HEAT SHOCK PROTEINS / NATURE'S IDEAS

The evolutionary origins of stress run surprisingly deep.

My work deals with how complex, mental effects, such as memory, arise from the behavior of simpler components — cells and molecules. What this work has taught me is how deep evolutionary ideas can run. There are molecules in living cells that have been doing the same thing for billions of years, even as the organisms for which they did those things became completely unrecognizable. There are molecules that, when turned on, make a living creature spend more energy and those that make it spend less — regardless of whether it is a plant, an animal, or a trypanosome, regardless of how it gathers its energy and how it chooses to spend it. There are molecules that create movement, molecules that defend against parasites, molecules that make cells grow — and they work in the exact same way across vast swathes of living creatures whose growth, movement and parasites look nothing alike. Some molecules are designed to discern patterns — and they can discern, in different organisms, patterns of neurotransmitters, patterns of sunlight, or patterns of water salinity. To put it another way, the ideas behind all these molecules — their essences — are more abstract than their specific implementation in a given species.

Besides memory and pattern detection (my own wheelhouse), another example of essences preserved in molecules even as organisms become unrecognizable is — stress.

Consider heat-shock proteins — one of the oldest parts in our cells’ molecular toolkit. Even bacteria have them, and not just similar devices independently invented, but apparently the very same design inherited from a common ancestor. The fact that they are so consistent across the tree of life means that heat-shock proteins must have been invented really early — at the very dawn of life on Earth.

What heat-shock proteins do is help fix other, damaged proteins. Proteins are complex machines consisting of intricately folded chains which can get easily twisted or unraveled. Heat can cause this, but so can many other things: wrong salinity, fluctuations in pH, chemicals. A misfolded protein, whatever it is doing in the cell, not only goes out of commission itself, but can also cause further problems, because misfolded proteins can cause more protein misfolding, and in the worst case scenario these proteins can all start clumping together, after which they become very difficult to get rid of (this happens, for example, in neurodegenerative diseases.) Heat-shock proteins prevent that by binding to a misfolded protein and wrangling it back into correct shape.

What did heat shock proteins originally evolve to do? Most likely, they did what it says on the package: help cells deal with heat, which can unravel and so render useless any protein — like cooking an egg. Ancient organisms, maybe still centered around an underwater hot spring where life is often thought to have originated, might have used HSPs to protect themselves from boiling alive. This would have been significantly earlier than even the most recent common ancestor of all life on Earth. As life diversified, other forms of protein damage became relevant, like oxidative stress. When oxygen first appeared on the planet (billions of years after life started), it was toxic, and still is — it is because oxygen destroys other molecules so violently that it’s useful for energy harvesting during respiration. Our bodies control oxygen’s violent tendencies and channel its destructive power using special oxygen-binding proteins in the blood and mitochondria. But some oxygen still leaks out and causes damage — it’s why we need all those antioxidants, and it is also something that HSPs help us deal with. Basically, the essence of HSPs was originally “heat protection”, which was later expanded to “stress protection” more broadly.

But get this: HSPs are also turned on in neurons in response to psychological stress. The stress doesn’t need to be physical. It might come from reading some stressful news and getting all worked up about them. Think about it. Some symbols get projected on your retina in sequence, from which you extract a mental pattern; you compare it to a memory — a pre-existing idea of how things should be; detect a discrepancy; anticipate a threat; alert a deep-seated cluster of neurons that specialize in making noradrenaline; they spray this noradrenaline across your brain; it is sensed by neurons all over; and in response to that, they start turning on their HSPs. Nothing has really happened to them yet. There is no heat, no boiling geyser, no chemicals, no proteins are getting wrecked. The cells are turning on the ancient program for “protein stress” in response to alerts sent to them by some distant ensembles of neurons in the visual and language parts of the cortex.

As a matter of fact, it makes a lot of sense. If your mighty, abstact-thinking, language-equipped brain has calculated that the world is not as it’s supposed to be, chances are, there’s going to be a lot of panicked activity in that brain going forward. Activity means energy use, depleted resources, strained production capacities, overuse of oxygen, collateral damage to proteins and other components of the cell. If you start preparing for this early, you will end up with less damage than if you simply react to it.

So stress is stress, and it involves some common themes and common ways to deal with them, no matter how complicated its causes are, no matter if you are a human living in a complex civilization, an animal running away from a predator, or a bacterium in a boiling geyser. A heat shock protein transcends the boundary between single-celled and multicellular creatures: in bacteria, you need to actually damage the proteins to get HSPs to respond, but in ourselves, the same response can be achieved using a special “danger” signal — a burst of noradrenaline. What you plug into this system changes — but its core essence remains the same.

Sometimes these biological essences are hard to discern. Sometimes they are redundant or not easily summarized. Absent a time machine and the ability to trace the fate of every living creature that had ever lived, it is impossible to know for sure what the essence of anything really is. But I believe that essences are, nevertheless, real — as real as human ideas, except they are ideas of nature itself, carved by selection into the logical structure of living matter. Figuring out those essences is what I am most interested in in my research. I do science so I can talk to God.