The immortality paradox part II: can we rejuvenate cells without making them "immortal"?

I've talked about the immortality paradox in an older post, but today I would like to continue the discussion in light of a recently published paper on telomere lengths. The paper is a bit of a spoiler alert from my detective thriller Chimeras. Given that my detective has some screwed up genes, it seemed natural that he would solve crimes revolving around genetics and, in particular, its exploitations in the medical and pharmaceutical world. One of such exploitations in my book is a magic formula to stay forever young. Well, not exactly magic, and, as it turns out, not so far fetched, as a paper very similar to what I describe in my book was published this past January 22 by Ramunas et al. [1].

In order to understand the paper, you have to know what telomeres are: these are bits of non-coding DNA at the very end of our chromosomes. Because every chromosome replication "wears out" the chromosome a bit, in order not to lose any important coding bit of DNA, the telomeres function as a disposable buffer zone at the end. With every cell division telomeres lose about 100 base pairs until they are so short that the cell can no longer divide and dies. The university of Utah has a nice, easy to follow article on telomeres.

Can the telomere keep shortening forever? Of course not. They get shorter with age, which is why, as we get older, our cells undergo fewer replication cycles and enter replicative senescence. That's the basis of how our body starts aging. However, some cells in our body need to divide more rapidly and more often than others, like for examples cells in the bone marrow, in the guts and in the lungs. And of course, cells in the developing fetus. In those cells an enzyme called telomerase is highly activated and its job is to replenish the telomere ends so they don't shorten too soon.

The enzyme telomerase is made of two components, each encoded by two genes, TERT and TERC. With the exception of the cells mentioned above, these genes are normally expressed at low concentrations. Without the intervention of the enzyme, telomere ends keep shortening with age (see the figure above) and this results in cell senescence. But... could that be changed? Could we manipulate cells so that they all express high levels of telomerase, forcing them to rejuvenate more? For example, we could use gene therapy to deliver the TERT gene to cells and thus activate the telomerase enzyme (which is exactly what happens in my book Chimeras). If we keep lengthening the telomeres, preventing them from getting too short, would this slow down senescence and keep us younger for a longer time?

Well, there's a catch. Remember the story of Henrietta Lacks who died in 1951 and yet her cancerous cells are still living today? A cancerous cell is a cell that keeps replicating for ever. So, while lengthening the telomeres can be a promising technique in regenerative medicine, it can be a tricky business as it may lead to cancer. Researchers have shown that many types of cancer cells have short telomeres but it's the activity of the telomerase enzyme that prevents them from dying by constantly replenishing the telomeres.

Short telomeres have been associated with numerous diseases, not just cancer (Duchenne muscular dystrophy, for example), and worse prognosis in transplant therapies with stem cells and hemotopoietic cells (because they limit the replicative capacity of the cells). Given that many diseases are associated with short telomeres, a lot of research has been focused on finding a way to lengthen them in a way that does not lead to cancer or generate malignant mutations.

In [1], Ramunas et al. show that by delivering mRNA encoding TERT (instead of the actual gene) to the cells, they could temporarily lengthen the telomeres of fibroblasts (cells that make collagen and are found in connective tissue) without turning them into cancerous cells. In other words, instead of using gene therapy to deliver the actual gene that encodes for the enzyme telomerase, Ramunas et al. delivered a product of that gene: you can think of mRNA as instructions, read from the gene, on how to make the enzyme telomerase. With those instructions, but without the actual gene, cells indeed made more telomerase but for a limited amount of time only.

This resulted in a delay in senescence markers and an increase in the cells' proliferative capacity. The technique was called "transient delivery" because it wasn't a permanent change in the genes, rather a delivery of gene products that momentarily increases the TERT activity in the cells. This is important because, like I explained above, a permanent over-expression of the TERT gene could result in "immortal" (hence cancerous) cells. The added proliferative capacity obtained with this method resulted in an increase in absolute cell number of more than 10^12-fold.

"Although the therapeutic potential of modified TERT mRNA delivery remains to be determined, the transient nonintegrating nature of modified mRNA and finite in- crease in proliferative capacity observed here are likely to render it safer than currently used viral or DNA vectors. Furthermore, the method extends telomeres rapidly so that the treatment can be brief, after which the protective telomere shortening mechanism remains intact. This method could be used ex vivo to treat cell types that mediate certain conditions and diseases, such as hematopoietic stem cells or progenitors in cases of immunosenescence or bone marrow failure [1]."

Delivery of mRNA in vivo is still challenging, so one of the first applications would be to use this to regenerate tissue for grafting and transfection. The road to an actual therapeutic use of these techniques is still long, but it is certainly an exciting result that paves the way to new therapies.

[1] Ramunas J, Yakubov E, Brady JJ, Corbel SY, Holbrook C, Brandt M, Stein J, Santiago JG, Cooke JP, & Blau HM (2015). Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology PMID: 25614443