A Biochemist’s View of Life’s Origin Reframes Cancer and Aging

The electrons from one side to the other come from the cells. The genetic code is a universal feature of life. The two simplest categories of cells,bacteria and archaea, have different mechanisms for generating energy that are not the same. It's hard to know how the first cells met their needs.

Nick Lane is a professor of evolutionary biochemistry at University College London. What if life arose in a geological environment where a primitive form of metabolism was supported by a series of small barriers? The place where this might be possible is on the deep seafloor, inside highly porous rock formations.

Lane has explored this idea in a variety of journal papers, and he has written about it in his books, such as The Vital Question. In his newest book, Transformer: The Deep Chemistry of Life and Death, he describes the idea in more detail. His view is that metabolism is central to life and that genetic information comes from it. The nature of cancer and aging are two big mysteries in biology.

There are many theories in origin of life studies. Most scientists believe that life began with self-replicating combinations ofRNA and other molecule, and that it arose on or near Earth's surface. Some people think that volcanic vents in freshwater are better for life than deep vents on the ocean.

Research into how the need for energy has influenced and constrained the evolution of life has always been a central theme of Lanes career as both a scientist and a science writer. The Royal Society of London presented Lane with its Michael Faraday Prize for excellence in communicating science to the public in 2016 for his contributions to the life sciences.

Lane andQuanta spoke via video conference. The interview has been edited to make it clearer.

The view of "information first" is based on the idea that some process in the environment makes the nucleotides and then they link up into a chain ofpolymers. We have a population ofRNAs who are capable of both catalyzing reactions and copying themselves. How did theRNAs create all of the structures? Today, genes don't do that Cells and genes are part of the ride. Why do genes do it at the beginning?

How could they do it? There are 10 steps in a biochemical pathway, and any one step alone is not very useful. It is not true that every product in a pathway needs to be useful for it to evolve. It looks like it's hard to evolve a single path.

What’s the alternative?

The alternative is that you get small amounts of interconversion from one intermediate to the next all the way down the path. It wouldn't be very fast, but it would be there, and it wouldn't be very far away. When a gene arises at a later stage, it can cause any of the steps in the pathway to be activated.

It makes the problem simpler. All of the chemistry in this pathway has to be favored. It becomes increasingly frightening when you say that the core of biochemistry is favored in the absence of genes.

There was no evidence for this position in the past. At least three or four of these pathways have been demonstrated to happen in the lab. Some of the pathways are incomplete. It seems as if it is not unreasonable to say that genes came into existence in a world where we already had some very sophisticated Proto-metaboloism.

Let’s talk about how the proto-metabolism could have evolved in deep-sea hydrothermal vents. What is it about the vent environment that makes you think it favored the beginnings of what we call the Krebs cycle, the metabolic process that derives energy from carbohydrates, fats and proteins?

Life begins with hydrogen and carbon dioxide, which don't react very quickly. Life makes them react. Life uses an electrical charge on the membranes to transfer electrons from hydrogen to iron sulfur in some organisms. The iron ion and sulfur ion clusters at the heart of ancient proteins are very small. There are thin barriers in the porous rock with an electrical charge on the minerals.

Is the structure at the vent effective in driving the reaction between carbon dioxide and hydrogen? The answer we are getting in the lab is that it does. We don't get a lot, but we are getting more as we begin to improve our process. Nitrogen will give you the same amino acids that life uses.

This chemistry is preferred by nature. The electrical charges on the vent seem to lower the barrier to the first step, so the rest can occur. You can imagine snuggling into the cell-like pores, structuring themselves into cell-like entities and making more of themselves if you have a continuous flow of hydrothermal fluids going through this reaction. It's a very rough form of growth, but it's realistic.

But then how did these first proto-cells become independent from the proton gradients they got for free in the hydrothermal vents?

The answer appears to be that you need genes to be independent. The fundamental question is where and when the genes come in.

We have shown that if you introduce a random sequence ofRNA and assume that the nucleotides in it can change, you will get small chains of nucleotides. Seven or eight random letters with no information in them. Two ways this can help you. It can templating an exact copy of the same sequence even if there is no information in it. The second thing it can do is create a template. There are no specific biophysical interactions between the letters inRNA and the amino acids.

You have a random sequence ofRNA that can be used to make a nonrandompeptide. There is a chance that the nonrandompeptide has some function in a growing cell. It could help the cell grow or grow worse, it could help theRNA replicate itself, and it could bind to cofactors. You have to choose between the peptides and theRNA sequence. We have just entered the world of genes, information and natural selection.

We went from a system without information to a system with information with no change in the system itself. RandomRNA was introduced all we've done. Is it real? According to them, ugly facts can kill the most beautiful ideas. I can't believe it's not true because it has such high explanatory power

So in the hydrothermal vents we get some Krebs cycle intermediates. But then how did they all come together as a cycle? Is it significant that this works as a cycle rather than as a linear chain of reactions?

The Krebs cycle performs the same energy generating reactions over and over. The Krebs cycle can do both things. In our mitochondria, carbon dioxide and hydrogen are taken out of intermediate molecule to create an electrical charge on a membranes. In ancientbacteria, it uses the electrical charge on a membranes to drive reactions with carbon dioxide and hydrogen to make the intermediates, which are needed for growth.

The Krebs cycle is still used by our cells in ancientbacteria. Since the 1940s, we have known that the Krebs cycle can run back and forth in our cells, and that its intermediate molecule can sometimes be used as a starting point for making Amino Acids. The needs of our cells are what determine the balance of the two processes. There is a sort of balance between the two.

The flight muscles of pigeons were the first to be discovered and they were the most energetic cells. The Krebs cycle is more like a roundabout than a cycle, with things coming in and going out. It is a roundabout that can go in either direction.

How was the rise of oxygen connected to the favored direction of metabolic flux and the evolution of the first multicellular animals? 

When oxygen levels were low, the first animals seemed to have evolved. The mud was full of sulfide and they crawled in it. The early worms had to deal with a lot of carbon dioxide in their environment and they needed some oxygen to crawl.

I realized that the only way to do that is to have different types of tissue. You need muscles and a respiratory system when you crawl. One of the two types of tissue has to provide oxygen when you need it and the other has to operate in the absence of oxygen. They have to do their chemistry in a variety of ways. You have to do two or three things at one time.

There was a group of simpler organisms called the Ediacaran fauna. About 540 million years ago, when oxygen levels in the environment fell, they were gone from the ocean. The Ediacaran fauna only had one thing to do at a time. They couldn't adapt to the new environment when oxygen levels fell.

You can do things in parallel if you have more than one tissue. It's possible to balance what this tissue is doing with what that tissue is doing You can't do both at the same time, it's more difficult to do one or the other We have different metabolisms in different parts of the body.

Tissue differentiation isn't just about having genes that say, "This is going to become a heart," or "This is going to become a brain." It allows lifestyles that were not possible before, and it allows the first worms to get through bad conditions. The explosion took place after that. The only shows in town were these worms with multiple tissues.

This ties into some of your ideas about cancer. Since the 1970s, most of the biomedical establishment working to cure and prevent cancers has focused on oncogenes. Yet you argue that cancer isn’t a genomic disease so much as a metabolic one. Can you explain why?

A decade ago, the cancer community was amazed by the discovery that certain cancer genes can lead to other cancer genes. The Krebs cycle is usually only used to generate energy, so it came as a big surprise. Carbon-based building blocks are what a cancer cell really needs to grow. The reversal of the Krebs cycle was seen as a type of metabolic rewiring that helped cancer cells grow.

The reinterpretation of the fact that cancer cells grow by aerobic glycolysis was caused by this discovery. Cancer cells switch from burning oxygen in their mitochondria to making energy from yeast cells even in the presence of oxygen. Otto Warburg focused on the energy side of the story. The cancer community now believes that the change is related to growth. Cancer cells are freed up by using aerobic glycolysis for energy. Building blocks of life are made by cancer cells.

You can see oncogene changes in cancer. The cause of cancer isn't simply a genetic variation that causes cells to grow. A permissive environment for growth is provided by metabolism. Genes come before growth in this sense.

What makes us more vulnerable to cancer as we get older, if it’s not an accumulation of mutations?

It's more likely to reverse into synthesis if there is damage to the Krebs cycle. The central part of our metabolism is more likely to go backward or not go forward as we age. It means that we will have less energy and that we will put on more weight because we will start turning carbon dioxide into organic molecule. Our metabolism is prone to growth that increases our risk of diseases.

The gerontology community has been discussing these topics for a long time. Being old is the biggest risk factor for age related diseases. Most age related diseases could be cured if we could solve the underlying process of aging. It seems very easy to understand. Are we going to live to 1200 or 1400? I don't think it will happen in the near future. The question is why not.

Why do we age? What causes the mounting cellular damage?

Over the last five or six years, we've found that Krebs cycle intermediates are potent signals. If the cycle slows down and goes backward, we will accumulate intermediates and things will start to go bad. They switch on and off thousands of genes. Your state of metabolism is reflected by aging.

metabolism involves 20 billion reactions a second, second after second, in your body The amount of molecule being transformed continuously in all these pathways is overwhelming. It is an inexorable river of reaction. We can try to channel it a little better between the banks.