I signed up to join Scientific Research and Design at the end of freshman year of high school. One of my teachers had noticed my growing interest in biology and encouraged me to pursue independent research. As a sophomore, I began the program under the guidance of a biology teacher, who coached me in narrowing down my field of interest. I began by reading issues of Scientific American and clipping out articles that interested me. After a few months of exploring various areas of biology at a surface level, I initially chose to research gene therapy. However, in the process of beginning my research on gene therapy, I stumbled across references to two intriguing diseases: Congenital Insensitivity to Pain with Anhidrosis (CIPA) and progeria. CIPA is an extremely rare disorder of the nervous system that leads to an inability to sense pain and is typically accompanied with an inability to sweat (anhidrosis). Progeria, another extremely rare disease, is a genetic condition where symptoms resembling those of aging are manifested at a very early age. The articles I began to read about this disease led me to investigate the cellular basis/mechanisms of aging--telomeres and telomerase.
In the early 70's, it was recognized that chromosomes could not fully replicate themselves - they would lose a small amount of DNA from their ends every time the cell replicated. Telomeres are regions of repetitive DNA (TTAGGG) at the ends of chromosomes and protect the end of the chromosome from being lost due to the end replication problem. Telomere length, generally measured in base pairs, functions as a sort of biological clock for somatic cells. As cells divide, they lose more and more of their telomeres. When the telomeres reach a certain 'critical length', the cell knows to enter a period of cellular senescence and eventual cell death. However, certain types of cells--stem cells, for example--employ an enzyme known as telomerase. Telomerase reverses the aging process at the cellular level; it rebuilds the telomeres, thereby creating "immortal cells". Unfortunately, the activation of telomerase is also responsible for the immortality of tumorigenic cancer cells. Ninety percent of cancers exhibit activation of the telomerase enzyme.
At this point in my research, I wondered if there were any potential methods of treatment to inhibit the telomerase enzyme in cancer cells. Such an ability would ideally help to eliminate the ninety percent of cancers that elongate their telomeres through the use of telomerase, as opposed to alternative lengthening methods. By the end of the year, I had begun to read a few journal articles regarding the inhibition of telomerase in malignant cell growths.
Throughout my junior year, I focused primarily on researching methods of inhibiting telomerase through oligonucleotides. One such molecule is being distributed by Geron Biotech, and is known as GRN163. I read various papers studying the effects of GRN163 in mouse cancers, and the effect of adding a lipid molecule to the end to help the oligonucleotide slip through the cell membrane. The studies were very promising, and a clinical trial for GRN163L is currently underway. GRN163L works by binding to the catalytic site of the telomerase enzyme and preventing it from building the telomeres up. However, a notable problem with the drug is its potential to damage or destroy stem cells that need telomerase to function appropriately. A more selective targeted approach is needed in the future.
In the end of my junior year, I began searching for a lab to work in. I initially hoped to find a place where I could conduct research on telomeres, telomerase, and their role in cancer. However, the only lab in the state of Texas studying this correlation is located in Austin, so I had to explore alternative research in Houston.
I got in touch with Professor Athanasiou at the Rice University Musculoskeletal Bioengineering Laboratory, where I secured a brief but interesting internship. I worked with graduate student Benjamin Elder on his project. However, I did not get the chance to do much research; I primarily assisted in the lab: entering data into computers, cutting cartilage constructs for examination under a microscope, and staining and photographing cells. Benjamin Elder was working on growing cartilage constructs without the use of scaffolding. During and after this period, I began reading articles written by Professor Athanasiou, Jerry Hu, and Benjamin Elder.
I continued this research for the first couple of months of my senior year. However, I ultimately decided that I was more interested was in telomerase and cancer therapy. I began reading more in-depth articles about various other methods for telomerase inhibition: immunotherapy, gene therapy, and small-molecule oligonucleotides. After learning more about the two other methods of telomerase inhibition (I had already researched small-molecule oligonucleotides while studying GRN163L), I read a fascinating journal article about cancer stem cells.
Like normal stem cells, cancer stem cells can self-renew and differentiate into diverse cell types. If the existing theory about cancer stem cells is, in fact, correct, then only a rare set of cells actually drives tumor formation. The goal of current research is to identify this population of cells and target these cancer stem cells, while sparing the normal tissue. Normal stem cells are speculated to have longer telomeres than cancer stem cells, leaving a potential window of opportunity to target cancer stem cells without damaging normal stem cells. Thus, the cancer stem cells would enter cellular senescene and soon die, while the normal stem cells would survive (albeit with slightly shorter telomeres) and remain phenotypically unaffected by the telomerase inhibitors.
While I wasn't able to continue my research at Rice University, I have been periodically keeping up with the latest research results as they emerge. I'm hoping to continue exploring this topic in some capacity in the future.