The whole idea of DNA containing information is, in my opinion, one of the main culprits in maintaining the myth of creationism and intelligent design. First of all, without the genetic code and the entire machinery of transcription and translation, DNA contains neither information nor meaning. Worse, strictly speaking, DNA does not even encode proteins— at least not functional proteins. DNA only encodes the amino acid sequence of a protein. The functionality of a protein comes from its three-dimensional shape and the physical properties of various parts of the protein. This shape is the result of protein folding, which is the result of physical forces (sometimes helped by chaperonins) acting on a sequence of amino acids. Much of the information to shape a protein into its functional form is contained in the laws of physics and the action of these laws in space and in time. How would you quantify the information input life receives from physics and space-time? You can’t. DNA only makes sense in the context of physical law, already-established order, and interactions with the environment. DNA does not tell us the final shape of an animal or a protein. Without context, DNA is meaningless.
An important statement of genetics is the central dogma: Information flows in only one direction, from DNA to RNA to proteins, never back from proteins to DNA. While the central dogma holds during replication, transcription, and translation, during the development of an organism, proteins control which parts of DNA are read at any stage of the development. There are feedback loops. The information to make a human being is therefore not encoded in DNA as in a blueprint. Although the word blueprint is often used for DNA, this is a misleading analogy. A much better analogy is recipe. To make a human being, DNA contains information to make proteins, which by their physical interactions with DNA, RNA, or other proteins, in the form of complicated regulatory feedback loops, shape the developing organism. This is similar to cooking a meal. A recipe does not contain a complete description of the result of cooking a meal; it just contains information about the ingredients (proteins) and the timing of adding the ingredients (regulation). Then the physical interactions between the ingredients take care of making the meal.
Another way to put this is that organisms are emergent phenomena, emerging from complex interactions according to a specifically timed recipe. There is no way you could completely specify, in genetic code, every cell in a human being. How would you specify the trillions of connections in our brain? A few years ago, it came as a bit of a shock when the Human Genome Project revealed there are only about twenty-three thousand protein-encoding genes in the human genome. This is not much more than the number found in simple worms. I think the utter insufficiency of the information in DNA to specify an organism is one of the most powerful arguments for evolution. As argued before, life is a complex game played on the chessboard of physics and chemistry. I can think of no better analogy. Development of an organism needs information about proteins, but also needs space, time, physics, and complex feedback loops. None of these are encoded in DNA.
Evolution, like life, is also a game on the chessboard of time, space, and physics. The outcome of this game cannot be determined a priori. The game can create an enormous number of possible outcomes, and the role of evolution is to find some of these outcomes. By tweaking a protein here, or regulating a DNA sequence there, we see what effect this has; evolution has created a world inhabited by a limited set of all possible creatures that could theoretically exist. One of them happens to be us.
Creationists argue that humankind is the goal of Earth’s history. If you start with this assumption, it would certainly be difficult to see how a playful process such as evolution could have necessarily ended up with us. Once you abandon this idea, however, and realize that evolution would have come up with some viable organisms, but not necessarily the same we encounter on our planet, it all starts making sense. Am I arguing for chance here? Chance is important, but I believe that life is inevitable and that myriad forms of life would have evolved in any case. As we have seen before, pure chance creates chaos; pure necessity, rigidity. Chance and necessity together become creation. What is created may be unpredictable, but creation itself is unavoidable.
This discussion is reminiscent of the differences between the views espoused by D’Arcy Thompson and Jacques Monod (Chapter 2). Monod believed that the existence of life is an incredible accident, the winnings of a cosmic lottery. It seems that Monod was too caught up in the DNA-centered view of life. Thompson, on the other hand, lived before we even knew about DNA. He emphasized necessity—he believed that all structures in living beings are the result of mathematical and physical laws. This is also clearly incorrect. Physical law by itself can make a rock, but without information, provided by evolution, we cannot make a living being. The views of Monod and Thompson can be combined to arrive at a fuller and more creationist-proof view of life: Information is important, but information comes from many sources—evolution, physics, chemistry, and the interaction of many complex entities in living cells.
Ratchets
The interaction of chance and necessity in evolution is mirrored by the interaction of chance (as molecular storm) and necessity (structure and physical laws) in the functioning of molecular machines. The second law of thermodynamics predicts that everything moves toward bland uniformity. Yet we have seen that the emergence of the bewildering complexity around us does not violate the second law, as long as we pay the free-energy cost. Still, to arrive at this complexity, we need some kind of free-energy-fueled mechanism. In our cells, directed motion, “purposeful” activity, is created by the action of molecular ratchets—molecular machines, enzymes, and motors, which by degrading free energy and due to their asymmetric structures, can rectify the random motions of the molecular storm to create order. Evolution is also a ratchet: It rectifies the random input from mutations into the creation of an ever larger number of possible creatures. This rectification is achieved by natural selection. Thus there is a pleasing analogy between evolution and its products, our molecular machines.
There is also a more direct connection between the molecular storm and evolution. As we saw from Delbrück’s green pamphlet, which inspired Schrödinger to write his book What Is Life?, thermal motion is the main contributor to mutations. Even more to the point, replication and DNA repair are performed by molecular machines, which are subject to the molecular storm and therefore sometimes, although rarely, make mistakes. These mistakes supply fodder for the ongoing evolution of life on the planet. Interestingly, evolution strives to minimize mutations. The extremely high fidelity of replication (one base-pair mistake in ten billion base pairs) shows that there is, paradoxically, an evolutionary advantage to not evolve. Evolution is rarely radical. The low error rate ensures that it is a gradual process. Nevertheless, small differences can sometimes have a large impact on the final result, because DNA encodes a recipe, rather than a blueprint. The same is true in cooking. For example, consider leaving the baking powder out of your cake!
The observation that evolution acts like a ratchet also discredits the probability arguments of the creationists. Evolution builds improbability step by step, mutation by mutation, selection by selection. The question “What is the probability of creating a kinesin by randomly combining amino acids?” is irrelevant to how evolution works. Kinesin did not spring into existence fully formed; nor was it a goal of evolution. It is simply something evolution stumbled upon, as it ratcheted up more and more complexity, one small change at a time.
There Is No Other Way . . .
Looking at molecular machines has made me realize that evolution is the only way these machines could have come to exist. As we have seen, life exploits all aspects of the physical world to the fullest: time and space, random thermal motion, the chemistry of carbon, chemical bonding, the properties of water. Designed machines are different. They are often based on a limited set of physical properties and are designed to resist any extraneous influences. The tendency of molecular machines to use chaos, rather than resist it, provides a strong case
for evolution. Why? If life started by itself, without a miracle, then life had to start at the molecular scale. The molecular scale has always been dominated by the molecular storm. The ability of life to somehow incorporate thermal randomness as an integral part of how it works—as opposed to giving in to the chaos— shows that life is a bottom-up process. It is not designed from the top down. A top-down design would have avoided the complications of thermal motion by making the fundamental entities of life larger, so they could resist the molecular storm more easily. This is what machines designed by humans do—until recently, as nanotechnologists have learned from life’s nanobots to create tiny machines of their own.
Molecular machines’ exquisite adaptation to their molecular environment is also a strong argument for evolution. Evolution is tinkering—the gradual improvement and better adaptation of biological structures. The history of life has been long, and evolution had ample time to create these amazing physics-exploiting machines that run our bodies. To achieve such near perfection, you need a process that designs dynamically. A onetime design is not enough. Conditions change over time, and our molecular machines need to remain adaptable. An external designer would do best if the designer used evolution to do the work. Adaptation is assisted by the fact that physical laws provide the missing ingredient. For example, many structures in our cells are made through self-assembly processes, which are the result of physical forces (vesicles, collagen, etc.). Evolution does not overdesign: It designs just enough to take advantage of physical laws. If physics does the work for you, then why bother designing what is already designed?
We also ought to consider the commonality of the molecular apparatus in the cells of every living being. Many molecules and cellular processes in an E. coli bacterium, a yeast, a bluebird, a begonia, or a human are almost identical. This strongly suggests common ancestry. At the same time, looking at the differences between organisms, we see how various molecular machines have been adapted to fulfill specialized functions peculiar to each species.
Yet, the best argument in favor of evolution and against a static-design view may be that any designer would have to work hard to keep organisms from evolving. This is what I alluded to in the beginning of the chapter. Paley’s reproducing watch would evolve. As we have seen, mutations happen. Some of these may impart an advantage to its bearer. Such an advantage would tend to spread through a population. How could you stop it? And why should anybody want to? If I were the all-powerful being in charge of the world, I wouldn’t bother. Why not sit back, relax, and enjoy what wonderful things evolution can create for you?
9
Making a Living
Neither DNA, nor any other kind of molecule can, by itself, explain life.
—LYNN MARGULIS, WHAT IS LIFE?
THE EMINENT HARVARD BIOLOGIST AND WRITER ERNST Mayr (1904–2005) wrote in This Is Biology that when scientists and philosophers have talked about life, they often considered life as opposed to the lifelessness of “an inanimate object.” The problem with this definition of life, according to Mayr, is that life seems to refer to some “thing”— an idea that has misled philosophers and biologists for centuries. If life is a thing, then it must be clearly distinguished from other things, and therefore the existence of a “life substance” or “vital force” must be invoked. However, Mayr explained, once we realize that life is not a thing, but a process, we can begin to scientifically study the process of living. We can make a distinction between living and nonliving. We could even attempt to explain how life’s processes can be the result of molecules.
Nobody can explain what life is. This has always been the problem with the question “What is life?”—a question that has led philosophers and scientists to look for a life force not only for centuries, but for millennia. While we cannot define life, we can explain how life works. We can explain the process. The molecular biophysics and nanoscience revolution has succeeded in explaining, as Mayr puts it, “how living, as a process, can be the product of molecules who themselves are not living.” This is an important step. To delineate life from the “lifelessness of an inanimate object,” we need to first understand how molecules can generate directed motion and activity, that is, how chaos becomes order. The new science of molecular machines has been successful in doing just that. But is that enough? Is “living” the sum total activity of all the molecular machines in our bodies?
Unfortunately, understanding kinesin or ATP synthase does not explain human life or even that of a single cell. I can throw all the molecules of a living cell into a test tube and shake them up—some of the motor proteins may wiggle for a while—but they will not assemble themselves into a living cell. Are we then back to square one? Do we require some invisible force, after all, to coordinate the molecular activity in our cells? No, we should have learned enough to see that this is not necessary. What distinguishes living organisms is not that they exist outside physics, but is that they are based on a self-organized, dynamic structure that perpetuates the organization of the organism from one point in time to the next. Life sustains itself. Life comes from life.
Every person’s atoms are replaced within seven years, yet we remain the same person. We are not the atoms that constitute us; nor are we our proteins, DNA, or molecular machines. We are, instead, a complex process, a program, as it were, running on chemomechanical hardware. The analogy of life with a computer program fits our modern times, where computers have taken over the iconic status once reserved for clocks or steam engines. However, we should be careful not to overuse the computing analogy of life. The “program” that constitutes the process of living is massively parallel, decentralized, self-adaptive, “squishy,” and controlled almost entirely by exchanges of matter (with the exception of nerve impulses, but even there, some matter exchanges are involved). It is also a program that has evolved over billions of years.
Living is programmed molecular dancing. We cannot allow molecular motors to move random cargo to random places. Specific cargo needs to go to specific places at specific times. The same is true for every activity of our cells: What proteins should be produced? When? How many? When should a molecular motor take on cargo, and when should the cargo be released? In Chapter 6, we glimpsed how cells regulate such decisions. Most complex proteins can be controlled through allostery—the change in structure and activity when the protein binds a control molecule. In our cells, proteins regulate other proteins, but also the transcription of DNA. In turn, proteins are made by the instructions contained in DNA and are controlled by other molecules, including sugars, ions, and lipids. The complicated program of “living” emerges from complicated feedback loops between all these molecules, linking them together in complex networks. The idea of a dynamic state of complex feedback loops is difficult to fathom. But that is what is going on in a cell. The complex molecules of our cells are marvels of evolutionary engineering. But the cell only becomes a cell when these molecules cooperate in a rich network of regulated interactions. This cooperative, self-sustaining, regulated activity is what we call living.
Regulation
How does regulation work? When we talked about how molecular machines work, we never mentioned how they know when to do their work. Do they work all the time, grabbing cargo, moving it, pumping ions in and out of the cell, or producing more ATP, even if it is not needed? That would be a recipe for disaster. Molecular machines are enzymes, first and foremost, and most enzymes in our bodies are regulated by inhibitory binding or allosteric interaction. Inhibitory binding is a direct way to regulate an enzyme or a motor. If a molecule other than the enzyme’s substrate binds to the enzyme’s binding pocket, and this molecule cannot be transformed by the enzyme, then this molecule “gums up” the enzyme’s function. This is inhibition. Allostery, as we have already learned, is the control of an enzyme’s activity by the binding of a control molecule to a separate binding pocket on the enzyme, which then through some conformational change controls the binding of the substrate, either enhancing or inhibiting
it.
Inhibitory binding is how most drugs (and many poisons) work. The antacid pantoprazole is a proton-pump inhibitor. The particular proton pump that this drug inhibits is a molecular machine in the membranes of the cells that line the stomach. The machine’s “job” is to take energy from ATP and use it to pump protons (hydrogen ions) into the stomach. Protons make the stomach acidic. Pantoprazole binds to the machine and blocks it temporarily, inhibiting an increase of acidity in the stomach. Inhibitor binding strength, or how long the inhibitor will remain bound before it again frees up the enzyme, depends on the height of the activation barrier. This allows nature to tailor inhibitors to control reactions over different time scales. The same is true of allostery: The binding of a control molecule is controlled by the binding strength (the affinity), the rate at which the molecule dissociates (which depends on the activation barrier), and the concentration of the control molecule in the cell (at low concentrations, the probability that an enzyme and a control molecule will meet is low).
Kinesins are a good example of how molecular machines are regulated in the body. Kinesins consist of one or two similar motor domains, which process ATP and bind to microtubules. In addition to the motor domain, kinesins can contain a number of other domains to bind cargo, to bind to specific locations, or for regulation. In the cargo-carrying motor kinesin-1 (as well as in kinesin-2, kinesin-3, and kinesin-7), the cargo-binding domain also serves a regulatory function, as it would be wasteful to have motor proteins running around in the absence of cargo. After all, they use up ATP. How is kinesin regulated? When no cargo is around, the kinesin molecule folds up, such that the cargo-binding domain can bind loosely to the motor domains. In effect, the molecule puts on its parking brake. If the cell wants to activate the motor, it sends two control molecules, which bind to the cargo domain and release it from the motor domains. The process essentially takes off the parking brake. This is not the only way kinesin-1 is regulated. For instance, the cell can control which microtubule a kinesin walks on using various proteins that bind to the microtubule. Some will “attract” kinesin, and some will inhibit its motion on the track. Another set of regulatory proteins controls the binding and release of cargo. It is quite typical for enzymes and molecular machines to be regulated in various ways to make sure they do the right job at the right time in the right location.
Life's Ratchet: How Molecular Machines Extract Order from Chaos Page 26
