Introducing Dyskeratosis Congenita
Chances are, you’ve never heard of DC before. And that’s not uncommon, considering that 1 in 1 million people are affected by this condition. Although it’s rare, this disease is unmistakeably deadly and those who suffer from it are yet to find a safe, effective remedy.
Well, until now, that is. With the use of telomerase mRNA to lengthen patients’ shortened telomeres, we could tackle this disease and put an end to it once and for all.
But first things first.
What Exactly Is DC?
Dyskeratosis Congenita, also known as DC, is a rare form of bone marrow failure, typically passed on from generation to generation. With this condition, one’s bone marrow fails to produce a sufficient amount of blood cells. The result — a high risk of developing life-threatening diseases. This includes myelodysplastic syndrome (when blood cells don’t develop properly), aplastic anemia (when the body stops producing an adequate amount of blood cells), and, in more severe cases, leukemia (or other types of cancer).
Those with DC have three distinct features: nail dystrophy, which is when the nails are splitting, cracking, underdeveloped, and/or abnormally-shaped; oral leukoplakia, which is identified by white patches on the inside of the mouth; and unusual pigmentation on the skin in the form of a web-like pattern.
There are two major types of DC: Hoyeraal-Hreidarsson Syndrome (HH) and Revesz Syndrome (RS).
Hoyeraal-Hreidarsson Syndrome is an intellectual disability that roots from DC. Patients with this subset display intrauterine growth retardation (when a baby is below normal weight during pregnancy), microcephaly (an abnormally small head), cerebellar hypoplasia (a small/underdeveloped cerebellum), immunodeficiency (a compromised immune system), and aplastic anemia. Over thirty cases of this condition have been recorded. Most with HH die before the age of four.
Revesz Syndrome is characterized by bone marrow failure and exudative retinopathy. Those with this subset showed signs of calcifications in the central nervous system, intrauterine growth retardation, severe aplastic anemia, ataxia from cerebellar hypoplasia, fine sparse hair, and cerebral calcifications (irregular calcium deposits in areas of the brain).
Currently, the only two treatment options for DC are androgen therapy and stem cell transplantation.
In androgen therapy, the patient is provided with steroid drugs to improve the CBC (complete blood count) in the body. The results, however, are only temporary. This means the patient would have to constantly receive these drugs — which can result in negative side effects.
Stem cell transplantation, aka bone marrow transplants, may improve blood issues caused by DC. However, with this treatment, there is an estimated 10-year-survival rate of only 23% and a high risk of death. Additionally, body tissue that was affected by DC will not be improved.
Needless to say, DC patients are forced into a corner with risky options and limited paths to take in order to treat the disease. Fortunately, telomerase is here to save the day.
Telomeres, Telomerase, and How They’re Affected
In most Hoyeraal-Hreidarsson Syndrome cases, Dyskeratosis Congenita is caused by gene mutations in TERC, TERT, DKC1, or TINF2. In Revesz Syndrome, mutations occur only in the TINF2 gene. To put this into simpler terms, shortened telomeres are the main cause of DC. That being said, it is crucial to understand what telomeres are and why the shorter they are, the more the body is negatively impacted.
Imagine a shoelace. Now imagine the hard part at the end that no one seems to ever remember the name of. This tiny tube holds the entire shoelace together and if it were to come off, the lace would slowly unwind and tangle all over the place. This is similar to how telomeres work.
Telomeres (sequence: TTAGGG) are caps at the end of chromosomes that prevent them from sticking together or deteriorating. They are crucial to protect the DNA. After each cell division, however, telomeres shorten. As a cell continues to divide, the telomeres get shorter and shorter until finally, they approach the point of no return. The cell reaches its Hayflick limit — in which it can no longer divide without damaging the DNA — and stops duplicating, undergoing cell death (apoptosis).
If the telomeres are shorter than usual — which they are in Dyskeratosis Congenita — then the cells will die faster since they aren’t able to divide as many times. If this process continues, the body won’t be able to account for the shortage of cells (due to the rapid rate of death). Eventually, there is no longer a sufficient amount of cells in the body. That’s where telomerase comes in.
Telomerase is an enzyme made from protein and RNA subunits. It aids in the lengthening of telomeres by adding repeated sequences of TTAGGG to the ends of chromosomes. This allows for the telomeres to become longer, therefore the cells can continue to divide for an enhanced period of time.
Telomerase is normally low in somatic cells, but active in cells that rapidly divide. For this reason, most cells do not actively use telomerase and they undergo division and death as per usual. With DC, due to the shortened telomeres, rapidly-dividing cells are vulnerable and issues may arise in various parts of the body (including nail beds and hair follicles).
As I mentioned before, mutations in the TERC, TERT, DKC1, or TINF2 genes result in DC. Each of these genes serve a vital purpose and contribute to the production/maintenance of telomeres and telomerase.
TERC (Telomerase RNA Component) produces hTR, which provides the template for creating TTAGGG to add to the ends of chromosomes. TERT (Telomerase Reverse Transcriptase) produces hTERT, which actually adds the DNA segment.
DKC1 supplies the instructions for creating the dyskerin protein, which binds with hTR in order to stabilize the telomerase complex.
The TINF2 gene supplies the instructions for creating part of the shelterin protein complex, which prevents the repair mechanism from initiating apoptosis or joining the ends of chromosomes together.
All four of these genes are quite important. When they aren’t functioning properly, part of the telomere-telomerase system is destroyed and cells will continue to die quickly in the body.
Here’s where telomerase can help.
Meet Helen Blau, an American biologist and director of Baxter Laboratory for Stem Cell Biology at Stanford University. In 2015, she and her team developed a new technique for lengthening telomeres in cells. Here’s how it works.
Normally, RNA transports instructions from genes to protein-making factories in the cell. In this case, the RNA contains TERT’s coding sequence (creating TERT mRNA). This RNA is meant to reduce the immune response of the cell, allowing the TERT message to stay longer than usual. Within 48 hours, the message fades and cell division will carry on as usual — except this time, the telomeres have been lengthened and the cell can divide numerous more times.
Blau’s team found that after three applications, telomeres were able to experience an increase of over 10%. During their experiment, they discovered that skin cells divided around 28 more times while muscle cells divided 3 more times.
“Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life.” — Blau
A benefit of this method is that it is temporary in such a way that the cells don’t divide forever. Because the TERT mRNA fades away, the cell will continue on regularly. This avoids the risk of developing cancer. Stanford Medicine compared the process to tapping the gas pedal in a group of cars slowly coming to a stop. The car with this energy surge will move farther than the others, but will eventually halt when the momentum is spent.
This experiment is just one of many working to safely increase the length of telomeres in cells. Dr. John P. Cooke, Director at the Center for Cardiovascular Regeneration and Chair of the Department of Cardiovascular Sciences at the Houston Methodist Research Institute, observed shortened telomeres in a rapidly-aging condition known as Progeria. He and his team tackled this case with a similar approach using RNA therapeutics to deliver telomerase-encoded RNA to the cells.
“What was most unexpected about our work was the dramatic effect the telomere-extending technology had on the cells. We were not expecting to see such a dramatic effect on the ability of the cells to proliferate. They could function and divide more normally, and we gave them extra lifespan, as well as better function.” — Cooke
The process of lengthening telomeres is becoming a reality with multiple experiments and various possibilities. If we are able to use this method on Dyskeratosis Congenita patients, it is possible to cure the disease entirely. With longer telomeres, their bodies will be able to retain more cells for a longer time, thus accounting for the lack of blood cells. This will restore the damaged telomere-telomerase system and increase the lifespan of the patients’ bodies.
Because the TERT gene is affected by this disease, if we can deliver it using RNA then that issue will be eliminated.
Vision of the Future
As research to lengthen telomeres continues, the number of conditions that will be eradicated/treated grows exponentially. By eliminating this variable in Dyskeratosis Congenita, the effects of the shortened telomeres will be reversed. In the future, this condition will become one of the past and no child — or parent — will be forced to suffer through the impossible treatment options, pain, and apprehension associated with the disease.
- Dyskeratosis Congenita (DC) is a rare form of bone marrow failure that results in an insufficient amount of blood cells in the body.
- DC is caused by shortened telomeres, which are caps at the ends of chromosomes.
- Telomerase is an enzyme that lengthens telomeres by adding repeated sequences of TTAGGG to each end.
- Scientists have discovered ways to lengthen telomeres using TERT mRNA to deliver telomerase-encoded RNA into protein-making factories in the cell.
- By lengthening DC patients’ telomeres, the root of the disease is eradicated and thus, the condition can be combated and potentially cured.