One of my classmates and friends in high school was a kid we nicknamed “Radar.” He was a cool kid who had special needs. He was mentally challenged. He was also funny and as good-hearted as they come, never causing any real problems—other than playing hooky from school, for days on end. Radar hated going to school.
When he eventually showed up, he would be sent to the principal’s office to explain his unexcused absences to Mr. Reynolds. And each time, Radar would offer the same excuse: his grandmother died. But Mr. Reynolds didn’t buy it—for obvious reasons. It didn’t require much investigation on the principal’s part to know that Radar was lying.
Skeptics have something in common with my friend Radar. They use the same tired excuse when presented with compelling evidence for design from biochemistry. Inevitably, they dismiss the case for a Creator by pointing out all the “flawed” designs in biochemical systems. But this excuse never sticks. Upon further investigation, claimed instances of bad designs turn out to be elegant, in virtually every instance, as recent work by scientists from UC Davis illustrates.
These researchers accomplished an important scientific milestone by using single molecule techniques to observe the replication of a single molecule of DNA.1 Their unexpected insights have bearing on how we understand this key biochemical operation. The work also has important implications for the case for biochemical design.
For those familiar with DNA’s structure and replication process, you can skip the next two sections. But for those of you who are not, a little background information is necessary to appreciate the research team’s findings and their relevance to the creation-evolution debate.
DNA consists of two molecular chains (called “polynucleotides”) aligned in an antiparallel fashion. (The two strands are arranged parallel to one another with the starting point of one strand of the polynucleotide duplex located next to the ending point of the other strand and vice versa.) The paired molecular chains twist around each other forming the well-known DNA double helix. The cell’s machinery generates the polynucleotide chains using four different nucleotides: adenosine, guanosine, cytidine, and thymidine, abbreviated as A, G, C, and T, respectively.
A special relationship exists between the nucleotide sequences of the two DNA strands. Biochemists say the DNA sequences of the two strands are complementary. When the DNA strands align, the adenine (A) side chains of one strand always pair with thymine (T) side chains from the other strand. Likewise, the guanine (G) side chains from one DNA strand always pair with cytosine (C) side chains from the other strand. Biochemists refer to these relationships as “base-pairing rules.” Consequently, if biochemists know the sequence of one DNA strand, they can readily determine the sequence of the other strand. Base-pairing plays a critical role in DNA replication.
Image 1: DNA’s Structure
Biochemists refer to DNA replication as a “template-directed, semiconservative process.” By “template-directed,” biochemists mean that the nucleotide sequences of the “parent” DNA molecule function as a template, directing the assembly of the DNA strands of the two “daughter” molecules using the base-pairing rules. By “semiconservative,” biochemists mean that after replication, each daughter DNA molecule contains one newly formed DNA strand and one strand from the parent molecule.
Image 2: Semiconservative DNA Replication
Conceptually, template-directed, semiconservative DNA replication entails the separation of the parent DNA double helix into two single strands. By using the base-pairing rules, each strand serves as a template for the cell’s machinery to use when it forms a new DNA strand with a nucleotide sequence complementary to the parent strand. Because each strand of the parent DNA molecule directs the production of a new DNA strand, two daughter molecules result. Each one possesses an original strand from the parent molecule and a newly formed DNA strand produced by a template-directed synthetic process.
DNA replication begins at specific sites along the DNA double helix, called “replication origins.” Typically, prokaryotic cells have only a single origin of replication. More complex eukaryotic cells have multiple origins of replication.
The DNA double helix unwinds locally at the origin of replication to produce what biochemists call a “replication bubble.” During the course of replication, the bubble expands in both directions from the origin. Once the individual strands of the DNA double helix unwind and are exposed within the replication bubble, they are available to direct the production of the daughter strand. The site where the DNA double helix continuously unwinds is called the “replication fork.” Because DNA replication proceeds in both directions away from the origin, there are two replication forks within each bubble.
Image 3: DNA Replication Bubble
DNA replication can only proceed in a single direction, from the top of the DNA strand to the bottom. Because the strands that form the DNA double helix align in an antiparallel fashion with the top of one strand juxtaposed with the bottom of the other strand, only one strand at each replication fork has the proper orientation (bottom-to-top) to direct the assembly of a new strand, in the top-to-bottom direction. For this strand—referred to as the “leading strand”—DNA replication proceeds rapidly and continuously in the direction of the advancing replication fork.
DNA replication cannot proceed along the strand with the top-to-bottom orientation until the replication bubble has expanded enough to expose a sizable stretch of DNA. When this happens, DNA replication moves away from the advancing replication fork. DNA replication can only proceed a short distance for the top-to-bottom-oriented strand before the replication process has to stop and wait for more of the parent DNA strand to be exposed. When a sufficient length of the parent DNA template is exposed a second time, DNA replication can proceed again, but only briefly before it has to stop again and wait for more DNA to be exposed. The process of discontinuous DNA replication takes place repeatedly until the entire strand is replicated. Each time DNA replication starts and stops, a small fragment of DNA is produced.
Biochemists refer to these pieces of DNA (that will eventually compose the daughter strand) as “Okazaki fragments”—after the biochemist who discovered them. Biochemists call the strand produced discontinuously the “lagging strand” because DNA replication for this strand lags behind the more rapidly produced leading strand. One additional point: the leading strand at one replication fork is the lagging strand at the other replication fork since the replication forks at the two ends of the replication bubble advance in opposite directions.
An ensemble of proteins is needed to carry out DNA replication. Once the origin recognition complex (which consists of several different proteins) identifies the replication origin, a protein called “helicase” unwinds the DNA double helix to form the replication fork.
Image 4: DNA Replication Proteins
Once the replication fork is established and stabilized, DNA replication can begin. Before the newly formed daughter strands can be produced, a small RNA primer must be produced. The protein that synthesizes new DNA by reading the parent DNA template strand—DNA polymerase—can’t start production from scratch. It must be primed. A massive protein complex, called the “primosome,” which consists of over 15 different proteins, produces the RNA primer needed by DNA polymerase.
Once primed, DNA polymerase will continuously produce DNA along the leading strand. However, for the lagging strand, DNA polymerase can only generate DNA in spurts to produce Okazaki fragments. Each time DNA polymerase generates an Okazaki fragment, the primosome complex must produce a new RNA primer.
Once DNA replication is completed, the RNA primers are removed from the continuous DNA of the leading strand and from the Okazaki fragments that make up the lagging strand. A protein called a “3’-5’ exonuclease” removes the RNA primers. A different DNA polymerase fills in the gaps created by the removal of the RNA primers. Finally, a protein called a “ligase” connects all the Okazaki fragments together to form a continuous piece of DNA out of the lagging strand.
Are Leading and Lagging Strand Polymerases Coordinated?
Biochemists had long assumed that the activities of the leading and lagging strand DNA polymerase enzymes were coordinated. If not, then DNA replication of one strand would get too far ahead of the other, increasing the likelihood of mutations.
As it turns out, the research team from UC Davis discovered that the activities of the two polymerases are not coordinated. Instead, the leading and lagging strand DNA polymerase enzymes replicate DNA autonomously. To the researchers’ surprise, they learned that the leading strand DNA polymerase replicated DNA in bursts, suddenly stopping and starting. And when it did replicate DNA, the rate of production varied by a factor of ten. On the other hand, the researchers discovered that the rate of DNA replication on the lagging strand depended on the rate of RNA primer formation.
The researchers point out that if not for single molecule techniques—in which replication is characterized for individual DNA molecules—the autonomous behavior of leading and lagging strand DNA polymerases would not have been detected. Up to this point, biochemists have studied the replication process using a relatively large number of DNA molecules. These samples yield average replication rates for leading and lagging strand replication, giving the sense that replication of both strands is coordinated.
According to the researchers, this discovery is a “real paradigm shift, and undermines a great deal of what’s in the textbooks.”2 Because the DNA polymerase activity is not coordinated but autonomous, they conclude that the DNA replication process is a flawed design, driven by stochastic (random) events. Also, the lack of coordination between the leading and lagging strands means that leading strand replication can get ahead of the lagging strand, yielding long stretches of vulnerable single-stranded DNA.
Diminished Design or Displaced Design?
Even though this latest insight appears to undermine the elegance of the DNA replication process, other observations made by the UC Davis research team indicate that the evidence for design isn’t diminished, just displaced.
These investigators discovered that the activity of helicase—the enzyme that unwinds the double helix at the replication fork—somehow senses the activity of the DNA polymerase on the leading strand. When the DNA polymerase stalls, the activity of the helicase slows down by a factor of five until the DNA polymerase catches up. The researchers believe that another protein (called the “tau protein”) mediates the interaction between the helicase and DNA polymerase molecules. In other words, the interaction between DNA polymerase and the helicase compensates for the stochastic behavior of the leading strand polymerase, pointing to a well-designed process.
As already noted, the research team also learned that the rate of lagging strand replication depends on primer production. They determined that the rate of primer production exceeds the rate of DNA replication on the leading strand. This fortuitous coincidence ensures that as soon as enough of the bubble opens for lagging strand replication to continue, the primase can immediately lay down the RNA primer, restarting the process. It turns out that the rate of primer production is controlled by the primosome concentration in the cell, with primer production increasing as the number of primosome copies increase. The primosome concentration appears to be fine-tuned. If the concentration of this protein complex is too large, the replication process becomes “gummed up”; if too small, the disparity between leading and lagging strand replication becomes too great, exposing single-stranded DNA. Again, the fine-tuning of primosome concentration highlights the design of this cellular operation.
It is remarkable how two people can see things so differently. For scientists influenced by the evolutionary paradigm, the tendency is to dismiss evidence for design and, instead of seeing elegance, become conditioned to see flaws. Though DNA replication takes place in a haphazard manner, other features of the replication process appear to be engineered to compensate for the stochastic behavior of the DNA polymerases and, in the process, elevate the evidence for design.
And, that’s no lie.
- The Cell’s Design: How Chemistry Reveals the Creator’s Artistry by Fazale Rana (book)
- “Uprooting a ‘Bad Design’ Argument” by Fazale Rana (article)
- “Pseudoenzymes Make Real Case for Intelligent Design” by Fazale Rana (article)
- “Pseudoenzymes Illustrate Science’s Philosophical Commitments” by Fazale Rana (article)
- “New Research Suggests Two Overlooked Functions of Junk DNA” by Fazale Rana (article)
- “How the Central Dogma of Molecular Biology Points to Design” by Fazale Rana (article)
- James E. Graham et al., “Independent and Stochastic Action of DNA Polymerases in the Replisome,” Cell 169 (June 2017): 1201–13, doi:10.1016/j.cell.2017.05.041.
- Bec Crew, “DNA Replication Has Been Filmed for the First Time, and It’s Not What We Expected,” ScienceAlert, June 19, 2017, https://sciencealert.com/dna-replication-has-been-filmed-for-the-first-time-and-it-s-stranger-than-we-thought.
Subjects: Biochemistry, Design, Fine-Tuning, Intelligent Design, Proteins