Fearfully and wonderfully made
ESSAY | Elegant molecular machines at the center of life belie Darwin’s theory
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At a recent conference, I watched a computer simulation of the most important machine in the world: ATP synthase. Without it, no life can exist. In the cells of every organism on Earth, from bluebird to blue whale, from amoeba to alfalfa to Aunt Millie, this molecular machine packages energy for cells to use, like AA batteries for so many game systems.
No batteries, no game.
I sat halfway back in the room on the center aisle, amid the hundred-odd scientists and casually dressed grad students watching the colorful animated machine, the center of which was turning like a mechanical egg beater. Narrating was 81-year-old John Walker, a British scientist who has studied ATP synthase for over 40 years—fully one-quarter of the time since his countryman, the naturalist Charles Darwin, first proposed his theory of evolution in 1859.
Evolutionary mechanisms such as random mutation and natural selection have been assumed by most scientists and public intellectuals to account for how life arose and developed over eons without any guidance or direction—or more pointedly, with no help from God. But Darwin proposed his theory long before scientists discovered such elegant machinery as ATP synthase humming at the molecular foundation of life.
Now, as ATP synthase whirred on-screen, John Walker revealed the latest science on this marvel, which in 1997 earned him the Nobel Prize in chemistry after he used state-of-the-art techniques to glimpse the outlines of its form. His audience of scientists (including me) was meeting in semi-secrecy for a conference whose theme was a specific controversial question: Did Darwinian evolution have any limitations?
Maybe, as Darwin thought, his idea really could help explain curious facts such as why modified species of animals on islands resemble ones on the closest mainland. But can it explain ATP synthase? John Walker thought so, and the assembled scientists leaned forward in their seats to hear why.
ATP synthase is not simple. Comprising thousands of amino acid building blocks in about 10 kinds of protein chains, its intricate structure carefully directs a flow of acid particles, beginning from outside the cell, through deep channels in the machine’s organization, into the cell’s interior. Somehow, like the cascade of water over a hydroelectric dam that turns a turbine, the flow of acid through the channels rotates a central camshaft. The cams push against multiple discrete areas of a stationary region of the synthase, distorting their shapes. The distortion forces together two bound feed-chemicals, ADP and phosphate, provoking them to react to yield the energy-rich-yet-stable molecule ATP. As the camshaft completes a turn, the ATP is released into the cell, and the machine begins another cycle. Incredibly, the many copies of the machine in each person produce about 150 pounds of ATP molecules every day, but each is used rapidly as energy—in effect, recharging each cell like a reusable battery.
And Walker’s more recent studies—using the newest, most powerful iteration of microscopy, called “cryo-electron” microscopy—would reveal its mechanism in unprecedented detail.
A Long Time Ago
David, Israel’s second king, did not have a microscope. But he could see, and in Psalm 139 observed that he was fearfully and wonderfully made. Not only could his eyes survey their surroundings, his ears could detect the sounds of wildlife, his tongue speak to others, hands grip a sword, muscles guide a plow, fingers ply a harp. Inanimate matter could do none of that. Far surpassing everything else, his mind could, at least to an extent, grasp, contemplate, and plan. No other kind of living thing could compose songs in praise of its Maker as David could. No wonder he was impressed with himself.
The ancient Hebrews did not have much interest in science. No surprise there, since for almost all of time, all people for all of history had been absorbed by the immediate tasks of survival. Yet the human mind is nothing if not curious, so, when some leisure time is available for reflection, questions about how life works arise quickly. Like everyone else, David knew from direct experience that his body came with all manner of cool features: eyes, muscles, and much more. But how did they work? What were they made of? How did they get here? When fingers guide thread through a needle, or an eye shifts its gaze from near to far, what exactly is going on? How does a chick develop inside an egg, or an acorn grow into an oak? All those things happen regularly and repeatedly under the right circumstances, so it seems that most if not all of the reasons should be found in the regularities of nature. But where?
Answers to questions about how life works trickled in slowly, painfully, over millennia. The first person credited with thinking about biology in even a vaguely modern sense was Hippocrates, born some 600 years after David, when earth, air, fire, and water were thought to be the basic elements of matter. Dubbed the Father of Medicine, Hippocrates knew next to nothing about healing. But he did at least urge his followers to classify common diseases and observe their progression, rather than to lazily attribute them to the Greek pantheon.
The next major figure in the history of science was Aristotle. Although many of us poorly read moderns think of him primarily as a philosopher, he was really the world’s first Renaissance man, interested in practically everything. Aristotle’s surprising honorific, the Father of Biology, is well-earned. Born less than a hundred years after Hippocrates, Aristotle worked hard to put flesh on the scientific skeleton. He introduced the blazingly obvious (in retrospect) idea of close observation: If you want to understand how nature works, get out of your armchair, go look, and write down what you see. With just his own observations, Aristotle was able to classify living things into broad categories that are remarkably similar to modern ones. That’s what Aristotle himself did as he walked the beaches of the Aegean Sea long ago. Here’s a snippet from his History of Animals:
The octopus breeds in spring, lying hid for about two months. The female, after laying her eggs, broods over them. She thus gets out of condition since she does not go in quest of food during this time. The eggs are discharged into a hole and are so numerous that they would fill a vessel much larger than the animal’s body. After about fifty days the eggs burst. The little creatures creep out, and are like little spiders, in great numbers. The characteristic form of their limbs are not yet visible in detail, but their general outline is clear. They are so small and helpless that the greater number perish. They have been so extremely minute as to be completely without organization, but nevertheless when touched they move.
Yet, as sophisticated as they are, Aristotle’s writings show not only the promise but also the peril of simple observation: Our unaided senses may not be able to perceive crucial details. We now know that those seemingly featureless baby octopuses Aristotle watched are actually exquisitely organized at a cellular and molecular level, far beyond the limits of any human’s bare eyesight.
Aristotle’s empirical heirs doled out more answers about how life works—at a snail’s pace, over thousands of years. By contrast, Dr. John Walker took only 40 minutes to regale a room full of scientists with amazing aspects of the molecular machine on which all life depends. How its detailed structure is needed to channel acid along the right path, to turn the camshaft, to capture chemical energy with the efficiency needed to power the fundamental unit of life, the cell.
Yet, as Walker lectured on, many in the audience shifted impatiently in their seats. Despite the explicitly skeptical theme of the conference—does Darwin’s theory hold water?—Walker was describing only how the machine worked but explaining nothing about how it arose.
Better and Worse
To understand nature, yes, one has to observe it, as Aristotle taught. But most of even the largish workings of life are on the insides of bodies, hidden from direct view. By using dissection, early naturalists such as the physician Galen, who practiced in Rome, were able to discover layer upon layer of further organization. For just the eye, Galen described the retina, cornea, iris, uvea, and tear ducts. With Galen’s work, David’s fearful body became even more so.
Yet Galen also made major mistakes, especially with his theory of blood. His naked eyes couldn’t see tiny capillaries even in dissected creatures, so in his thinking blood didn’t recirculate—it was consumed by tissues to nourish them.
Fast-forward to around the time of Shakespeare. In his study, English physician William Harvey is scratching his head. Since classical times, Galen had been revered as the ultimate authority on anatomy, and his work went unquestioned. Yet, by taking advantage of the newly introduced Arabic numerals, Harvey had just performed a simple calculation demonstrating that a typical human heart, pumping 2 ounces in each of its 72 beats per minute, would send out 540 pounds of blood in only one hour—triple the weight of a large man! The body couldn’t make blood that quickly, so it must be reused. It had to recirculate. Galen was wrong.
The fall of Galen’s ancient authority and the rise of mathematical reasoning helped launch modern science. But the study of biology needed more than that—it needed better vision.
Science Gets Glasses
Lenses had been known from antiquity, but only in the 17th century were they ground and aligned with sufficient skill to make a working microscope. To support William Harvey’s back-of-the-envelope calculation, Marcello Malpighi employed a microscope to directly observe the movement of red corpuscles through capillaries that connected arteries to veins, visually confirming blood circulation.
Microscopes also changed humanity’s very conception of the world. Imagine looking closely at some familiar object and suddenly realizing it is utterly different from what you had thought—like, say, a piece of paper that had tiny, previously unseen machines on it to actively fasten ink into place. That’s how the first microscopists felt when they examined what they had thought were simple insects and discovered alien, compound eyes; bizarre mouthparts; and specialized structures such as the pollen sacs of bees. What had been familiar creatures of field and forest were suddenly a complete mystery.
At least insects had been known before, even if not in the detail now revealed. But completely new classes of beings were soon discovered—microorganisms, or animalcules in Dutch microscopist Antonie van Leeuwenhoek’s coinage. He seemed even more impressed with them than David had been with himself. “From all these observations, we discern most plainly the incomprehensible perfection, the exact order, and the inscrutable providential care with which the most wise Creator and Lord of the Universe had formed the bodies of these animalcules.” The deeper science peered, the more sophisticated life became.
Despite those amazing initial discoveries, the use of microscopy fell out of favor for the next century and a half. Historian John Wootton has argued that, even though animalcules would turn out to be the cause of much human disease, the medical profession of the age, worried that those upstart microscopists would trespass on its turf, wielded its influence to discourage the use of the instrument.
Commencing late in the 18th century, the Industrial Revolution led to a general increase in wealth and leisure time, including time needed to pursue questions about life. Microscopy was revived, and the study of biology never turned back.
Yet the basic questions remained what they were in David’s day: How did they (then eyes and muscles, now cells and the nucleus) work? What were they made of? How did they get here? Mid-19th-century microscopes were reaching their limits, but the profound depths of life had yet to be plumbed. For biology to continue to progress, scientists needed better ones. Gradual, cumulative improvements came over the decades, including better lenses, oil immersion, and—with the invention of the electric light—better illumination for ever-smaller, harder-to-see samples. Many other tricks would be added in the 20th century, including the use of lasers and fluorescent tags to make regions of the cell more visible.
In the meantime, other branches of science pioneered nonvisual techniques for the study of life. In 1828, a discovery by German chemist Friedrich Wöhler jolted the world. He had heated ammonium cyanate in a flask and was astounded to find it produced urea. That wasn’t supposed to happen, because ammonium cyanate is an inorganic chemical and urea is a biological waste product. Wöhler’s work was the first to show that inanimate matter could give rise to something from life, and it shattered the distinction science had made between life and nonlife. What’s more, if life is made of chemicals, then chemists, too, could study it. That birthed the field of biochemistry. It wasn’t long before the cell was shown to be composed of immensely complex, discrete chemical substances—enzymes, proteins, nucleic acids, carbohydrates, lipids, vitamins, and more—all with myriad, specific, critical roles to play.
That threw a monkey wrench into the struggle to visualize biology. The foundation of life consists of enormously complicated, working molecules. And that required enormously complicated working microscopes. Happily, physics came to the rescue. Late in the 19th century, J.J. Thomson discovered the electron. Decades later the electron microscope (EM) was invented, and its use blossomed after the Second World War.
EM detected many intricate features of the cell that common light microscopy had missed. The same nucleus that had appeared to be a featureless black blob was now seen to have window-like portals. (Later work would show them to be elaborate, tightly regulated tollgates, where only substances that carry the right molecular “ticket” are permitted to pass.) In a classic EM photo, a single molecule of DNA was caught spilling out of a punctured virus—one long gossamer thread of information.
It would take another half century, until the early 2000s—the dawn of cryo-EM—when improved optical equipment and massive computer power allowed scientists for the first time to visualize some molecular machines in exquisite detail. One of those machines was ATP synthase.
Discerning a Purpose
By now, the scientists assembled before Dr. John Walker had run out of patience. The man had just held forth for nearly an hour on this miracle of biological architecture. Elegant and complex, precision-engineered, multiplied daily in the billions across the biosphere and on which the entirety of life depends. Finally, during the Q&A period, a questioner asked him directly: How could a mindless Darwinian process produce such a stunning piece of work?
Walker’s entire reply (paraphrasing): “Slowly, through some sort of intermediate or other.”
Far out of earshot I muttered two simple words: “Game over.”
If a Nobel laureate who has worked on one of life’s most fundamental systems for four decades can’t give an account of how it supposedly arose through a series of lucky mutations and natural selection—despite knowing its innermost workings in spectacular detail—then it’s reasonable to conclude no such account exists, and the effort to find one is a snipe hunt.
And yet, almost all evolutionary speculation proceeds in the teeth of that hunt. If it’s any consolation, Galen’s theory of blood did ultimately collapse. It only took 1,400 years. While we wait, how do we account for molecular machines? If not Darwin, who or what? Whether it sits well with our modern clerisy or not, David had the basic answer three millennia ago: He, his eyes, and his ATP synthase all were purposely made, planned by an intelligent being.
How could a former shepherd, ignorant of nearly all biology, beat 21st-century scientists to the punch? Easy. Recognition of the work of a mind doesn’t demand uncovering obscure details that can’t yet be seen—it only requires grasping the relationship in what already can be seen. The dictionary defines design as “the purposeful arrangement of parts.” So to perceive a mind’s work—a design—we need only see that some parts are arranged for a larger purpose. That’s crystal clear in ATP synthase, thanks to the work of John Walker and others. But even with just his unaided vision, David could see the purposeful arrangement of his fingers, bones, and muscles.
Designs—purposeful arrangements—aren’t in doubt just because the composition of their materials is unknown. Ancient Greeks could easily recognize a purposely sculpted statue even though they had no knowledge of the chemical composition of its stone. On the other hand, the functioning of an obviously designed system might rely on even-more-sophisticated, not-yet-understood arrangements. A child can quickly perceive that the exterior of her cell phone is designed, but she would need to study engineering principles before understanding all the phone’s mechanisms.
The same goes for life. The visible parts that dazzled David are purposefully arranged, and so are the hidden and microscopic parts undergirding them that took millennia of scientific progress to comprehend. Thanks to the stunning progress of science, we now know that it’s fearfulness and wonderfulness all the way down.
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