I’ve always been told that I have a fast metabolism. I stay thin no matter what I eat; it’s only in the past few years, as I’ve entered my mid-thirties, that I’ve experienced growing horizontally. I play squash a few times a week, run with a friend on Thursdays, and walk the dog. Otherwise I spend whole days at the computer, then sedentary on the couch, then asleep. And yet I stay lanky and get “hangry” easily; in the afternoons, after a hearty breakfast and two helpings at lunch, I go looking for another meal. I sometimes wake up hungry in the middle of the night. Where’s all the food going?
Our bodies require a lot of calories, and most of them are spent just keeping the machine running. You don’t particularly feel your liver, but sure enough it’s always there, liver-ing; likewise your kidneys, skin, gut, lungs, and bones. Our brains are major energy hogs, consuming around a fifth of our calorie intake despite accounting for just a fiftieth of our body weight on average. Possibly mine is less efficient than yours: I have an anxious cast of mind—I ruminate—and maybe this is like running in place. I sometimes feel sluggish while writing, after working a paragraph over in my head, and I used to assume that this meant I needed caffeine. Eventually, I discovered that a sandwich worked better. The effort of thinking had run my calories low, and it was time to throw another log on the fire.
Fire isn’t merely a metaphor for metabolism. In the eighteenth century, the French chemist Antoine-Laurent de Lavoisier conducted a series of ingenious experiments to prove that our life force was fire. First, he figured out what air was made of; he then, through precise measurements, showed that fire removed oxygen from the air and deposited it in the form of rust. Later, he made a device in which packed ice surrounded a compartment that could be filled with either a lighted flame or a small animal; by measuring how much ice melted, he could relate the energy burned by the flame to that “burned” by the creature. He even created a “respirometer,” an apparatus of tubes and gauges that measured a person’s precise oxygen consumption as they took on various tasks. He concluded that “respiration is nothing but a slow combustion of carbon and hydrogen, similar in all respects to that of a lamp or a lighted candle.” Both flames and living beings exchange energy and gases in what’s known as a combustion reaction. In fire, this reaction runs fast and out of control: energy is ripped from fuel with violent abandon, and nearly all of it is released immediately, as light and heat. But life is more methodical. Cells pluck energy from their fuel with exquisite control, directing every last drop toward their own minute purposes. Almost nothing is wasted.
Clearing up how exactly this is accomplished took another several hundred years. The breakthrough came in the nineteen-thirties, when a brilliant Hungarian chemist named Albert Szent-Györgyi made a study of pigeons’ breast muscle. The muscle, which was strong enough to keep the birds in flight, turned out to be metabolically hyperactive even after it had been pulverized. Szent-Györgyi put some ground-up tissue in a dish, then made careful measurements of the gas and heat emitted as he introduced various chemicals. He found that certain acids increased the muscle’s rate of metabolism more than five-fold. Strangely, these acids weren’t themselves consumed in the reactions: Szent-Györgyi could take as much out of the dish as he’d put in. The acids, he realized, participated in a kind of chemical roundabout, speeding up, or catalyzing, metabolism even as they were constantly being broken down and rebuilt.
A few years later, a German biochemist named Hans Krebs described this chemical cycle more completely, and today it’s known as the Krebs cycle. You may dimly remember the Krebs cycle from high-school biology class—or perhaps you forgot it right after the test. For a long time, the Krebs cycle was a symbol of what I disliked about school—a perfect emblem of boredom and bewilderment. Sitting at desks arranged in rows, we were told the monstrous names of its component parts—succinate, pyruvate, Acetyl-CoA, cytochrome c—while, on the blackboard, we counted NAD+s and FADH2s, and followed “redox” reactions as they “oxidized” or “reduced” elements. I memorized the diagrams in the textbook—arrows, small fonts, tiny plus and minus signs—without ever really understanding what the cycle was for. I was hardly alone in my incomprehension. In the thirty-eight-year run of the modern “Jeopardy!,” the Krebs cycle has been asked about only six times. It has stumped all three players onstage twice.
It’s a shame that organic chemistry has such dread associations, when really there’s so much beauty in it. As the biochemist Nick Lane writes, in his book “Transformer: The Deep Chemistry of Life and Death,” the Krebs cycle is particularly magical—it’s the foundation not just of metabolism but of all complex life on earth. And it’s not really that hard to grasp. Nowadays, even those of us who skipped A.P. Bio are conversant with genes; thanks to the pandemic, we may even know what we’re talking about when we use words like “protein” and “mRNA.” Lane argues that our DNA literacy is actually a form of genetic chauvinism. The secret of life isn’t entirely written in our genes; it also has to do with how we pull energy out of the world—with our ongoing, lifelong slow burn. Understanding the Krebs cycle is worth it because it helps you better understand what it means to be alive.
It’s through the Krebs cycle that we get energy from the food we eat. To grasp how the cycle works, it’s useful to remember what food is made of. Like everything else in the universe, the stuff we eat is made of atoms. An atom is like a little solar system, with a nucleus at its center. Electrons orbit the nucleus like planets circling a sun. (Although actually, according to quantum mechanics, you can’t know exactly where an electron is at any moment—and so really this orbit is less of a fixed path than a sort of cloud of possible positions.) There might be one electron or several within any given atom; they orbit at certain typical distances, known to chemists as orbital shells. Only a finite number of electrons can occupy an orbital shell at any one time: two in the first shell, eight in the second, eighteen in the third, thirty-two in the fourth, and so on—a pattern that defines how the rows of the periodic table are laid out. All of chemistry depends on the fact that electrons that aren’t part of fully filled shells are less stable, especially as they get farther from the nucleus. It’s as if an electron is not meant to wander too far from home.
From time to time, something bumps into an atom. If it’s a photon—a particle of light—then energy from the collision knocks an atom’s electrons into orbits that are more distant from the nucleus. These “high-energy” electrons are like marbles poised on the lip of a bowl—they want to release their potential energy by rolling back down toward the center or, if another atom is near, by spilling over into its bowl. Which way they fall depends on the precise balance of instabilities in each atom—in other words, which has the shell most desperate to be filled. When an atom poised to give up an energetic electron gets close to a neighbor eager to take it, that electron rolls from the lip of one bowl down into the other. In falling, it releases energy. However abstract this may seem, it is the very essence of life. Photons careening from the sun bang into electrons in chlorophyll in plants; a series of chemical reactions transfers those energized electrons from one atom to the next, until eventually they are stored up inside the sugars or starches in fruits, stalks, and seeds.
On a molecular level, a potato isn’t so different from petroleum: it contains molecules rich in high-energy electrons. Through our metabolism, we hope to capture the energy possessed by those electrons in a manageable way. Szent-Györgyi is often credited with saying that life is nothing but an electron looking for a place to rest; the marbles roll downhill, and life makes use of their force. The difficulty is that the electrons with the most energy available don’t just present themselves for the taking. Food is complicated and full of different molecules, many of which contain raw materials that we recycle into the physical structures of our cells. Finding the atoms that are especially dense with energy inside our food is like sifting through a heap of wrecked cars to find the still-charged batteries.
A surprising amount of this sifting happens before we even swallow our food, as the saliva in our mouths breaks down its starches. (Try spitting in a cup of Jell-O pudding and see what happens.) We start to feel sated well before we digest, because our mouths tell our brains that energy is coming and that it’s safe to release some short-term stores. In the meantime, acids in the stomach and enzymes in the small intestine start processing what has arrived. By the time they’re through, the energy-rich molecules in food have had their most restless electrons reshuffled and packed into glucose, a simple sugar. Glucose is like a chemical shipping container. It is an ideal electron transporter, in part because it is high-capacity, conveniently shaped, and easily opened up. It’s also unusually soluble, which means that it travels well through the bloodstream. And it consists only of carbon, oxygen, and hydrogen atoms. The latter two types of atoms are highly reactive—there’s a reason why tanks of hydrogen and oxygen are marked “flammable”—and many unstable electrons circle each atom of carbon, eager to move into other molecules. Our brains, whose parts have especially unpredictable energy requirements—as neurons fire, they create spikes in demand—depend almost exclusively on glucose for energy. Hummingbirds, which have the fastest metabolism of any animal and no time to spare to fuel their wingbeats, similarly feed on a mixture of pure glucose and sucrose.
When glucose reaches our cells, it is—unlike a shipping container—dismantled systematically. A series of reactions strips its highest-energy electrons and uses them to form a small “carrier molecule” known as an NADH. If glucose is like a shipping container, then NADHs are like delivery trucks. The process of loading the electrons into the trucks is called glycolysis. It’s ancient; in fact, it’s how yeast cells harvest energy. When glycolysis occurs in the absence of oxygen, it is known as fermentation. If your muscles are pushed to their limit and there’s not enough oxygen in your bloodstream, your cells ferment glucose as a stopgap measure for energy production.
If there is oxygen involved, the breaking down of glucose becomes much more refined. Oxygen is so hungry for electrons—its outer shell needs only two more to get a complete set—that in effect it pulls them all the way through the Krebs cycle, which is the real powerhouse of our metabolism. The cycle itself is complex, with sequences of chemical formulas that seem purpose-built to traumatize students. But, essentially, glucose is broken in two, and its halves are fed into a series of reactions that strip them for parts; the backbones are then reused for another turn of the cycle. The main thing is that, along the way, energy-rich electrons are peeled off and loaded up onto yet more NADHs—far more than in glycolysis alone. Almost no energy is lost to heat; instead, it is preserved and transformed. Any electron that had a high orbit in glucose is likewise poised at its full potential in NADH.
These NADH molecules will be further transformed. Inside a typical cell in your body are hundreds of thousands of mini-cells called mitochondria—structures believed to have descended from a free-floating bacterium that was ingested by one of our ancestors long ago and coöpted. A mitochondrion is divided into an internal and external chamber by a convoluted border with many folds, which create a huge surface area. Proteins protrude from this membrane like rabbits poking their heads through a hedge. These proteins capture an NADH, then pull its electrons through to the inner chamber, where they finally come to rest in molecules of oxygen. (When oxygen isn’t present, the electrons back up, and the work comes to a halt.) The movement of each electron is timed and arranged just so to cause a proton in the form of a hydronium ion, which is positively charged, to head in the opposite direction. At the moment that the protein pulls each electron inward, it also disgorges the proton, pushing it from the internal chamber to the external one. This extrusion happens everywhere across the membrane. The result is that many positively charged protons build up outside, separated by a wall from the negatively charged electrons held inside. An electrical field comes into being. Quite literally, each mitochondrion becomes a battery, waiting to discharge.
“This charge is awesome,” Lane writes in “Transformer.” The electrical field generated by the process, he explains, has a strength of around thirty million volts per metre—“equivalent to a bolt of lightning across every square nanometre of membrane.” At any moment, in each of your cells, the clouds are gathering, crackling with potential. And yet even this understates the absolute craziness of metabolism; it is wild what happens to those protons. Pulled by the electrical current, they desperately want to get back to the inside of the mitochondrion, where the electrons are. Their only way back, however, is to squeeze through tiny mushroom-shaped conduits that litter the membrane. In 1962, scientists discovered that these conduits are actually little turbines. Seen in minute detail through electron microscopes, they resemble waterwheels; the protons turn them as they pass.
In hibernating bears and newborn humans, the turbines generate heat, which is stored in fat. More commonly, though, each turn of the wheel assembles a molecule of adenosine triphosphate, or ATP—the energy currency of our cells. By dint of its structure, ATP is extremely willing to give up its energy, but it is prevented from doing so by a few precisely controllable molecular speed bumps—like a loaded-up spring held fast with a lock. The generation of ATP amounts to the generation of order out of chaos. In our food, energy is stored in an arbitrary way. But each molecule of ATP is endowed with a standard amount of energy, created by the physical motion of a molecular gear. ATP is used in every kind of cell, where it’s converted into kinetic, chemical, or electrical energy. Our muscles contract when a protein called myosin climbs along a microfibre, crunching it more tightly—each step along the fibre costs one ATP. In our kidneys, ATP powers a chemical pump that recovers ions from our urine. In our brains, ATP endows neurons with their electrical charge. The thunderclouds in our mitochondria are bottled up, shipped, and uncorked.
Lane writes that the “proton motive force” of those little turbines is one of the few mechanisms present in all life forms. In you and me and everything that lives, high-energy electrons are stripped slowly of their verve. Metabolism achieves something miraculous: through painstaking atomic transformations, it extracts from practically any organic chemical a universal unit of energy, deployable in every corner of every cell, and it does this while wasting nothing. Life’s use of a standardized part like ATP is almost Taylorist; the efficiencies are unfathomable. A body ingests charged particles and sends them through tiny windmills; a brain crackling with a hundred trillion electric connections can be powered for a whole day by a sandwich.
It was bold of Lane to write an entire book about the Krebs cycle. Although “Transformer” is aimed at laypeople, it’s not a particularly easy read: there are diagrams of chemical reactions alongside talk of succinate, oxaloacetate, and the reduction of this and that. Reading it, I had to consult Wikipedia and Khan Academy. And yet Lane is passionate about the complex biochemistry he describes, in part because he thinks that understanding metabolism could help us understand a great deal more, from cancer to the origins of life.
Biologists have been somewhat gene-obsessed ever since the discovery of the double helix, in 1953. The central dogma of molecular biology—it is actually called that, the Central Dogma—puts information at the heart of life, and describes how it flows from DNA to RNA to proteins. In the nineties, the gene’s-eye view culminated in the multibillion-dollar Human Genome Project, which promised that genetic sequencing at great scale would answer many of biology and medicine’s most vexing questions. Cancer researchers, accordingly, have tended to take a gene-centric approach to studying the disease: one major effort in the style of the Human Genome Project, the Cancer Genome Atlas, has catalogued millions of potentially cancer-causing mutations across tens of thousands of genes. On the treatment side, the biggest breakthrough in recent memory, immune therapy, can involve genetically modifying immune-system cells so that they target tumors that express a unique DNA sequence. The approach has “really revolutionized therapy,” Raul Mostoslavsky, the scientific co-director of Massachusetts General Hospital’s cancer center, told me. But genes are only part of the story. “It’s very well established that unique features of metabolisms are key in cancer and aging,” Mostoslavsky said. In the past few decades, there has been “an explosion of research done in this area.” Perhaps because it is newer, and rooted in biochemistry rather than genetics, it has had less success working its way into the public imagination.
Much of the new work has centered on the Warburg effect, named for Otto Heinrich Warburg, a German biologist who won a Nobel prize for his research in cellular respiration. The Warburg effect describes the peculiar fact that cancer cells tend to behave as if they’re in a metabolic emergency. When normal cells are short on oxygen, the mitochondrial turbines slow; anaerobic glycolysis, or fermentation, takes over. What’s strange is that cancer cells do this even when oxygen is abundant. The Warburg effect is considered almost universal across cancers; one relatively common sign of a tumor’s presence is a buildup of lactate, caused by the cancer cells fermenting. It’s unclear whether this fermentation is a cause or consequence of the disease. Do cancer cells ferment because they are growing out of control—or is fermentation driving the growth?
Maybe it’s both, but Lane suspects we pay too little attention to the latter possibility. He argues that it might explain the outsized correlation between cancer and aging. From age twenty-four to fifty, your risk of cancer increases ninety-fold, and it continues to grow exponentially from there. A popular hypothesis holds that the root cause of this mounting risk is the accumulation of genetic mutations. But some scientists have argued that the rate of accumulation isn’t nearly fast enough to explain the extraordinary trajectory that cancer risk takes over a lifetime. Nor does the gene’s-eye view explain why some tumors stop growing when moved into a different environment. For Lane, these facts suggest that cancer is best thought of as a derangement of metabolism.
As you age, your mitochondria accumulate wear and tear. Often, the cause is inflammation—whether from disease, injury, or periods of stress. Inflammation itself becomes chronic with age, for reasons that are still not entirely understood. Meanwhile, a process known as mitophagy, in which old mitochondria are eaten by the body so that new ones can grow in their place, slows down. The result of all this is that our mitochondria get tired, and do a slightly worse job. “Overall,” Lane writes, “we have less energy, tend to gain in weight, find it harder to burst into explosive action and suffer from chronic low-grade inflammation.” (“Aging, eh!” he notes.) The conditions grow ripe for cancer: mitochondrial waste products start to pile up, as at a broken assembly line; perhaps, if it gets bad enough, a cell might believe that the backup is due to a lack of oxygen. Alarm signals will be sent to the nucleus to flip a series of epigenetic switches—“we’re suffocating!”—that put the cell into fermentation mode. In that mode, when glucose arrives, the priority becomes stripping it not for its high-energy electrons but for molecular building blocks. The cell reverts to one of its earliest programs, active during embryonic development, in which the prime directive is not to work but to grow. “What actually turns a cell cancerous?” Lane asks. A cancerous environment might “be induced by mutations, infections, low oxygen levels . . . or the decline in metabolism associated with aging itself.”
As a researcher, Lane’s primary interest is in the origin of life, and here, too, an emphasis on metabolism offers a dramatically revisionist account. When we think about how life started, we tend to tell ourselves a story about genes. We say that, in the beginning, shallow seaside pools were filled with a primordial chemical soup; among the chemicals was RNA, a single-stranded, less stable version of DNA. RNA had the ability to catalyze the construction of other molecules, and eventually a version came into existence that could catalyze its own copying. Some energy source must have powered these chemical reactions—perhaps lightning or ultraviolet light from the sun. Regardless, we say, once the copying began, mutations that led to faster or more robust replication won out. Metabolism emerged only later, when ancestors of our cells learned to digest other nearby organic chemicals.
This story was complicated somewhat by the discovery, in 1977, of life in some of the deepest, darkest parts of the ocean. Marine biologists found that huge tube worms were living in places with no light and no plants to eat. How were the worms surviving? It took decades, but scientists eventually uncovered the first link in this dark food chain. Crowds of primitive bacteria live alongside volcanic vents in the seafloor, and they are unusual for being “autotrophs.” The word describes the fact that these bacteria, like plants, build their biomass not by eating but directly from inorganic matter, such as molecules of carbon dioxide floating in water. For autotrophy to work, a steady energy source is required. Plants use sunlight. But these bacteria live in total darkness. How could they possibly be autotrophs?
It turns out that, at the interface between sea and mantle, salt water reacts with the earth in a process called serpentinization. Serpentinization produces energy-rich chemicals, and Lane speculates that they were the primordial energy source that powered the ancestors of the autotrophs. In our metabolisms, the Krebs cycle runs in one direction—food molecules go in, and energy comes out. But the cycle can actually spin both ways, like a turntable. The bacteria surrounding the deep-sea vents run the Krebs cycle in reverse, taking in energy from the vents and using it to assemble the matter of their bodies from simpler parts. They are like candles unburning. Only later, when membranes happened to enclose these reactions, would the need for RNA have arisen. As the first proto-cells floated away from the vents, they lost contact with their energy source; only those carrying the right kind of RNA would have had the tools necessary to survive. The RNA’s job would have been to help catalyze reactions that formerly depended on the vents. Over the next few billion years, the descendants of these primitive organisms would have begun spewing oxygen into the atmosphere as a waste product. Only then would the Krebs cycle as we know it have come into being: by reversing the metabolism of the autotrophs, an organism could take advantage of all that oxygen and turn its body into a kind of furnace. It was this reversal, Lane claims, that begat the Cambrian explosion, an enormous proliferation in the variety and complexity of life that took place some five hundred million years ago.
Any book about just one thing, especially if the author feels like it hasn’t gotten enough attention, runs the risk of becoming a theory of everything. The impression I got from “Transformer” was that the Krebs cycle was the key not just to life and its origins but to aging, cancer, and death. More likely it is just a part of all those things.
Still, there is something to be said for immersion. Recently, I spent a long weekend in a small rented house a few hours north of New York City. The whole time, I had metabolism on the brain. One morning, a friend and I drove to an outdoor restaurant for a late breakfast. The car was running low on fuel; so was I. While we waited for the server, I sat quietly, feeling a little sour and depressed. The sun was beating down on my back—electrons in the wrong form. It was only after the first few bites of my scrambled eggs that I felt the flood of glucose, and became myself again. I could picture what was happening inside my cells. The image would have appealed to an eighteenth-century philosopher: I was a clockwork man charging myself up through the spinning of a billion tiny waterwheels.
Later, back at the house, we played basketball in the driveway. How many ATPs does a jump shot cost? After making a run toward the basket for a layup, I thought about all it had taken to launch my body through the air: a voltage made of protons, a million simultaneous discharges across synaptic clefts. Every motion was an exquisitely controlled lightning strike.
After the game, in the late afternoon, we watched small birds outside the window, their heartbeats racing. I imagined the fastness of their world. If your metabolism speeds up enough, does time slow down? Is that why it’s so hard to catch a bug in your hands?
We decided to make s’mores that night. A friend and I built the fire. We gathered electrons from a woodpile nearby, set them loose with a little butane and a spark, then watched the sun go down. It was strange to imagine that energy from fusion ninety-two million miles away had now taken the form of a marshmallow. Happily, I popped one into my mouth. ♦
