By Jenny Kay, Research Translation Core director and Project 4 Postdoc
Welcome back to the MIT SRP Blog!
We have quite a variety of scientists and research projects in our program, so over time you’ll have the chance to hear many different perspectives in this blog. Since I have the privilege of writing the first few posts, I’m going to begin with my specialty, the development of cancer. I want to start this conversation with the basics: where does cancer come from?
This is a HUGE question with lots of facets, more than I can address in one post, so let’s take it one step at a time.
Cancer arises from normal cells misbehaving (proliferating when they’re not supposed to, migrating where they’re not supposed to, surviving when they’re not supposed to, etc.). Such misbehavior can be caused by alterations to the genetic instruction manual that provides the basis of all cellular activity. In fact, many of us in the field consider cancer to be a disease of the genome.
The instructions for all cellular behavior are coded in DNA, comprised of the nucleotide bases adenine (A), thymine (T), cytosine (C), and guanine (G) strung together into long strands (called chromosomes) that get bundled into the cell nucleus. DNA is comprised of two complementary strands that twist around each other, known as a double helix, where A should always pair with T and C should always pair with G (thanks to hydrogen bonding patterns, which is more chemistry than I’m going to get into today). Having the information coded in two complementary strands is sort of like having a backup copy; if there’s a problem on one side of the helix, the other side can be used as a template to correct the issue.
Cells read the sequences of nucleotides in their DNA as instructions for assembling the proteins that perform cellular functions (generally, each DNA sequence that encodes a protein is called a gene). Every cell has a complete copy of the genetic code, but different cell types use different sets of genes to accomplish their particular roles. Broadly speaking, if a gene’s sequence is altered (called a mutation), then the protein may be assembled incorrectly, and that particular function of the cell won’t be executed properly.
As cells divide, they copy their DNA so that the daughter cells are genetically identical. The cell copies both complementary strands, always pairing A with T and C with G to create two identical chromosomes, one for each daughter cell. Every cell division requires accurate replication of the entire genome, but replication provides opportunities for genetic information to be copied incorrectly (imagine trying to transcribe an entire book without missing a single letter). Once a cell acquires a mutation, every time it divides from then on, all of the daughter cells will contain that mutation as well. As those mutant cells divide, cells within the lineage have more opportunities to acquire new mutations, allowing the accumulation of errors in the genetic code.
Cancer arises when cells accumulate multiple mutations that enable escape from normal behavior. The most common carcinogenic mutations include inactivation of genes that keep behaviors in check (e.g., moderating cell division, regulating migration, inducing programmed death) or improper activation of genes that enable behaviors (e.g., enhancing proliferation, activating migration, resisting programmed death). Mutations enable cancer cells to evolve, continually altering their behavior to enhance growth, escape normal physiological confines, and resist cell death. (By the way, this accelerated evolution is what makes cancer so difficult to treat, since cancer cells are constantly altering themselves to resist chemotherapeutics, but that’s a story for another time.)
Mutations become more likely when the cell’s DNA has undergone damage, such as alterations to the nucleotide structure. If the nucleotide looks wrong, the cell will have difficulty interpreting it properly. (In our book analogy, if the top bar on a capital T is gone, you might incorrectly transcribe it as a lowercase l. Similarly, if the cell doesn’t recognize G as G due to a change in its structure, it won’t know to pair it with C.)
One prominent source of DNA damage is chemical exposures – indeed, many toxic chemicals are carcinogenic precisely because they damage DNA. MIT’s Superfund Research Program is centered around two such DNA-damaging classes of chemicals, N-nitrosamines (e.g., NDMA) and polycyclic aromatic hydrocarbons (PAHs). NDMA causes DNA damage by adding a single methyl group (-CH3) to nucleotides, which in itself can be enough to mask the identity of the base. One mutagenic product of NDMA exposure is O6-methylguanine, which changes guanine’s hydrogen bonding pattern and can confuse the cell into pairing it with T. Then, during replication, one of the strands ends up with A-T where a G-C should have gone.
PAHs create large adducts on DNA, and it’s easy to see how a giant lesion could obscure the identity of the nucleotide or block cellular machinery from copying the DNA altogether. Cells have evolved various mechanisms to fix different types of DNA damage, and we refer to these as DNA repair pathways. DNA repair is absolutely essential for every organism, and when there are deficiencies in DNA repair, mutations become a whole lot more common.
Two of our research projects are specifically aimed at studying the genetic impacts of exposures to NDMA and PAHs. Project 3 will determine the unique patterns of mutations that occur when animals are exposed to these chemicals, and Project 4 will study how the inability to repair DNA damage impacts cancer susceptibility.
In our next entry, we’ll dive into how DNA repair pathways help protect against mutations and discuss why some people are more likely to get cancer than others.