SCIENCE!!!!! YA-AH!!

WARING: THE FOLLOWING CONTAINS HIGH DOSES OF SCIENCE. THE PHYSIOLOGICAL EFFECTS OF SCIENCE VARY WIDELY AMONG INDIVIDUALS, BUT CAN INCLUDE DIZZINESS, NAUSEA, OR INTENSE EUPHORIA. IMBIBE WITH CAUTION.

Cambridge has a long and distinguished history in natural science research. Charles Darwin formulated his theory of natural selection here. Watson and Crick solved the DNA code here. Researchers from Trinity College won the first thirteen Nobel prizes in medicine. Thirteen!!! That’s more than most countries have. With its illustrious history, it seems natural that an emphasis on scientific research would be placed in this city. Sometimes I think every other person I meet is a biochemist. It almost seems like research institutions outnumber restaurants (but certainly not pubs, the pubs nearly outnumber people.). Besides the University departments, there is the Medical Research Council’s Laboratory in Molecular Biology (home of several current Nobel laureates), the Hutchison Research Institute, and the Wellcome Trust for Cancer Research. As if that weren’t crazy enough, those places I’ve listed are only the ones based at Addenbrooke’s Hostpital!!!

I may be a little biased, but my favorite is the Cambridge Research Institute (CRI), which is the fourth national laboratory of Cancer Research UK, the world’s largest cancer charity. CRI is three years old, the queen herself cut the last construction tape in 2006. It houses 19 research groups with over 200 scientists and graduate students. The work conducted here is exclusively cancer research, and ranges from basic molecular gene expression investigations to pre-clinical studies in developing new cancer therapy drugs. It is truly a world-class facility. Articles in Nature and Science (two of the top scientific journals) are routinely published here. The equipment, facilities, and technical expertise unparalleled; nearly anything a biologist could want is available here.

The work being done here is serious. (Okay, kids prepare for some science jargon) Two months ago, one research group published a paper in Science detailing a drastically new approach to treating pancreatic cancer. The group had previously constructed a genetically modified mouse model which contained mutations in K-ras and p53 with restricted expression to pancreatic ductal epithelial cells. Unlike previous mouse models, the pancreatic neoplasia which resulted from these mutations recapitulated the pathophysiology of human pancreatic cancer almost perfectly. Using this mouse model, the group showed how most pancreatic tumors are characterized by very inefficient vasculature, which inhibits the delivery of chemotherapeutic drugs. They hypothesized that vascular efficiency could be improved by reducing the mass of stromal tissue surrounding the tumor. Using an inhibitor of the sonic hedgehog signal transduction pathway (Yes, that is the real name for it; the discoverers must have had a sense of humor), the group was able to decrease the volume of surrounding stromal tissue, increase tumor blood flow, and deliver conventional chemotherapeutic agents more efficiently. The results: 65% of mice showed a significant response to chemotherapy, and had survival rates of above 50% after 6 months, which is a really long time for a mouse. To give a comparison, the human 5-year survival rate of a pancreatic cancer diagnosis is less than 5%.

(More jargon) I work in the lab of Dr. Doug Winton, who is well known for his seminal work on developing the Cre-Lox system of genetic recombination. The Winton lab studies the development and differentiation of intestinal stem cells, and how aberrant stem cell behaviour can lead to colorectal carcinogenesis. My project involves analyzing stem cell differentiation by using a super cool cell line, called HRA-19. HRA-19 cells were derived from a primary rectal adenocarcinoma, and have the unique ability to differentiate in vitro into three different colon cell types . I am using this system to investigate how the timing of the replication of certain developmental genes correlates with differentiation status (For example, in stem cells some genes replicate early during S-phase, and when the cell differentiates, these same genes switch to late-replicating). I want to understand how these changes in replication timing are associated with the expression of these genes, and whether the changes in replication timing induce differentiation or are a side-product of the differentiation process. (I’ve got some vague ideas of how I might do this, but they probably won’t work. C’est la science).

IF, (and it’s a big if) changes in replication timing are a prerequisite for a differentiated phenotype, this could provide an interesting strategy for analyzing the epigenetic basis for differentiation. Why is this important? Many tumors show dysplasia, which is basically when cells turn into something they’re not supposed to. For instance, colon tumors may have stomach-looking cells in them, and breast cancer tumors have been shown to contain cells which produce enamel (teeth cells). This abnormal differentiation phenotype usually correlates with increased malignancy, metastasis, and a generally sucky prognosis for the patient. Finding new molecular pathways in this process could present new targets for drug therapy.

There are a lot of mights and maybes. My mentor at UPenn once told me that out of every 100 research ideas, 80 are crap, 10 just won’t work, 9 get published, and only 1 really makes a difference. Though I seriously doubt my project will culminate in a revolutionary scientific breakthrough, maybe I’ll get a journal article out of it!!

Speaking of publishing, I just found out that I’m going to be an author from my intersnship at UPenn several years ago! “Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of Survivin” is being reviewed in the Journal of Clinical Investigation. I can’t wait to PubMed myself (God that sounds egocentric).

Next up, more about my neighborhood, English dancing, and the British version of beer pong. Stay tuned.