# Understanding Randomness

On April 08, 2010

In this article, Kathryn Applegate addresses the concern that randomness implies the absence of God’s activity and involvement in the natural world, focusing on the mechanisms of the immune system to demonstrate that God works through random processes to preserve life. Far from being an indication of a “godless” universe, one might conclude that randomness is one of God’s favorite mechanisms for creating and sustaining life!

## #That’s Random! A Look at Viral Self-Assembly

You hear it all the time: “That’s so random!” When used by people of my generation, the word “random” can simply mean “cool” or “surprising.” Or it can mean something like “disconnected,” as in the phrase, “I had a random thought” (which returns 189,000 results on Google, by the way—random!).

Despite this usage, most of us know that randomness has something to do with probability, and that it often implies a lack of conscious intentionality. But what do mathematicians and scientists mean when they say something is random? Can a random process lead to an ordered, even predictable outcome? Is there evidence that God makes use of random processes to fulfill his creative purposes?

These are big questions, and we won’t address them all today. But I think randomness is an important topic to cover for two reasons: 1) it is integral to many processes in biology (and math, physics, chemistry, etc.), and 2) it is commonly misunderstood to be incompatible with Christianity.

As I said above, most of us know that randomness has something to do with probability. If you pick a card “at random” from a shuffled deck, you have a small probability of drawing an ace (4 out of 52, or a 7.7% chance). If you flip a coin, you have an equal probability of getting heads or tails.

Randomness also seems to imply a lack of intentionality or purposefulness. After all, you might hope for an ace when you draw a card, but you can’t choose one on purpose. You might call heads when you flip a coin, but you can’t know beforehand what the outcome will be. Thus the outcome is indeterminate, but is it purposeless? Not necessarily. Indeterminacy simply means the result cannot be predicted from the outset.

It should be noted that indeterminacy does not imply that God does not have foreknowledge of future events. Christians ought not to be uncomfortable with the idea of God interacting with his creation through chance. We often describe a seemingly-random (i.e. unplanned by us) sequence of events as being “providential,” or planned by God.

In biology, it is very hard or impossible to calculate precise probabilities for most processes, so when we say a process is random, we typically mean it is extremely unpredictable. Eventually we will discuss randomness within biological evolution, but first we must consider some simpler processes, like the self-assembly of a virus.

Viruses are remarkably efficient entities. Coiled tightly within a protein-based shell is a small amount of DNA needed for self-replication. The shell, called a capsid, is made of many repeating protein subunits and is therefore highly symmetrical (see figure). Important biomedical insights have certainly been gleaned from structural studies of viruses, but viruses also teach us about the emergence of order from non-order.

The virus life cycle has four main steps: 1) enter a host cell, 2) hijack the cell’s replication and translation machinery to make many copies of itself, 3) assemble into many virus particles, and 4) exit the cell to invade another host.

When I first learned about this process, I found it very hard to believe it just “happens.” The idea that a bunch of molecules bumping into each other inside a crowded cell could spontaneously assembly into a fully-functional virus seemed a bit far-fetched. Many viral capsids have over 100 protein subunits that must interact with each other in just the right way, or it won’t work. Surely there must be something driving this process, right?

There is! Random motion. I had to see it to believe it. I distinctly remember sitting in class during my first year of graduate school when the professor demonstrated self-assembly of a virus using a 3D model as shown in the following video. In less than 30 seconds, you can watch a jumbled heap of proteins become a beautifully ordered structure.

As the narrator explains, sub-assemblies form and break apart en route to the most stable structure, the full capsid. As the sub-assemblies begin to form, further associations with free subunits become more favorable and as a result occur rapidly, while the final steps may take considerably longer. While the subunits in the model are rigid, in reality the proteins take on multiple conformations, allowing the capsid to “breathe.”

Amazing as it is, the system we just considered—one virus capsid in a jar—is pretty simple. One wonders how self-assembly can happen in a crowded cell, where there are countless other molecules diffusing around, potentially getting in the way. We can’t directly see how it happens in a cell, but we can reconstitute the process in a test tube using different combinations of constituent molecules.

Consider two viruses, where each protein subunit in one virus is the mirror image of the corresponding subunit in the other. Putting the two viruses together by hand would be pretty tricky, because the constituent parts look so similar. But random motion can do the job in short order:

From this model, we can see clearly, in real-time, how distinct complex structures can arise from their parts randomly interacting with one another. Many large viruses also use special scaffolding proteins to assist in the assembly process, and some even use their own genomes as a scaffold. In addition, two closely-related viruses that happen to infect the same cell can exchange parts to create a new virus. This is one way viruses can evolve quickly to evade the host’s immune system.

Here we have seen how viruses demonstrate a principle inherent in God’s world—that order can emerge out of chaos from random processes. In my next post, we will look at some other biological processes that make use of—rather, depend on—randomness. This will set the stage for us to see that such processes can not only assemble a structure within seconds or minutes, but also generate complex, information-bearing molecules over billions of years. Even though the freedom inherent in nature sometimes produces unintelligently-designed structures (like viruses, which can kill us), we see that God has made, and continues to oversee by his providence, a good creation that, at least in part, is capable of creating itself.

Up next: how God created the body to heal itself, and how can random mutations can be both harmful and benign.

## #Adaptive Immunity: How Randomness Comes to the Rescue

The last time my husband and I went camping in the desert, we noticed something: it’s a dangerous place! Everything seems to be trying to kill you. Besides extreme temperatures and little green men (which we didn’t see, sadly), you have to watch out for things like snakes, scorpions, spiders, ticks, cacti, and the rare but devastating hantavirus.

Even in the relative safety of your home, viruses, bacteria, parasites, and fungi are an inescapable part of life. Without a functioning immune system, we would easily succumb to infection from these pathogens. All animals share a basic set of defense strategies called the innate immune system, which includes protective barriers like skin and special cells that gobble up foreign material. In addition to this first line of defense, vertebrates have a highly sophisticated secondary system in place, called the adaptive immune system.

Previously, we examined the role of randomness in self-assembly processes and chaotic systems. In this section I want to explain how the adaptive immune system harnesses the power of randomness to protect the body from assaults it has never seen before. To me, this topic represents a compelling example of the way God works through natural processes that he has put in place to preserve and uphold life.

Adaptive immune responses come in two types: antibody responses and cell-mediated responses. Each type is executed by a different kind of white blood cell, or lymphocyte. B cells, produced in the bone marrow, generate antibodies, while T cells, produced in the thymus, directly or indirectly kill pathogen-infected cells. Here we will focus on how antibodies are made within B cells, as their production requires randomness at multiple levels.

### Antibodies: Signposts for Destruction

The main function of an antibody is to bind tightly and specifically to an antigen, usually an exposed portion of a virus or bacterium. This binding can inhibit the normal function of the pathogen, just as your ability to walk is inhibited when a toddler hugs you around both legs. Antibody binding also acts as a signpost, alerting cells of the innate immune system to destroy the pathogen.

Antibodies are proteins. Like all proteins, antibodies are strings of amino acids that fold up into a particular 3D shape. As you can see from the illustration at left, antibodies are Y-shaped proteins made from four separate amino acid chains: two “light” chains and two “heavy” chains. (The heavy chains are about twice as long as the light chains, so they have a higher molecular weight.) All antibodies are identical in the blue “constant” region but are quite different from each another in the orange “variable” region. The shape of the variable region determines what the antibody will bind to (if anything) and is consequently called the antigen-binding site.

If the antibody were a tool in your garage, it might be an 8-in-1 screwdriver, with the constant region being the handle and the variable region being an exchangeable bit. Each bit is designed to work with a different kind of screw, and as you probably know, using the wrong size or shape of bit can be fruitless and frustrating. Similarly, the shape of the antibody’s variable region must be exactly complementary to the antigen for it to bind.

### Mix-and-Match Mutations Create Diversity

Amazingly, animals can manufacture antibodies for not just eight but literally trillions of foreign particles, even synthetic compounds never encountered in nature. How can a B cell design an antibody for a novel antigen when its shape depends on the amino acid sequence, which, in turn, is encoded by a gene? Humans only have about 25,000 genes total, so it can’t be that each potential antibody is generated by a separate gene.

Surely the design of a highly specific antigen-binding site could not be accomplished by random mutations! Actually, yes, though as we will see, the story is not as simple as a single gene undergoing spontaneous mutations every now and then. The mutations are programmed to occur in just a tiny part of the genome, and instead of involving changes in single DNA “letters” (bases), they involve random rearrangements of whole gene segments.

I’ll explain by way of analogy. Imagine packing for a trip. You will be gone for two weeks, but because your airline charges ridiculous fees to check luggage, you opt to take only a small duffle bag. You have a wide variety of events planned, so each day will require a different outfit. Since space is limited, you grab your favorite pair of shoes—they go with everything (work with me, ladies; analogies aren’t perfect)—along with three pairs of pants and five tops. Assuming each top matches each pair of pants, you can make 15 unique outfits. Some are more casual while others are dressier; some are better for hot weather while others are more appropriate for rain. In other words, by including a variety of styles, you can cover all your fashion needs with great efficiency.

Amazingly, B cells are able to produce a huge variety of antibodies by mixing and matching DNA segments to create unique antigen-binding sites. The pair of shoes is like the constant region; it is used with every “outfit.” Each pair of pants is like a different heavy chain, while each top is like a different light chain. When a new B cell begins to mature, it randomly picks some combination of gene segments (an outfit) from many options in the genome (the suitcase). It then physically stitches the segments together and from now on only produces one kind of antibody. (That’s like only getting to wear one outfit for the rest of your life!)

I’ve dramatically oversimplified the picture here. In reality, to make the variable region for its heavy chain, the maturing B cell randomly chooses one possible segment from each of three segment types, called V, D, and J (for variable, diversity, and joining, respectively). There are 51 V segments to choose from, 6 J segments, and 27 D segments, which yield 8,262 (51x6x27) possible heavy-chain variable regions. The light chains are a bit simpler, as they don’t use D segments. There are 316 possible combinations of V and J segments for the light chain. Thus, there are 2.6 million (8,262×316) different antigen-binding sites possible from this mix-and-match process.

### More Diversity from Built-in Imprecision

2.6 million is a lot, but not even close to the trillions of antigens out in the world. Where does the rest of the diversity come from? As it turns out, the process of stitching together the V, D, and J gene segments into light and heavy chains isn’t very precise. To recombine (reshuffle) the gene segments, two lymphocyte-specific proteins, RAG1 and RAG2 (for recombination activating genes), form a complex to first physically break the double-stranded DNA in specific (but unpredictable) places. Then the complex works together with a cleanup crew of other proteins to rejoin the DNA segments in a different order.

Normally when DNA breaks occur, say due to radiation from the sun, this same kind of DNA repair occurs to rejoin the two ends very precisely. In developing B cells, however, a few bases can be added or removed, analogous to lengthening the hem of your pants or cutting the sleeves off your shirt. This built-in imprecision leads to an estimated 100 million-fold increase in the diversity of antigen-binding sites.

This boost in diversity comes at a significant cost, however. Since each amino acid is encoded by three DNA bases, the addition or deletion of only one or two bases will cause a shift in the “reading frame” such that the DNA code becomes meaningless and the B cell cannot make a functional antibody. Many developing B cells suffer this fate and die in the bone marrow, never getting to debut their one outfit. Yet, the cost is worth it to the organism for the benefits that come with a robust immune response.

### What’s the Point?

We have seen two ways in which B cells exploit the power of randomness to make an enormous repertoire of antibodies. First, the RAG proteins break and rejoin the DNA at random sites to create unique combinations of V, D, and J gene segments. Second, a random small number of bases can be added or lost when the DNA ends are rejoined, leading to the insertion or deletion of one or more amino acids in the antigen-binding site.

The point of this section is not to reveal the ingeniousness of the adaptive immune system, though I hope it accomplishes that also. Rather, I want to emphasize that God uses natural processes—indeed, even a “blind” system for generating massive amounts of diversity—to carry out his purposes. If God uses natural mechanisms that work over short time scales (less than a week) to evolve life-giving solutions to disease, mightn’t he also use a similarly elegant approach to creating life over long periods of time?

In the next section, we will continue to see how B cells and antibodies function and begin to see if there is any evidence for evolution of the immune system.

## #Evolution and Immunity: Same Story?

I’ve had ample opportunity this week to reflect on God’s goodness in providing me a working immune system; I’m nearing the end (hopefully) of a bad cold. Normally I would bewail the havoc caused by the virus itself, but after writing the last section on how antibody diversity is generated, I have become increasingly grateful for this life-protecting process.

### Antibody fine-tuning

At this moment, millions of B cells are patrolling my spleen and lymph nodes, each sporting a different antibody on its surface. If a foreign molecule from the cold virus happens to stick to an antibody on a particular B cell, the cell can get “activated.”

Pathogens are like cockroaches. If you see one roach, you can bet there are many more lurking under cupboards and between walls. Just as one shoe won’t kill them all, one B cell can’t make enough antibodies to deal with an infection. Activation causes the B cell to reproduce, creating more and more B cells that can produce the same kind of antibody.

As is typical during cell division, most of the DNA in dividing B cells is copied with extremely high accuracy. But in the gene segments coding for the variable region of the antibody, mutations accumulate about a million times more often than normal. Why would this be? Isn’t the point of B cell replication to make more identical antibodies?

Almost. It turns out that these frequent random mutations contribute to optimize the antibody. A shopping story helps to illustrate. I was recently at the mall and found a fabulous pair of shoes on sale. Sadly they were out of my size, but it was such a good sale that I decided to buy the half-size down, figuring the shoes might stretch out a little and grow more comfortable with time. Bad idea! That great bargain turned out to be pretty expensive when I got blisters and never wore the shoes again. Clearly this was not an optimized choice.

Just because you can get your foot into a shoe does not mean it fits. Likewise, just because an antibody binds to an antigen does not mean the two are perfectly complementary. Descendents of the activated B cell have a mechanism to induce mutations so each one can make a slightly different version of the antibody. If one of the resulting B cells makes a better-fitting antibody than its kin, it will have a selective advantage and proliferate. The other cells will not become activated as often and will end up dying by apoptosis, a kind of cellular suicide. This mechanism of mutation and selection, called affinity maturation, produces a highly specific, strong interaction between the antigen and the antibody.

### Antibody production and evolution both involve mutation and selection

I believe God is sovereign over all of creation, but I don’t imagine he is presently curing my cold by directly controlling the specific gene rearrangements and optimizing mutations in each of the millions of B cells in my body. Could he do so? Of course! But if that were the case, why bother making billions of antibodies in the first place? The evidence suggests that God has chosen to work through a random process, one which involves the routine creation and destruction of millions of cells that never get used. This is the ordinary means by which God maintains our health. The miracles of healing recorded in the Bible are miraculous precisely because they don’t occur by this normal, natural process.

In my last post, I stated that the generation of antibody diversity is an example in which God uses a “blind” system to sustain and preserve life. I then suggested a link to evolution by asking, “If God uses natural mechanisms that work over short time scales (less than a week) to evolve life-giving solutions to disease, could he also use a similarly elegant approach to create life over long periods of time?”

Some may argue that a small-scale process like antibody production isn’t comparable to the processes of mutation and natural selection that are supposed to have caused macro-evolution. Intelligent Design proponent Michael Behe, for example, accepts that all creatures (including humans) have a common ancestor, but he believes random mutations are not powerful enough to have brought about the diversity of life we see today. He argues that there is an “edge” of evolution: mutation can bring about drug resistance and other small-scale adaptations, but beyond a certain point it can’t really produce anything new.

Clearly, antibody production creates something new: the random recombining of whole gene segments generates highly specific, never-before-seen protein functionality within just a few days. The body can respond toany foreign entity, simply by sorting through billions of ready-made possibilities. Furthermore, a pretty-good solution can be made even better by generating many variations on a theme and sorting through these for the optimal antibody.

Evolution works by the same kinds of mechanisms, except the mutations occur in germ cells (which give rise to egg and sperm) rather than in B cells, and the sorting (selection) process occurs at the population level rather than the cellular level.

### Though often neutral or destructive, mutations sometimes create new functionality

Most people are familiar with point mutations, in which a single DNA “letter,” or base, gets changed. However, mutations come in several other varieties. Short sequences of DNA can be inserted or deleted at random. Chunks of DNA can get cut out and inserted in the opposite direction. Individual genes or even whole chromosomes can get lost or duplicated. In rare cases, the entire genome can get duplicated!

The effect of a mutation principally depends on where it occurs, not on the size of the DNA segment affected. A large deletion occurring within a long stretch between two genes may do nothing at all. On the other hand, a single point mutation within a critical gene may cause a devastating disease. There is also a third possibility though: new functionality may emerge as a result of a mutation.

Let’s consider the protein hemoglobin, for example, which binds oxygen and transports it throughout the body in the blood. Hemoglobin is made from two pairs each of two amino acid chains, called α and β (blue and red in the figure at right). The corresponding genes that code for α and β have similar sequences to each other, and are believed to have arisen when an ancestral globin gene (still present in marine worms, insects, and some fish) duplicated and slowly changed over time. While the ancestral form can bind oxygen just fine, the four chains of hemoglobin cooperate to do so even better.

Both the α and β genes have undergone further duplications followed by smaller mutations. As expected, many of the resulting genes have become irreparably damaged by mutations, but they continue to exist in the genome as inert DNA “fossils.” Others, however, remain active and now perform specialized functions. For instance, one set of β genes binds more tightly to oxygen than the others; it becomes active only during development to ensure that the fetus gets enough oxygen from the mother’s bloodstream. A few months after birth, fetal hemoglobin turns off and the adult form turns on.

To summarize, mutations come in many forms (e.g. rearrangements, insertions, deletions, duplications) and can lead to good, bad, or neutral effects within an individual. B cells depend on random mutations to produce novel antibodies. A few are productive, but the vast majority of B cells die unused. Yet the entire process works for our good! In the same way, mutations in germ cells can lead to no effect, disease, or new and better solutions, as we saw in the hemoglobin example. These are the ordinary (but masterful!) means by which God creates and sustains life.