CANCER, HEALTH, AND BIOLOGY
CCBE — Part 10: New ideas about causes of and treatments for cancer
How discoveries in evolutionary biology and metabolic science are providing novel tools in the fight against cancer
Recap
Last time, we covered findings that raise issues with the genetic-mutation theory of cancer. Although genes do contribute to cancer, the nature of their contribution isn’t as clear as advocates of the genetic-mutation theory once suggested. These discoveries have encouraged researchers to reimagine the causes of and treatments for cancer, with some interesting ideas that build on points we’ve covered in the series so far.
This includes thinking about multicellular organisms as cellular collectives, understanding how evolution plays out at a cellular level within organisms, and the role of metabolism. Based on these principles, Kat Arney discusses clever research and novel approaches for how we may be able contain cancer rather than chase cures that seem unlikely to materialise soon.
There’s also fascinating evidence that metabolism itself may be a more potent driving force behind cancer than we previously realised. Nick Lane has many interesting things to say on the topic, with some simple and practical advice about managing risk factors for cancer.
Today
We’ll start with Nick Lane, and then hand the mic to Kat Arney. As we go through their ideas and suggestions, we’ll see how cooperation and competition can help us to make sense of cancer as a phenomenon in biology and evolution.
Cancer and metabolism
Nick Lane is an evolutionary biochemist who specialises in metabolism. As it turns out, this perspective offers useful insights which explain findings that defy the standard genetic-mutation theory of cancer. If you find this interesting and you’d like to learn more, I highly recommend his recent book Transformer: The Deep Chemistry of Life and Death.
The Krebs cycle (aka citric acid cycle)
Metabolism is a complicated beast. It is conventionally explained using the Krebs cycle. Also known as the citric acid cycle, this system of metabolic pathways was painstakingly pieced together by Hans Krebs in the mid-20th century. It occurs inside mitochondria, and involves an open exchange with the host cell.
The details don’t matter, but the point is that metabolism inside cells and mitochondria was found to involve a set of chemical reactions with a typical direction of flux. The conventional direction of flux uses electron theft (oxidation) as its mechanism.
This view remains the orthodoxy today, and is found in every textbook. But research has shown that metabolism is more flexible than we thought. Contrary to our assumptions, the Krebs cycle is just one way in which metabolism can function.
Different patterns of metabolic flux
For example, the direction of flux can also work in reverse, with some evidence that this might even be the original direction of metabolic flux. The reverse direction uses electron donation (reduction) as its mechanism.
And metabolism can do more than spin in two directions. The conventional view of metabolism as a cycle turns out to be too narrow, as metabolic pathways can take on a variety of different configurations.
The exact configuration that cells and their mitochondria adopt seems to depend on the requirements of the cell, and the conditions of the cell and its local microenvironment. What’s more, some of these requirements and conditions seem to encourage the growth of cancers.
For example, we mentioned in an earlier article that cancerous growth can be induced if a cell is starved of oxygen. We shift towards fermentation, with important consequences for the way our cells behave. Unfortunately, this type of microenvironment appears to tell our cells to grow.
If this microenvironment persists, or the cell picks up a few unlucky genetic mutations that lock this pattern of metabolic flux in place, studies suggest that this can drive the growth of cancers. The same can also happen if unlucky genetic mutations trick the cell into thinking it’s starved of oxygen, resulting in the Warburg effect.
Age, activity and fermentation
But there are other ways that our patterns of metabolic flux can be pushed in a cancerous direction. Even when our metabolism follows the classic flux of the Krebs cycle, this only works so long as the end product keeps being used. If the end product builds up, then the cycle can’t spin, and our metabolism is forced to work some other way.
In the Krebs cycle, one crucial end product is the universal energy currency: ATP. This means that so long as ATP is being consumed quickly enough, the Krebs cycle can continue to spin. But if ATP consumption gets too slow, cells will need to reorganise their metabolic pathways due to accumulation of an end product.
This principle is also the reason why wines can only ferment to around 15% alcohol content. When our cells ferment sugars, the end product is lactate, leading to lactic acid. When yeasts ferment sugars to make wine, the end product of their metabolic pathway is ethanol. But the process can’t continue once too much of the end product (ethanol) has accumulated, resulting in a roughly 15% ceiling on the alcohol content of wines.
Sedentariness and patterns of flux that promote cancer
What has this got to do with age, activity and cancer? Crucially, some metabolic configurations will increase the risk of cancerous growth. This happens when the Krebs cycle is choked up by too much unused ATP. The question then becomes, when do we not use enough ATP?
This brings us to two risk factors for cancer: sedentariness and age. The idea is straightforward. If we’re too sedentary, we don’t use enough ATP. This forces a shift in the metabolic pathways of our cells, putting us at greater risk of cancer.
In line with this idea, sedentary lifestyles are associated with a higher risk of cancer. Nick Lane suggests that this may also explain the number one risk factor for cancer: age.
Although young people do get cancer, childhood cancer is mercifully uncommon. In fact, our risk of cancer is quite low for most of our life. It starts to increase around our 40s, and climbs sharply as we reach our 70s.
Conventionally, this was explained by the accumulation of genetic mutations over a lifetime. But as we saw in the previous article, genetic mutations alone can’t explain the behaviour of cancer.
Instead, people like Nick Lane now suggest that the link between ageing and cancer may be related to metabolism. Specifically, we get more sedentary with age, and studies suggest that sedentariness can increase our risk of cancer.
More research is needed, but in my opinion, the perspective and arguments of people like Nick Lane have many impressive strengths. While nothing is certain, you can see why a lot of people are excited about fields like cancer metabolism.
Based on these insights, Nick Lane also offers some practical advice:
We are then at the mercy of our own lives — unfortunate genes, one cigarette too many, poor diet, bad sunburn, exhaust fumes, viral infection: sharp focus for the command ‘grow!’, set in a permissive metabolic context. If my argument in this chapter is right, the best we can do is keep our mitochondria active. Keep exercising. Breathe deeply. Eat carefully. Don’t fall back on fermentation, [use aerobic respiration] in your mitochondria as far as possible. … Nothing is failsafe, but there’s no doubt that regular exercise and a healthy diet will help to protect you against cancer. … I am asking you to nurture your mitochondria. Don’t let cell respiration run down, which is the underlying cause of cancer as we age … because declining respiration perturbs the Krebs cycle. — Transformer
Kat Arney on the mixed blessings of new cancer therapies and cellular collectives
To discuss Kat Arney’s ideas, we need to zoom out a bit. In her book Rebel Cell, she focuses on the body as an ecosystem and what we can learn about cancer by understanding ourselves as a cellular collective.
We’re a living symphony of cooperation, but cancer cells are cheats. They take space and resources from hardworking, rule-abiding neighbours. They belch out waste products that other cells clean up. Some waste products even damage other cells, generating debris that the cancer consumes in an insidious feedback loop. Cancers are bad cellular citizens.
As a geneticist and cancer researcher, Kat Arney hoped that we’d discover cures for cancer lurking in the science of genetics. To be sure, cases like Gleevec are a big achievement. But it’s an exception to the rule that the genetic-pharmaceutical approach has found limited success.
Techniques keep getting smarter and our understanding is always improving, but Kat Arney points out that most new treatments are prohibitively expensive. More importantly, they’re also not a big improvement on older treatments.
Using evolutionary thinking to outrun cancer
The core issue is that no matter what treatment we throw at the cancer, there’s virtually always a subgroup of cells that’ll be resistant to the treatment. The cancer may appear to go away, but in time that subgroup grows and the cancer returns.
Only this time it’s worse: the cancer’s now resistant to the treatment you used before. Variation in the population of cancer cells enables some to survive and propagate their genes when the cellular environment changes due to medical treatment. This is evolution at the cellular level.
We’re boxed in by this evolutionary dynamic. Right now, our goal is usually to kill all the cancer cells. This is intuitive, but turns out not to work very well due to treatment-resistant cancer cells.
To add insult to injury, treatment costs can be astronomical, especially in the USA, and many make you feel awful. This can be a grim way to spend the twilight of your life.
So how can we escape this trap? Kat Arney discusses ideas for how we can use the competitive nature of cancer cells to turn them against each other. Researchers are testing cancer treatments that take the evolutionary dynamics into account.
They apply the treatment, wait for the cells to go into remission, and then stop the treatment. That may sound bizarre, but there’s method to their madness. The idea is that you’ve now weakened all the cancer cells except for the treatment-resistant cells.
If you keep going, eventually the resistant cells will just regenerate the cancer, and you’re back at square one. But if you pause the treatment, the cancer cells will now fight amongst themselves for territory and resources. And while they’re busy fighting amongst themselves, you can carry on with your life.
This isn’t a cure, but early studies suggest that it can prolong length and quality of life. In theory, we may be able to at least manage cancer until we die of old age.
Key points
What have we learned? As usual, cooperation and competition are central to the workings of cancer specifically and biology in general. We saw how understanding cellular metabolism provides a powerful window into the principles of life and death.
Sadly, there are no guarantees or easy answers, especially when it comes to cancer. Because of the yin and yang of cooperation and competition, as long as there’s multicellular life, it’ll have to deal with cancer. But there’s hope that we may be able to manage cancer long enough to live to a ripe old age, at least in the future.
Next time
In the next article, we’ll discuss ourselves as an ecosystem. We’ll talk about the astounding (and partly creepy) discovery that we are essentially a living super-colony for microorganisms.
The tiny microbes that call us home turn out to have a lot to do with our biology, both in health and disease. And of course, they have loads to do with cooperation and competition. Until then!
