Telomeres and Cloning
Is Bret Weinstein’s finding predictive of gaps in cloning science?
While browsing Reddit, this post appeared on my feed. It asked, “Why do clones die so quickly?” In the text of that post, the author reflected on how Dolly, a famously cloned sheep, died early. A top comment noted:
Dolly the sheep didn’t die from cloning related complications, and she lived a long enough life to give birth to 6 lambs. Ultimately she died of lung cancer caused by Jaagsiekte sheep retrovirus (JSRV), a virus that was infecting the rest of her herd. She was euthanized due to the tumors in order to prevent her from suffering.
Her death due to exterior circumstances did not put out a question in my mind, one that spawns from Bret Weinstein’s (former professor at Evergreen State College and current host of The Dark Horse Podcast) anecdote dated in the 90s. In summary, he supposed that selective pressures on laboratory mice, given their artificial breeding environment, would cause them to have elongated telomeres on their DNA. He shared his hypothesis with Nobel laureate Carol Greider, asking her to perform a study that compared the telomeres of laboratory specimens with those from the wild, since he lacked the resources to do. Greider performed the study and found that mice with longer ancestries from laboratories did, in fact, have elongated telomeres when compared to ones more recently derived from the wilderness.
The story ends with Greider refusing to give minimal credit to Weinstein for his share of the study and for suppressing the conclusion that laboratory mice may have been unintentionally sabotaged by scientists who need them to test drugs and other chemicals, since elongated telomeres would give them greater capacity for cell repair against these tests. Because of this, I wondered if the elongation of telomeres in laboratory mice might be overlooked in science on cloning.
I started by looking at the Wikipedia article on cloning. Sure enough, there is a section on Dolly. In that section, an excerpt leapt out at me:
There were early claims that Dolly the sheep had pathologies resembling accelerated aging. Scientists speculated that Dolly’s death in 2003 was related to the shortening of telomeres, DNA-protein complexes that protect the end of linear chromosomes. However, other researchers, including Ian Wilmut who led the team that successfully cloned Dolly, argue that Dolly’s early death due to respiratory infection was unrelated to problems with the cloning process. This idea that the nuclei have not irreversibly aged was shown in 2013 to be true for mice.
The bold part is the where the bells started ringing. Thankfully, the study is cited, and I quickly followed it. I read through it and came upon the section that discusses telomeres. It offered the following text and figures:
Telomeres are vital for maintaining chromosomal integrity and genomic stability in normal cells in vivo, and they shorten with each cell division. In normal reproduction, the telomeres are repaired by telomerase in the germline, but cloned animals develop from somatic cells directly and, therefore, miss this step. Telomere lengths have been examined in cloned animals of several species (Konishi et al., 2011; Lanza et al., 2000; Miyashita et al., 2011; Shiels et al., 1999; Wakayama et al., 2000), and most reports have concluded that the telomeres of cloned animals are repaired during genomic reprogramming. In this study, we examined telomere lengths in the recloned mice at 3 months of age and compared them with those of age-matched control mice. We also collected samples from earlier generations of recloned mice still living at the same time, which were older at the time of collection. As shown in Figure 2A, these experiments revealed that there was no evident shortening of telomeres in the recloned mice of any generation or at any age.
The study revealed that there was no “evident” shortening of telomeres. In that same excerpt, there are citations to analyses of telomeres of other cloned species.
The Konishi study observed:
These results suggest that the lifetime productivity of SCNT cows was favorable, and their survival time was more strongly influenced by environmental burdens, such as pregnancy, delivery, lactation and feeding management, than by the telomere length.
The Miyashita study, meanwhile, noted:
Moreover, this study revealed that the offspring had normal-length telomeres in their leukocytes and major organs. Thus, cloned animals have normal functional germ lines, and therefore germ line function can completely restore telomere lengths in clone gametes by telomerase activity, resulting in healthy offspring with normal-length telomeres.
The other articles were unfortunately behind paywalls, so that stopped me. I decided to look at another study, which I found here. Also by Miyashita (2004), it read:
In both cases, however, less telomere erosion or telomere extension from nuclear transfer to birth in most cloned cattle was observed in comparison with telomere erosion from fertilization to birth in control cattle. Embryonic cell-cloned cattle and their offspring calves were also shown to have telomeres longer than those in age-matched controls. These observations indicate that cloning does not necessarily restore the telomere clock but, rather, that nuclear transfer itself may commonly trigger an elongation of telomeres, probably more or less according to donor cell type. Remarkable variations among cloned cattle are suggested to be caused by variation in telomere length among donor cells and more or less elongation of telomere lengths induced by cloning.
In summary, Konishi didn’t detect impacts of advanced aging but was conclusively agnostic; Miyashita in 2011 found that clones who reproduce have offspring with normal telomeres; Miyashita in 2004 determined that the tissue of origin played a role, and the process of transferring a nucleus into an ovum for the purpose of cloning may actually elongate the telomeres.
I would like to delve deeper, but more thorough analyses of the data we have are hard because most any other study that comes up requires a subscription. With what I have been able to view, I have questions floating in my head that remain unanswered, and so I hope to spark some discussion. I would then like for readers here to see where they can pick up the torch and find useful answers.
1. Do the test subjects already have elongated telomeres?
I figure this goes without saying, but I thought I would mention it anyway. Since Bret indicated that nearly all mice in experimentation are bred in labs, and since these are found to have elongated telomeres, is this true of cows and sheep that go through cloning studies? Even if the clones were specifically from laboratory lines, is there a comparison of them with those of livestock as well as with those of the same species or genus that can be found in the wild?
2. Do reproductive differences mean the extent of elongation is different?
Lab mice can begin breeding within a couple of months, with gestation usually being 20 days. A ewe can usually reproduce after a couple more months (sometimes longer) and have a gestation of five months. A cow needs to be a little over a year old to breed, and gestation is around nine months. Thus, the rate at which these specimens are subjected to the selective pressures of scientific breeding is different, implying that telomere elongation would be more pronounced among lab mice, as opposed to lab sheep and lab cows. After all, once could expect four new generations of mice in a year, about one for sheep per year, and (mathematically) half a generation of cows per year. This means that mice have more episodes for this elongation to occur across a similar period of time.
3. Is mouse data obfuscating patterns in pan-mammalian cloning science?
It is interesting that the Wikipedia section on Dolly the sheep, addressing her potential for shortened telomeres, used a study on the fickle subject of mice to make the point. Why not studies on other sheep or even the more closely related cows? Is mouse data frequently being applied to cloning principles for other organisms? If human cloning takes off, will it be based on a similar conflation?
4. Did apparent non-shortening in these studies result from artificial elongation?
If scientists did not detect evidence or effects of shortened telomeres in clones, is this because the source material may have been subject to such elongation that even modest shortening is not noticeable?
I leave the answers for you to find. Hopefully even Bret himself could offer some insights.