3 Lessons About Cancer and Scientific Progress From Dr. Lewis Cantley
Dr. Lewis Cantley has spent much of his career studying signal transduction, the process by which cells make decisions, such as whether to grow, divide, or replicate. Cantley offers the following analogy:
If we think of every cell in our bodies as a microcomputer that has to respond to hormones and growth factors, a wiring diagram inside the cell allows for all these decisions. Studying signal transduction is the attempt to unravel that wiring diagram and understand how decisions are made at the molecular level.
Considering the fact that all diseases involve defects in signaling transduction, understanding these processes is crucial. On a podcast episode of People Behind the Science, Dr. Cantley shared some of the most significant lessons he learned over the course of his career.
1. Intravenous vitamin C can kill cancer cells via a Trojan horse mechanism.
A few decades ago, in the 70s and 80s, Linus Pauling became obsessed with the idea that vitamin C (ascorbic acid) could cure a lot of diseases and even ended up persuading several physicians to run clinical trials in which very high doses of vitamin C were injected into the bloodstream of cancer patients. These trials produced remarkable responses, but later studies with oral vitamin C didn’t produce such convincing results.
Cantley discovered that in colorectal cancer cell lines, vitamin C was converted into a different molecule by the reactive oxygen species (ROS), i.e. peroxide, produced by cancer. Peroxide converts ascorbic acid into dehydroascorbic acid, which uniquely resembles glucose and can, therefore, enter cancer cells through a glucose transporter.
Cancer cells have high rates of glucose metabolism, so the dehydroascorbic acid is able to sneak into the cancer cell like a Trojan horse and kill it. In some ways, cancer kills itself by producing the peroxide that converts ascorbic acid into dehydroascorbic acid.
This particular mode of action allows for a favorable efficacy/toxicity ratio in the way that cancer cells are very susceptible to being killed while normal cells are not. Now Cantley’s lab is performing a clinical trial to test their hypothesis that cancers with very high rates of both glucose uptake and ROS production will be most likely to respond to intravenous vitamin C.
2. Dietary sugar can fuel the growth of certain cancers via an enzyme called PI3K.
Type I diabetics can’t make insulin; Type II diabetics are insulin resistant. In the 1980s, Cantley discovered PI3K, an enzyme that mediates insulin’s many activities. PI3K is an oncoprotein that becomes mutated in various cancers. PI3K has two primary modes of operation:
- Directs insulin’s activities
- Causes cancer growth when hyperactivated
High blood levels of insulin, as observed in Type II diabetes, can drive the growth of cancer cells. Sugars and simple carbohydrates increase insulin levels by rapidly increasing blood glucose levels. Therefore, a high-sugar diet may be a risk factor for the development of cancer by increasing insulin, a growth factor for many types of cancer.
3. Current scientific paradigms are slow to accept change.
Dr. Cantley drew on his personal experiences to offer some commentary on the structure of scientific revolutions. When Dr. Cantley first discovered that PI3K copurified with other oncoproteins, the scientific field was slow to accept his discovery.
When other labs tried to replicate his experiment, they failed to produce the same results; the reason for this discrepancy was the fact that Cantley’s lab used sonicated lipids to create synthetic membranes that closely resembled cellular membranes while other labs simply used detergents to solubilize their lipids into micelles instead.
The PI3K enzyme requires its lipid substrate to be presented in a membrane-like environment. Performing the assays using detergent, therefore, yielded no activity.
As a consequence, many scientists, including Nobel Prize-winners, began publishing papers stating that Cantley’s results could not be replicated. Eventually, graduate students from Cantley’s labs visited these other labs with their synthetic membrane equipment, which allowed for the successful replication of the results described.
About five years passed before Cantley’s discovery was generally accepted, as Cantley went on to show PI3K made an enzyme that had never before been seen in nature. Many people in the field were skeptical that such an enzyme could have evaded discovery for 40 years.
Dr. Cantley’s experiences provide proof that persistence pays off. Even if the scientific community does not initially accept your discoveries, good science will eventually be recognized, so stay curious and keep investigating!
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