Cancer and the origins of life: The Age of Metabolism

The NYT has an interesting article on the Warburg Effect and how it can be used to provide a new weapon in the treatment of cancer (the article is part of a larger series on cancer in the weekend magazine). The effect which is named after the Nobel Prize winning German biochemist Otto Warburg pertains to the fact that tumors can grow by disproportionately consuming glucose from their environment. More specifically it deals with anaerobic respiration in tumor cells which allow them to persist even in the absence of oxygen.

This is clearly a mechanism that could be potentially targeted in cancer therapy, for example by blocking glucose transporters. But more generally it speaks to the growing importance of metabolism in cancer treatment. It seems to me that since the 1970s or so, partly because of discoveries regarding oncogenes like Ras and Src and partly because of the explosive growth in sequencing and genomics, genetics has become front and center in cancer research. This is a great thing but it's not without its pitfalls. In the race to decode the genetic basis of cancer, one gets the feeling that the study of cancer metabolism has fallen a bit by the wayside and is now being resurrected. In some sense this almost harkens back to an older period when cancer was conjectured to be caused by environmental factors affecting metabolism.

It's gratifying therefore that things like the Warburg Effect are being recognized. As the article points out, one of the simple reasons is because while many (frighteningly many in fact) genes might be mutated in cancer, a cancer cell usually has only a few ways to get energy from its surroundings: the range of targets is thus potentially fewer when it comes to energy. The recognition of this effect also speaks to the commonsense view that we should have a multipronged approach toward cancer therapy: genetics, metabolism and everything in between. Judah Folkman's idea of starving off a cancer cells's blood supply is another approach, what we may call a 'mechanical' approach (all of cancer surgery is a mechanical approach, in fact).

I could not help but also note the interesting coincidence that this tussle between emphasizing genetics vs metabolism has played out in another area which seems quite far removed from cancer medicine: the origin of life. For the longest time people focused on how DNA and RNA could have been formed on the primordial earth. It's only about 20 years ago or so that "metabolism first" started getting emphasized too: this approach emphasized the all important role that the evolution of life's energy generating apparatus (in the form of proton gradients and ATP) played in getting life jumpstarted. The metabolism first viewpoint really took off with the discovery of deep sea hydrothermal vents which can generate primitive energy-creating biochemical cycles based on proton gradients, alkaline environments and diffusion through tiny pores in the vents. Biochemists like Nick Lane and Mike Russell have been pioneers in this area.

The renewed focus on metabolism in treating cancer as well as in exploring the most primeval characteristics of life seems to me to bring the study of life in both health and disease full circle. Just like you cannot discuss the genetics of life's origins without discussing life's source of energy, so can you also not disrupt cancer's spread by disabling its genes without disabling its source of energy. Both are important, and emphasizing one over the other seems mainly to be a function of research fads and fashions rather than objective scientific reasoning.

As an amusing aside, the father of a very close friend of mine knew Otto Warburg quite well when he worked in Vienna in the 50s. Here's what he had to say about Warburg's scrupulous lab protocols: "One story I've always remembered was that he would clean his own glassware, used in experiments. He didn't trust any low-level dishwasher or junior staff around the lab. He wanted to make sure everything was perfect. I can confirm that even a tiny 'foreign fragment' in glassware can wreck an experiment."

Linus Pauling's last laugh? Vitamin C might be bad news for mutant colorectal cancer

Linus Pauling holding enough rope to make sure we
can hang ourselves with it if we don't run the right
statistically validated experiments

During the last few decades of his life, Linus Pauling (in) famously began a crusade to convince the general public of the miraculous benefits of Vitamin C for curing every potential malady, from the common cold to cancer. Pauling’s work on ascorbic acid resulted in many collaborations, dozens of papers and at least two best-selling books.

The general reaction to his results and studies ranged from “interesting” to “hey, where are the proper controls and statistical validation?” Over the years none of his work has been definitively validated, but vitamin C itself has continued to be interesting, partly because of its cheap availability and ubiquitous nature in our diet and partly because of its antioxidant properties that seem to many people to be “obviously” beneficial (although there’s been plenty of criticism of antioxidants in general in recent years). Personally I have always put vitamin C in the “interesting and should be further investigated” drawer, partly because oxidation and reduction are such elemental cellular phenomena that anything that seeks to perturb such fundamental events deserves to be further looked at.

Now here’s an interesting paper in Science that validates the potential benefits of ascorbic acid in a very specific but well-defined case study. It’s worth noting at the outset that the word ‘potential’ should be highlighted in giant, size 24 bold font sizes. The authors who are part of a multi-organization consortium look at the effects of high doses of the compound on colorectal cancer cells with mutations in two ubiquitous and important proteins – KRAS and BRAF. KRAS and BRAF are both part of key signaling networks in cells. Mutations in both of these proteins are seen in up to 40% of all cancers, so both proteins have unsurprisingly been very high-profile targets of interest in cancer therapy for several decades. The mutation is additionally important because it also turns out that cancers with these mutations show poor response to anti-EGFR therapies.

One of the hallmarks of cancer cells which has been teased out in fascinating detail in the last few years is their increased metabolism and especially their dependence on glucose metabolism pathways such as glycolysis that allows them to feed hungrily on this crucial substance. The current study took off from the observation that a glucose transporter protein called GLUT1 is overexpressed in these mutant cancer cells. Incidentally this transporter protein is also involved in transporting vitamin C, but in its oxidized form (dehydroascorbate – DHA). Presumably the authors put two and two together and wondered if ascorbate might be more rapidly absorbed by the mutant cancer cells and mess up the oxidation-reduction machinery inside.

It turns out that it does. Firstly, the authors confirmed by the addition of reducing agents that it’s the oxidized form of vitamin C that interferes with the cancer cells’ survival. Secondly, they looked at mutant vs wild-type cells and found that the mutant cells are indeed much more efficient at ascorbate uptake. Thirdly, they looked at various markers for cell death like apoptosis signals and found out that these were indeed more pronounced in the KRAS-BRAF mutant cells (addition of a reducing agent rescued these cells, again attesting to the function of DHA rather than reduced vitamin C). Fourthly, mice with known as well as transgenic KRAS mutations showed favorable tumor reduction when vitamin C was intravenously administered.

Fifth and most interesting, they performed protein metabolite analysis of the cells’ machinery after treatment with vitamin C and found that there was a significant accumulation of chemical intermediates which serve as substrates for the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH is a central enzyme of the glycolytic pathway and its inhibition would unsurprisingly lead to cell starvation and death. Lastly, they were able to make a statement about the mechanism of action of vitamin C on GAPDH by determining that it might interfere with post-translational modification of the protein and NAD+ depletion.

The authors end with some ruminations on the history of vitamin C therapy for cancer and the usual qualifications which should apply to any such study,. As they note, vitamin C has a checkered history in the treatment of cancer but most studies which failed to show benefits only involved large oral doses of the vitamin (Pauling himself was rumored to ingest up to 50 g of the substance a day). Intravenous administration however has suggested that far higher doses may be required for effective results. And of course, this study was done in mice, and time after time we have seen that such studies cannot be measurably extrapolated to human beings without a lot of additional work, so you should pause a bit before you rush off and try to inject yourself with Emergen-C solution.

Nonetheless, I think the detail-oriented and relatively clear nature of the study makes it a good starting point. Google searches of vitamin C and colorectal cancer bring up at least a few tantalizing clues as to its potential efficacy (along with a lot of New Age, feel-good piffle). As usual the key goal here is to separate out the wheat from the chaff, the sloppy anecdotal evidence from the careful statistical validation and the detailed mechanistic rationales from the stratospheric theorizing. When the dust settles we would hopefully have a clearer picture. And who knows, maybe the ghost of Linus Pauling might then even allow himself the last laugh, or at least an imperceptible smile.