Using Sea Urchins to Increase Telomere Length
Abstract:
Our solution, involves using the telomere functions within sea urchins, in which we see a high lifespan, in human cellular function, and restoration using Crispr Cas9 technologies.
What is Telomere Shortening & Senescence
Every time a cell splits, the telomeres shorten. Telomeres work sort of like the ends of shoelaces if we replace the shoelace with DNA. Every time your cells split, the telomere wears out a little more, just like if you were to step on a shoelace. Eventually, the telomere runs out, and the DNA mutates, causing the birth of a senescent cell. Now, senescent cells just won’t leave. They hang around calling the immune system to clean them up, and while doing that they annoy and inflame the cells surrounding them. Over time, these cells build up, stopping blood flow to major organs and tissues, as well as cause a weakening of the immune system, secrete pro-inflammatory cytokines, which trigger chronic immune reactions that may drive many ageing-related diseases and contribute to other ageing factors like wrinkles, cardiovascular disease, and immune system failure.
What do sea urchins do?
Even though they look pretty ordinary, sea urchins have some of the longest lives comparative to their size and environment. The red sea urchin, is an extreme case of this, easily reaching a life of 100 years, and some specimens reaching 200+. And the most interesting part of their anatomy, is they never get biologically older. They continuously regrow tissue, muscle, and even organs, but most interestingly over their 200-year life span, they don’t show signs of senescence build-up.
How?
The sea urchin is an interesting species, and unlike humans, sea urchins continuously express telomerase through their lives and maintain them. This means that telomeres that capsulate the chromosome, never wear down. As well, this system of constant telomere regeneration doesn’t slow down over time, meaning that the telomerase is constantly being supplied to the urchin for most of its life. As well, urchins maintain their telomeres using different genetic functions. There is a lack of shortening of telomeres due to constant telomerase by the TERT, and therefore the urchin does not age or have major senescence.
Similarities with Humans
Even though sea urchins seem extremely different from humans, genetically they show similarities. They prosses over 23,000 genes that similar to humans and other vertebrates. As well, their telomer system and TERT system is somewhat similar to humans. What’s the main kicker is that, even with their different genetic code, their telomere caps, contain the exact telomeric sequence of humans(TTAGGG), meaning that if we implemented them on a chromosome, they would keep it intact. As well, the telomeres, as well as being the same sequence, also measure at an adequate length compared to the human telomere, while as an embryo they are around 6 kb in relation to the human 5–15 kb.
Our solution
TERT (Telomerase Reverse Transcript) is a gene that creates part of telomerase (the proteins that control telomere length and maintenance). This TERT is usually the reason that telomeres shorten over time, and most of the telomere focuses on it. We propose using CRISPR Cas9 to genetically identify, extract and modify TERT and Telomerase from Urchin Somatic cells, and plant them into mice to test and iterate.
Working with mice has been very prominent in gene-editing therapies. Since mice and humans are very similar genetically, it will be easy to replicate the process of TERT extraction and plant it into human beings.
This proven pathway of gene testing using lab mice will accelerate our quest to find a plausible solution to increase human longevity.
Gene therapy testing in mice has been ongoing for years, and it has reduced the suffering caused by debilitating diseases and also improved the health and survival of these mice. However, there have been issues with gene therapy testing in mice A gene can’t easily be inserted directly into your cells. It usually has to be delivered using a carrier, called a vector. The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop the disease.
Removing the original disease-causing genes from the virus and replacing them with the genes needed to stop the disease causes the following risks:
- Unwanted immune system reaction
- Targeting the wrong cells
- Infection caused by the virus
- Possibility of causing a tumour
When it comes to TERT and transferring it into mice, we will not come across the same problems as it did with Gene Therapy.
Identification
We could use dCas to image the TERT. Basically what you do is label telomeres with fluorescent proteins, and you can track their movement and pattern, making it easy for extraction
Extraction
By using CRISPR Cas9, you can remove these telomeres from the gene, much like the CRISPR Cas9 treatment, done by Kyounghae Kim, from bone marrow. A similar treatment can be used on the somatic cells of sea urchins
Modification
By using Crispr on the telomeres and TERT itself, we can edit to a single nucleotide. In all we would be trying to edit the gene in such a way that it could be inserted into the human genome. By editing at the nucleotide level, we are able to reach high precision.
Editing the genome
By using crispr we can cut out the old TERT in mice and replace it with a modified Urchin TERT, that produces the same type of telomerase as before, but at a different rate, keeping the telomere length the same.
