We're All Bags of Bitchy, Demanding Enzymes

and that's okay. Don't overthink it.

My mom was a molecular biology professor and I was something of a delinquent skateboarding child on the school-to-prison pipeline. During my occasional bouts of suspension, I would go to my mom’s office for the day. Sometimes she’d put me to work cleaning glassware, other times I’d be plating yeast or counting cells on a hemocytometer to think about what I’d done. Occasionally, I’d be free to roam the department and, every time I was free, I went straight to Eric Toolson’s office.

Eric Toolson is a legend in my mind. He is biology professor who looks and talks more like a Hells Angel. With long grey hair, sophisticated glasses and imposing facial hair, Eric would drive a Harley Davidson to work, occasionally swear like a sailor, but think and talk like philosopher. When the glassware was cleaned, the yeast plated, and the cells counted, I would roll up to Eric’s office with my skateboard and he’d ask me if I wanted to see snakes eat mice.

Who could say no to that?

As the mice were devoured, Eric would bring the scene to life with detailed explanations of how constrictors cut off the gas exchange and oxygen circulation in their prey, how hemoglobin carrying CO2 in the brain would just sit there and hemoglobin in the lungs would not have any O2 to bind because the force of constriction from the snake exceeds the force of expansion from the diaphragm. The mouse would exhale, the snake would constrict like a vice, leaving no more room for inhalation.

There were also venomous snakes in the department that needed feeding. I had established myself as an experienced reptile handler, having bred a few generations of bearded dragons, and my uncle at one point had what I’m told was the largest personal rattlesnake collection in the US. As mice dangled in the cage and rattlesnakes snakes stared at the mice with serpentine tongues licking the air, Professor Hells Angel regaled the tale of how venom works. The snake lunged at the mouse, fangs flying through the air and piercing the skin of the mouse. While the snake kept the mouse submitted in its jaws, a corrosive, destructive cocktail of enzymes spread through the mouse’s blood stream. “Cellulolytic” enzymes capable of breaking down cells, “proteolytic” enzymes that break down proteins, “neurotoxins” that jam the airwaves to interfere with neurons trying to send critical messages to the lungs to breathe or the heart to beat - these enzymatic bad-asses make venom what it is. Every snake species had a unique cocktail of toxins, and their portfolio of pain would degrade the tissues and inhibit critical systems in the mouse.

Eric would say that if you were to zoom into the body of a snake, zoom inside the cells, and zoom up close to all the molecules that make the snake what it is, you would see a chaotic swarm of chemical reactions occurring as cells from the mouse inside the snake are broken down into fats, fats converted to sugars in a process called gluconeogenesis, sugars burned with oxygen and converted to water, carbon dioxide, and tiny packets of energy called ATP in the Kreb’s cycle, and all of these reactions, all the changes in states of matter in life, are being catalyzed by enzymes. That’s worth repeating. All these chaotic changes in states of matter in life are not changing willy-nilly, but being ushered from one form to another, catalyzed by enzymes. The degradation of skin, the conversion of fats or sugars to ATP, the little firecracker explosions of ATP that powered the muscles that caused the snake to strike - everything, everything was done by enzymes, Dr. Toolson told me.

Enzymes are proteins. Proteins are the primary things whose instructions are encoded in DNA. This always requires explaining, but with enough iterations it becomes clear, the connection between DNA and proteins and all of life.

Chains of nucleic acids in DNA are rich with information in the form of A’s T’s G’s and C’s lined up from one end to another in sequence. The DNA sequence is “translated” from a chain of nucleic acids to a chain of other compounds called ‘amino acids’ and that translation is done by - you guessed it - enzymes. RNA polymerase is an enzyme that “transcribes” DNA books in the nucleus of a cell into RNA photocopies sent outside the nucleus, and ribosomes are enzymes that “translate” the RNA photocopies into chains of amino acids.

Amino acids in that long chain contain positive and negative charges, side-chains that are attracted to water and other side-chains that are like oils & ‘afraid’ of water or ‘hydrophobic’. Those sticky, charged, and hydrophobic chains of amino acids then roll & fold up like a chain of magnets that crumple into a ball to make a protein like the keratin or an enzyme like the ribosomes that make other enzymes. Those ribosomes hang out inside the cell while the keratin is then put in the right place and becomes the hard stuff your hair & fingernails are made of. Other proteins made by other sequences of DNA become the hemoglobin that shuttles O2 and CO2 around the body, the pumps on neurons that make them “fire” and produce our entire conscious experience from what we see when our eyes look at a snake eating a mouse to how we feel when we read about predation in a tank, and more.

Thousands of such sequences of DNA encode all the proteins in our body and those sequences of DNA make all those others structural proteins and catalytic enzymes that either make the molecules the mouse is made of, break down the mouse into its constituent molecules, or break those molecules down into even simpler packets of energy that help the snake strike again tomorrow. As your eyes follow these words across the page, they are moved by muscles, and those muscles are moved by tiny proteins that more or less pull connected cables back and forth to expand and contract muscles, helping your eyes move from one side of the page to the other. If you’ve had food in the last 48 hours, then inside your belly there is a supernova of chemical reactions converting energy and nutrients from your food into simpler packets your body can transport across the linings of the intestines (using enzymes!) ship around in the blood and use elsewhere (with enzymes). That same enzymatically guided supernova of digestion, absorption, and transport inside of us happens inside the snake as energy and nutrients in the mouse are bundled up into simpler packets the snake can use, plus some leftover products the snake poops out.

I probably learned more on days when I was suspended from school than on days I spent in school, all thanks to the *ahem* easily digestible descriptions of animal physiology provided by a professor who drove a Harley and who saw the intellectual potential in a young delinquent.

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After graduating from high school, I put my delinquent days behind me. There are reasons for that, but that’s another story. In college, I studied diligently, got straight-A’s, and did research on everything from studying the atoms and isotopes that flow through lizards in the grasslands south of Albuquerque to studying the catalytic evolution of enzymes that evolved to break down penicillin. In my later years in school, I had the honor of continuing my physiology education in Professor Toolson’s Animal Form & Function class. I thought I’d seen that legend shine in my youth, but little did I know - this man was one hell of a professor.

The class started off with Big Eric Toolson telling us stories about a tiny little snail in the British Isles called the periwinkle. Periwinkles live in the intertidal zones of a cold ocean, meaning that during high tide the periwinkles live underwater and their body temperatures get close to the freezing temperatures of the northern seas. When the tide rolls out, the periwinkles stay put and live for hours on dark rocks exposed to air that heat up like cast iron skillets in the sun. Every day the periwinkles go from freezing cold to scorching hot and back again.

How do periwinkles manage to survive such a massive range of temperatures?

Just like the snake eating the mouse, the periwinkle is really, if you zoom in far enough, just a massive galaxy of chemicals and chemical reactions. Its shell is a protein, its blood is like our hemoglobin shuttling oxygen back & forth, its enzymes are like the snake’s breaking down food, converting sugars to ATP, and lighting ATP firecrackers to power its muscles.

As temperatures rise, chemical reactions happen at a faster rate - this is why we heat water and sugar to form starch, caramel, or fudge, as heating water and sugar increases the rate at which water reacts with sugar to join simple sugars together into longer, stickier chains. Conversely, as temperatures cool, chemical reactions slow down - this is why we refrigerate food, as decreasing the temperature decreases the rate at which bacteria or other contaminating microorganisms can eat, digest their own food, manufacture their own proteins & reproduce on our food. This is why milk goes sour faster when it’s left out than when it’s refrigerated.

Organisms maintain a delicate balance of chemicals, all in the right ratios of one-another. We are made up of waters, sugars, fats, amino acids, salts, and more. In order to survive, our bodies must maintain the right ratio of sodium or potassium to water in the blood or else our neurons that rely on pumping potassium might not fire the way textbooks idealize (e.g. causing cramps). We must maintain the right concentration of salts in our brains, the right concentrations of CO2 in our blood, the right concentration of sugar in our blood (diabetics can easily get too much or too little sugar in their blood). Our lives are a delicate, balancing act of trillions of chemicals reacting with one-another. When we zoom in far enough and see this dizzying mess of chemical reactions, it’s a wonder of the world that we exist in the first place. In order to persist, we have to keep this galaxy of chemicals in balance.

That balance has a name: “homeostasis”.

So, when the tide recedes from the British Isles and the sun cooks the skillet of a rock, the periwinkle sits there and its body temperature rises perilously. All else equal, the busy metropolis of chemical reactions should start happening at faster rates. The chemicals sit there like cars in traffic in a vast network of roads, and increasing the temperature is like taking traffic in NY and telling everyone to hit the gas. How does the periwinkle not get chemical pileups and backlogs throughout the metabolic highways as temperatures rise?

How does the periwinkle not die when it’s cooking on the hot rocks in the sun?

Professor Toolson smiled: “Enzymes, and evolution.”

The proteins and enzymes that catalyze reactions inside all of us are something like tractors of the cell that move chemicals from one form/pile into another (in this analogy, DNA contains the blueprint of the tractor). However, proteins differ from tractors in that if you were to sit down and look at a tractor, it would stay more or less the same shape. Proteins, on the other hand, are wobbly, wiggly, objects whose structure changes with changing chemical conditions. All those positively or negatively charged amino acids behave differently if there is more sodium, a positively charged ion, or more carbonate, a negatively charged ion, a higher pH, a lower pH, and so on.

When an organism survives a lifetime in the intertidal zone, “makes it” and reproduces, that organism has persevered not only thanks to its ability to acquire resources at the scale of a snake eating a mouse or a periwinkle eating algae but also because it was able to survive at that messy, molecular scale of wobbly proteins and chemical reactions occurring in a vast network whose reactions accelerate and decelerate with changing temperatures.

Over millions of years of evolution, natural selection acts on these wobbly proteins not just to help them catalyze reactions at an optimal rate on the average temperature experienced by snail, but also to change their structures with changes in the environment to ensure the snail can maintain "homeostasis” as temperatures swing and the periwinkle experiences the full variance of temperatures it experiences in its day. As temperatures rise, the periwinkle’s proteins change their shape to become slightly less able to catalyze key chemical reactions that would otherwise lead to chemical pileups. While temperature rises would typically increase the rate of chemical reactions, these “conformal” changes to the structure of the periwinkle’s enzymes counteract that, slowing the rate of the reactions and helping the snail maintain homeostasis.

Professor Toolson spent two weeks talking about Periwinkles and beyond. Not only does this apply to snails, but it also applies to dogs. Every dog breed needs to maintain a constant body temperature, but dog breeds differ in how well they can maintain a constant body temperature. As temperatures get too hot, the dogs pant. As temperatures get too cool, the dogs shiver. Panting and shivering consumes energy. Dogs get energy from converting sugar into H20 + C02 (with enzymes of course), and so the rate at which dogs exhale C02 can be used to estimate their metabolic rate.

If you plot the metabolic rate of dogs - and other mammals - as function of temperature, you see a curve that typically looks like a cross-section of a plate with a flat bottom that rises up on both sides. The flat bottom of the plate is called the “thermal neutral zone” - it’s the range of temperatures we can inhabit without panting, sweating, or shivering, using only those Periwinkle-esque protein tricks to maintain homeostasis despite changing temperatures. Outside the thermal neutral zone, extreme temperatures require extreme measures, increases in metabolic rate as our bodies sweat to cool our skin & maintain a constant body temperature in hot environments or shiver to generate heat & maintain a constant body temperature in cool environments.

“Everything,” Dr. Toolson said, “everything about our physiology is driven by enzymes, and enzymes were selected over the course of evolutionary time.”

“Now go home and think about this,” said Professor Hells Angel, “but don’t think about it too much. If you think about it too much, you’ll realize that all of us - you, your parents, your dog, your crush, everyone - we’re all just bags of bitchy, demanding enzymes. You’re setting up an umbrella at the beach to please your demanding enzymes that can’t stand the heat outside your thermal neutral zone. You’re drinking Gatorade after you run to please your demanding enzymes on your neurons that can’t stand having inadequate electrolytes in the blood. You’re feeling something like love because of a complex swirl of neurotransmitters, neurotransmitter receptors, and downstream enzymes that react to neuronal activation in your brain have all evolved to make it feel good to reproduce. Every breath you take, every beat of your heart, every piece of food you digest, is all done by and for the proper functioning of enzymes. Think about this, but don’t think about this too much.”

“If you think about this too much, I worry that you’ll fall into a nihilistic funk, drop out of school, become an unhappy bag of enzymes, and your parents will write me hate mail. So, study this, come to my office hours if you have any questions and do well on the test. Don’t dwell on it, because no matter how close you zoom in to the mess of life, you’ll never find the answers you’re looking for.”

With that, Eric dropped the chalk, nodded to the class, hopped on his Harley Davidson motorcycle, and rode off into the sunset.