Diets and Medicine Working Together

If you have been following me for any amount of time, you might know my opinion on the use of diet/supplements to treat cancer. If you don’t know, I’ll save you some time – I think it’s a waste of time.

To be clear, do I think you can eat only junk food and be fine? Absolutely not. You need a healthy diet to be, well, healthy, but I don’t think diet and supplements (alone) will ever be useful in treating diseases like cancer. You should stick with modern medicine.

That being said, I was shocked when I stumbled upon an article by one of my favorite authors, Siddhartha Mukherjee, entitled “It’s Time to Study Whether Eating Particular Diets Can Help Heal Us.” Mukherjee became prominent when he wrote the book The Emperor of All Maladies, which is a biography of cancer, explaining the history behind cancer research and treatments. (It’s an amazing book and everyone should read it). He’s a medical doctor specializing in cancer treatment and has come to be known as an expert in all things cancer. You can imagine my surprise (and probably my annoyance) when I saw this title.

Luckily, I didn’t take the title at face value and I read the article (something everyone should learn how to do…*ahem*). I’m going to lead off this commentary with my main takeaway: this was not a good title for the paper. I get that perhaps it was supposed to be a kind of clickbait, but I would expect The New York Times to be a bit above that. It gives the wrong idea of what Mukherjee is arguing, which isn’t diets as the sole healing agents, but rather diets and medicine working together to optimize the healing process.

An idea I am much more inclined to accept.

There are many things about this article that I found interesting, and a few I found concerning. The first concerning aspect is Dr. Mukherjee’s apparent typical Monday morning breakfast of a bar of chocolate and an espresso.

If I had that for breakfast, my heart rate would be too high for the rest of the week.

We can console ourselves by knowing he is not a nutritionist, but an oncologist. Throughout the history of cancer research, nutrition and cancer have been pretty much mutually exclusive. The biggest overlap comes from a discovery made by Otto Warburg in the 1920s, when he discovered an alternative metabolic pathway for cancer cells.

Let’s take a bit of an aside to provide some background information on what’s now known as the “Warburg effect.” In case you don’t know, my specialty is cancer research. It may surprise you, therefore, that I know next to nothing about the Warburg effect. My entire master’s degree is the molecular biology of cancer, and we never once had a lecture on the metabolism of cancer cells. (I was very disappointed about this, because it’s a topic I find fascinating and criminally under-taught). So here’s a “quick” summary of what the Warburg Effect is, given my own personal limited knowledge of it.

Spoiler: it ended up a bit lengthier than expected because I find this interesting. There’s a lot of biology words in here that I can’t really change, so my apologies for that. Don’t focus on the names, just try to get the main idea.

The Warburg Effect

First, let’s talk about how a normal cell gets energy. Normal cells use a process called oxidative phosphorylation to generate energy. This involves taking glucose (carbs/sugar is another way to think about that) and breaking it down to pyruvate in a process called glycolysis (lysis = break apart, pretty good name if you ask me). Pyruvate is then taken into the mitochondria (powerhouse of the cell, am I right?), broken down further into acetyl-CoA, which then enters the citric acid (TCA) cycle, which is a pretty complicated cycle so I won’t go into specifics. But it involves additional cofactors (cofactors = secondary molecules needed to achieve something) called NADH and the exchange of electrons (a convenient way for cells to exchange energy). This NADH is then used in oxidative phosphorylation and again is pretty complicated but involves the exchange of electrons with NADH and another cofactor called FADH₂ and oxygen (completing the ‘oxidative’ portion of oxidative phosphorylation) and finally, the all-important ADP. This ADP accepts a phosphate (completing the ‘phosphorylation’ portion of oxidative phosphorylation) to become ATP, which is the basic ‘unit’ of energy that cells use.

From this process, the mitochondria can generate about 36 molecules of ATP from a single glucose molecule. That may not seem like a lot, but this is incredibly efficient. Thanks, evolution! Because of this, the body has plenty of energy to use for the hundreds of thousands of cells it needs to feed.

Now, let’s think about cancer cells. Cancer cells divide quickly and require a lot of energy and a lot of ‘building blocks’ to make everything the cells need. But do cancer cells use this highly efficient, perfected-over-millions-of-years oxidative phosphorylation to satisfy its insane amount of energy needs?

No.

If you’re like me that first time I learned this, you’re probably thinking…what?

WHAT ARE YOU THINKING, CANCER CELLS!?! YOU FOOLS!

In actuality, this is an incredibly clever switch. Cancer cells just want to make more cancer cells as quickly as they can. This requires a lot of energy, but it also requires a ton of raw material to build cellular structures (mainly amino acids for proteins). To handle this, cancer cells switch from oxidative phosphorylation to aerobic glycolysis. This switch in metabolism is the Warburg effect (I know, we finally got there). Aerobic glycolysis is significantly less efficient and only generates about 4 molecules of ATP for each molecule of glucose. However, while doing so, cancer cells take a lot of the carbon molecules found in glucose and uses them for generating cellular components, such as palmitate, a critical component of cell walls (and you can’t have a cell without a wall, am I right?). In contrast, oxidative phosphorylation uses up most of the glucose carbons to make ATP – aerobic glycolysis provides a balance of energy and cellular building blocks, which is the perfect set up for a rapidly dividing cell.

Just Get to the Point of the Post Already…Please

So, what does this have to do with the Mukherjee article? It’s simple, really – Mukherjee makes the argument that altering diets will affect the cancer cell’s ability to function. Specifically, he focuses on the ketogenic diet (not just because it’s all the rage right now, it serves a purpose). In a keto diet, you essentially deplete glucose as the source of energy in the body. This occurs because keto diets are high-fat, low-carb diets. The liver soon runs out of carbohydrates (i.e. glucose) and switches to converting fat into fatty acids and ketone bodies – this is called being in ‘ketosis.’ These ketone bodies can then be used as the main source of energy instead of glucose. This way, the cancer cells are deprived of their main source of basically everything they need to grow so fast.

Outside of these nutrients, keto diets serve another, more complex purpose. One way to prevent the Warburg effect from occurring would be to attempt to prevent aerobic glycolysis from becoming the main energy source. To do this, we need to force our cells to signal that there is ‘low energy’ (i.e. low levels of glucose). This would force the cells to maximize energy production (ATP) and drive oxidative phosphorylation. This ‘low energy’ state lowers insulin and mTOR signaling (for those less versed in biological pathways, don’t worry about this it’s just a common pathway that happens in cells), while increasing a critical component of ATP production – a protein called AMPK (again, don’t worry about this, too complicated to go into right now). Guess what can force us into this ‘low energy’ state? That’s right – ketogenic diets.

Consequently, fasting also does this but people get hungry.

Mukherjee and his lab tested this hypothesis in lab mice and found that feeding mice a keto diet to suppress insulin along with standard chemotherapies improved outcomes. Specifically, the Mukherjee lab tested a common treatment, called PI3K inhibitors. The PI3K pathway is a main driver of cell growth and proliferation. This pathway can be activated in a couple of different ways, one of them being insulin. PI3K inhibitors have been used in cancer treatment for a while now to suppress this signaling pathway, in the hopes that cancer cells will then stop growing. However, PI3K inhibitors also raise glucose levels. This increase in glucose signals to the body that more insulin should be made, and this elevated level of insulin can counteract the effects of the PI3K inhibitor, rendering it useless. The findings from this paper showed that by reducing overall glucose (and therefore insulin) levels through a ketogenic diet, the PI3K inhibitors were more effective, thereby providing preliminary evidence that diets and standard medicine can work together to improve outcomes.

Of course, the promising results must be taken with a (rather large) grain of salt. Firstly, this was tested with one specific cancer treatment and one specific diet intervention. There’s no guarantee this would work in other circumstances – many, many more studies will be needed to definitively prove this hypothesis. Secondly, this was tested in mice (as most things are to start). Humans are vastly more complicated than mice and have many more variables to consider when it comes to treatments. Even minor things such as sleep schedules can affect how any diet affects us. However, the Mukherjee is in the midst of planning clinical trials to test this combination of PI3K inhibitors and keto diets, which is the true test of whether this hypothesis can hold true in humans.

Even with clinical trials, it’s going to be years before there are any definitive answers to this problem. It’s an immensely complicated issue that would have to be tested very strenuously. There are so many cancer treatments available today, and each one would have to be examined and specific diets determined for each one and various factors taken into account such as weight and sleep schedules and exercise and…well, you probably get the point. Do I think it’s impossible? Of course not. These findings from the Mukherjee lab surprised me, and I do think they are really promising. However, it’s going to take a lot of time and resources to find answers, and not many people are focused on this sort of research. Not impossible – just incredibly laborious.

Further reading:

• NYT article – Siddhartha Mukherjee
• Nature research article from Mukherjee’s lab
• Summary of Nature research article
• Ketogenic diet – Wikipedia
• Ketogenic diet – scientific article
• Warburg effect – Medium article
• Warburg effect – more scientific article
• Warburg effect – understanding it (scientific article)
• Emperor of All Maladies (seriously, read it)