Life's Ratchet: How Molecular Machines Extract Order from Chaos (2 page)

My conversion started when I was a doctoral student in materials science at Johns Hopkins University. My Ph.D. advisor, Peter Searson, was fascinated with a new, powerful instrument invented just eight years earlier: the atomic force microscope (AFM). Since he was not familiar with the AFM’s operation, he put me and my friend Arun Natarajan in charge of figuring out how it worked. An AFM is a thousand times more powerful than the best optical microscope. Unlike conventional microscopes, AFMs do not use light to obtain images but rather visualize samples by touch: A tiny, sharp tip is moved across a sample, and the minute forces pushing on the tip are used to create an image. Tips are very sharp, only a few nanometers across, which allows for very small objects to be imaged.

One day, a fellow student brought in samples to image. He had deposited DNA molecules on a flat substrate and was wondering if our AFM could make them visible. We were blown away when we saw little wormlike strands appear on the computer screen—each a single DNA molecule, only two nanometers in diameter. We had touched the molecule of life.

Life took a few more turns before I finally converted to the wonders of biology. After a stint as a research fellow at Oxford University, I arrived at Wayne State University in Detroit as a fresh-faced assistant professor. Initially, I concentrated on what I knew: using AFM to look at atoms and molecules on surfaces and measuring forces between them. Two subjects fascinated me: the preponderance of randomness at the scale of atoms and the connections between the microscopic world of atoms and our macroscopic world. At the tiny scale of atoms and molecules, chaos reigns, yet at the scale of humans, order prevails (at least for the most part). How does this order arise? This is the subject of statistical mechanics, and in my research, I probed the transition from “noise” to “order” (and thus the limits of statistical mechanics) as I measured forces in small clusters of atoms and molecules.

As it happens often in life, new opportunities arise quite by chance. Another AFM researcher, Heinrich Hoerber, joined Wayne State University. Hoerber, a pioneer in new nanotechnology techniques applied to molecular biology, had been a postdoc with Gerd Binnig, the Nobel Prize–winning co-inventor of the AFM. I was fascinated with Hoerber’s work, and when he subsequently left to take a position at University of Bristol in the United Kingdom, I inherited his Wayne State collaboration: to measure the motions of particular molecular machines implicated in the spread of cancer. Here was an opportunity to combine my interest in statistical mechanics and the tools of nanotechnology with something new: molecular biology. At the same time, I had the opportunity to contribute to a cure for cancer. So I beefed up on biology and started a new research direction. As I learned more about molecular biology, I discovered the fascinating science of molecular machines. I realized that life is the result of noise and chaos, filtered through the structures of highly sophisticated molecular machines that have evolved over billions of years. I realized, then, there can be no more fascinating goal than to understand how these machines work—how they turn chaos into life. This is the story I will share in this book.

What
is
life? Scientists have tried to answer this question for as long as science has existed. For Aristotle, the body was matter, but a soul was needed to give the body life. Even today, such views are common in the general public. Books like
The Secret
tell us we have vast untapped reserves of “life energy” that can help us attract riches and happiness. Yet, a special
life force has never been detected. If we look at the balance sheet of energy intake (food) and output (motion, heat) of any living organism, there is no missing energy or untapped energy source.

FIGURE 0.1.
The first living cells observed and recorded. From Robert Hooke’s
Micrographia
, 1665.

At the other extreme we have the view of living creatures as complicated and intricate machines. The French philosopher René Descartes believed animals (but not humans) to be machines without souls. According to his view, animals did not feel pain. To explore animals’ internal machinery, he promoted vivisection, a practice we find barbaric today.

Beginning in the seventeenth century, with the invention of the microscope, scientists searched for the secret of life at ever smaller scales. Biological cells were first described in Robert Hooke’s
Micrographia
in 1665 (
Figure 0.1
). It took until 1902 for chromosomes to be identified as carriers of inheritance. The structure of DNA was deciphered in 1953, and the first atomic-scale protein structure was obtained in 1959. Yet, even while scientists
dissected life into smaller and smaller pieces, the mystery of life remained elusive.

Is this reductionist approach doomed to fail? Many people, including many eminent biologists, think so. But I believe they are wrong. To be sure, reductionism is not enough: Many unexpected and important phenomena emerge only from the complex interaction of many parts. These emergent phenomena cannot be explained by looking at the parts alone.
Holism
(the understanding that the whole is more than its parts) is part and parcel of any explanation of life.

Nevertheless, the reductionist approach of looking at smaller and smaller pieces of living organisms has been a story of continued success. And it may finally be claiming a very big prize—one of the great mysteries of life: What creates “purposeful motion” in living beings? This was one of the original mysteries of life, formulated by Aristotle more than two thousand years ago. Aristotle assigned this motion to purpose. But today, having penetrated into the realm of molecules, we do not find purpose. Instead, we find random motion. Today, this great question has morphed into another question: How can
molecules
create the “purposeful” action that characterizes cells and bacteria? How do we go from assemblies of mere atoms to the organized complex motions in a cell?

In this book, we will find answers to these questions that have plagued science and philosophy for thousands of years. What kept us so long from solving this mystery? What we lacked were the right tools and concepts to study life at sufficiently small scales. How small is small enough? The secret of life’s activity is found at the scale of a nanometer—a billionth of a meter.

Thanks to the advances of nanotechnology, we can now see the smallest parts of life at work: autonomously moving molecules performing specific tasks like tiny robots. Our cells are cities full of molecular-sized worker bees, who, like magic, built themselves, go where they are needed, do what they need to do and are recycled again. How can mere molecules move in specific ways to perform specific tasks? Are these amazing molecular robots imbued with a special life force? Are they controlled by a higher consciousness? Astoundingly, the force that drives life at the smallest scale is not a mysterious, supernatural force, but it is a surprising one nevertheless. The force that drives life is chaos.

As a newcomer to molecular biology and with the unique perspective of a physicist, I feel well suited to tell the story of the new discoveries of life at the nanoscale. I have not been in the field long enough to take anything for granted—everything is new and exciting, and I want to share this excitement with my readers. Yet, I owe this story to the wonderful researchers who have come before me: The biologists who painstakingly figured out the detailed pathways of cellular activity, the biochemists who identified the chemical nature of the molecular machines of our cells, and most recently, the physicists who are trying to find the general principles behind the hustle and bustle of our cells. The fundamental goal of this book is to follow the discoveries of these scientists and to find out what it takes to turn a molecule into a machine; and many molecular machines into a living cell.

When we follow the path of reductionism to understand life, the starting point of our quest must be the molecular scale. Deep down, life is a complex dance of molecules which can be understood in the context of physics. In 1945, the Nobel Prize–winning physicist Erwin Schrödinger predicted that genetic information, the blueprint to make a human, is coded in the structure of molecules. In his book
What Is Life?
he envisioned the genetic code to be contained in chemical “letters” as part of an aperiodic crystal (today we call it a polymer), and the size of each letter in the genetic code to be a few nanometers in size. These physics-based predictions inspired a young Francis Crick to decipher the mystery of DNA just thirteen years later. Crick and his coworker James Watson found Schrödinger’s predictions to be quite accurate. Everything we have learned about life at the molecular scale has conformed to known physical principles. In this book, I follow the path Schrödinger first walked on and look at life from the point of view of a physicist.

Yet, even at the molecular scale, life is incredibly complex; without this complexity, life could not function. In 1970, another Nobel winner, the French biochemist Jacques Monod, concluded, in
Chance and Necessity
, that the complex machinery of our cells must be the result of an unbelievably lucky cosmic accident: “The universe was not pregnant with life nor the biosphere with man. Our number came up in the Monte Carlo game. Is it any wonder if, like the person who has just made a million at the casino,
we feel strange and a little unreal?” Many scientists have embraced Monod’s support for chance over necessity. They are concerned about opening the scientific floodgates to vitalism (the idea that life requires special forces) and religion. Necessity implies there is an external reason for life to exist. If there is such a reason, there must be a driving force outside physics or biology.

Other scientists saw things differently. In 1917, D’Arcy Wentworth Thompson, a British biologist and mathematician, published a unique book,
On Growth and Form
. Thompson showed how shapes of living plants and animals have analogues in the nonliving physical world. He argued that the shapes of our bodies are not due to chance, but are the
necessary
result of physical forces and geometrical constraint. Thompson found a way to favor necessity over chance without implying religion or vitalism. For him, the structure of the living organism was the necessary result of mathematics and physics.

As we enter the microscopic world of life’s molecules, we find that chaos, randomness, chance, and noise are our allies. Without the shaking and rattling of the atoms, life’s molecules would be frozen in place, unable to move. Yet, if there were only chaos, there would be no direction, no purpose, to all of this shaking. To make the molecular storm a useful force for life, it needs to be harnessed and tamed by physical laws and sophisticated structures—it must be tamed by molecular machines.

The fruitful interaction of chance and necessity also explains how these chaos-harvesting machines were “designed” by evolution. Chance and necessity may even explain how our minds work, how we have new insights, and why we have intuition. This book is a vindication for randomness, a much maligned force. Without randomness, there would be no universe, no life, no humans, and no thought.

Where does chaos come from? Why are atoms in perpetual random motion? The random motions of the atoms in our bodies are an afterglow of the creation of the universe, the big bang. The big bang created a universe full of energy, and, eventually, it created stars like our sun. With the sun as intermediary, the energy of the big bang shakes the atoms of our cells—making life on Earth possible.

Like it or not (and I hope you will like the idea by the time you have read this book), chaos
is
the life force. Tempered by physical law, which
adds a dash of necessity, chance becomes the creative force, the mover and shaker of our universe. All the beauty we see around us, from galaxies to sunflowers, is the result of this creative collaboration between chaos and necessity. The potential for life was already written into the book of our universe as soon as physical law met the violent motions of elementary particles. For me, this insight makes the story of life a beautiful, even spiritual story.

Understanding life is not an easy task. The fundamental nature of life is one of the most enduring hard questions of science. Scientific literature is replete with articles that attempt to explain various aspects of life—yet much is still conjecture; much controversial. The public rarely hears about the exciting developments in science, because understanding requires advanced knowledge of biology, chemistry, and physics. To make matters worse, scientific literature is written in a language that makes it difficult even for scientists to understand each other. In this book, I will cut through the fog of scientific hieroglyphics and make the latest theories of life accessible to the intelligent reader. I do not have all the answers, and some things I write in this book will turn out to be wrong. But science is not an old, dusty book of settled facts. It is a living, breathing story of discovery, a true adventure of the human mind.