a high-upside experiment which even someone with relatively little domain knowledge could just go do. The main investment would be time—it would take at least a couple years of mouse-care, and hopefully longer.
If the project were undertaken by someone with more domain expertise, the main value-add (relative to the bare-minimum version of the experiment) would probably be in checking more endpoints, especially as a debugging tool. For instance, since the CRISPR/CAS targets would presumably have very high copy number, it might be hard to get it to actually remove all the live transposons and not be saturated by dead copies which share a lot of the sequence. Checking that it actually worked would require sequencing, and special tools are needed to get accurate transposon counts from sequencing data. Also, it might require some nontrivial design to find CRISPR/CAS targets which actually work. Then there’s the possibility that CRISPR/CAS9 themselves trigger transposon derepression (they involve snipping then repairing DNA, after all), which probably wouldn’t be a game-breaker but could throw some general weirdness into things. There’s also the question of which transposons to target, since there’s a few major families and presumably a long tail of minor families...
Anyway, point is, there’s a lot of potential failure points which could be addressed with some effort and expertise. The bare-minimum version of the experiment would be huge if it worked, but if it failed, it would be hard to tell whether the theory was wrong or the experiment was flawed in some way. That said, the chance of success and the potential upside are high enough that it seems worthwhile even for the bare-minimum version.
I could imagine Constantin being interested in this—it’s not exactly the thing she set up LRI for, but it’s not a huge number of steps removed, and she’d probably at least have useful advice on how to make it happen and what to watch out for in terms of execution.
I’m also curious if anyone knows of existing groups already running this kind of experiment; I would not be surprised if it were already underway and we saw results published in another year or two (since the mice take a while to age). (More generally, do people have advice on searching for projects which have started but not published yet? I frequently stumble on them on the “projects” pages of the websites for particular labs, but I don’t know a good way to search for them.)
But new experiments are planned. For example, the team will purposely encourage expression of transposable elements to see if that undermines health and lifespan. Another approach could be to use the powerful CRISPR gene editing technique to specifically disable the ability of transposable elements to mobilize within the genome. If that intervention affected lifespan, it would be telling as well, Helfand said.
The wording is a little ambiguous as to whether the CRISPR approach is merely being contemplated, or whether they’re just floating the idea. Working with flies first makes sense, since it gives you a faster feedback loop on whether transposon elimination affects lifespan.
Stephen Helfand, the researcher quoted in the article, seems not to have published a new article since 2016, when the report I linked was published appears not to have updated his publication page since 2016, but you can find his later works on Google Scholar by searching his name (SL Helfand).
I’ve emailed him to ask whether this idea has been acted upon. I’ll post back here if I hear from him. In the meantime, I’m going to investigate the work of the followup project and the leaders associated with it.
It does look like this cluster of researchers is making progress.
Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues.
Lamivudine is also called 3TC, and it’s already approved for use against HIV. A clinical trial on its efficacy against Alzheimer’s is underway and scheduled to be complete in June 2022.
Wow, I had no idea that methylation was that impermanent, thank you for the belief update. I guess that leaves upregulation (via acetylation?) of transposon-suppressing RNA, extending lifespan by varying expression of other genes that alter chromatin structure to be more transposon-hostile, or as this comment says, using Crispr/CAS9 to incapacitate transposons. I wonder if anyone has done/will soon do an experiment like this in mammals.
The first steps are (probably) to come up with an estimate of both material and labor costs for all 3 of the above options. The labor costs might be mostly nullified if you can find altruistic biologists, or biologists that are status-seeking and have sufficient confidence that the transposon hypothesis is true. Or if a motivated person who isn’t a biologist takes a crack at it.
UMichigan offers a transgenic mouse service for $5,800. From the item description:
This is the service for C57BL/6 (C57 black 6) mice, the mice most commonly used as disease models, and the best-selling mice from mouse-breeding laboratories. For another $1,100, UMich will also “build CRISPR/Cas9 reagents to target a specific location in the mouse or rat genome”. So, for $7,000, one can get a founder population of transgenic mice, targeting any genome location the customer desires. Another transgenic mouse service from UMich, also for $5,800, guarantees at least 3 transgenic founder mice will be produced. ‘Founder’ implies that the actual experimental subjects will be the children of the transgenic mice you get, so you’d need to head down to PetStop and buy a few dozen hamster cages, some rodent chow, and a mouse-breeding manual.
Jackson Labs, the primary provider of experimental mice, sells C57BL/6 mice for $90 per mouse at 25 weeks old, and at $430 per mouse at 90 weeks old, with cost per mouse growing roughly linearly in between. At 25 weeks old, that’s $2,700 for 30 mice (enough for a pilot study’s control group).
There’s also the cost of shipping and handling live mice, which will vary depending on where the experiment is conducted. There are probably a bunch of auxiliary costs I haven’t considered yet as well. My main point is, as far as the Crispr route goes at least, I don’t anticipate material costs over $50,000, meaning an unofficial pilot study is probably quite doable by a small group of motivated individuals / one crazy person in a shed / crowdfunding.
In terms of experimental endpoints, would this mainly just be an experiment to see how long the mice live? If so, that does seem like a high-upside experiment which even someone with relatively little domain knowledge could just go do. The main investment would be time—it would take at least a couple years of mouse-care, and hopefully longer.
If the project were undertaken by someone with more domain expertise, the main value-add (relative to the bare-minimum version of the experiment) would probably be in checking more endpoints, especially as a debugging tool. For instance, since the CRISPR/CAS targets would presumably have very high copy number, it might be hard to get it to actually remove all the live transposons and not be saturated by dead copies which share a lot of the sequence. Checking that it actually worked would require sequencing, and special tools are needed to get accurate transposon counts from sequencing data. Also, it might require some nontrivial design to find CRISPR/CAS targets which actually work. Then there’s the possibility that CRISPR/CAS9 themselves trigger transposon derepression (they involve snipping then repairing DNA, after all), which probably wouldn’t be a game-breaker but could throw some general weirdness into things. There’s also the question of which transposons to target, since there’s a few major families and presumably a long tail of minor families...
Anyway, point is, there’s a lot of potential failure points which could be addressed with some effort and expertise. The bare-minimum version of the experiment would be huge if it worked, but if it failed, it would be hard to tell whether the theory was wrong or the experiment was flawed in some way. That said, the chance of success and the potential upside are high enough that it seems worthwhile even for the bare-minimum version.
I could imagine Constantin being interested in this—it’s not exactly the thing she set up LRI for, but it’s not a huge number of steps removed, and she’d probably at least have useful advice on how to make it happen and what to watch out for in terms of execution.
I’m also curious if anyone knows of existing groups already running this kind of experiment; I would not be surprised if it were already underway and we saw results published in another year or two (since the mice take a while to age). (More generally, do people have advice on searching for projects which have started but not published yet? I frequently stumble on them on the “projects” pages of the websites for particular labs, but I don’t know a good way to search for them.)
It does sound like this research is already planned or underway.
The wording is a little ambiguous as to whether the CRISPR approach is merely being contemplated, or whether they’re just floating the idea. Working with flies first makes sense, since it gives you a faster feedback loop on whether transposon elimination affects lifespan.
Stephen Helfand,
the researcher quoted in the article, seems not to have published a new article since 2016, when the report I linked was publishedappears not to have updated his publication page since 2016, but you can find his later works on Google Scholar by searching his name (SL Helfand).I’ve emailed him to ask whether this idea has been acted upon. I’ll post back here if I hear from him. In the meantime, I’m going to investigate the work of the followup project and the leaders associated with it.
It does look like this cluster of researchers is making progress.
Lamivudine is also called 3TC, and it’s already approved for use against HIV. A clinical trial on its efficacy against Alzheimer’s is underway and scheduled to be complete in June 2022.
Bingo, thanks.
Have you thought of https://www.vium.com/ to reduce labor costs?