Life’s Layers of Complexity: When All Isn’t All

Life’s Layers of Complexity: When All Isn’t All

Looking back on 2018, I give thanks for the blessings God has rained upon me. I can’t help but think how my vision of God’s goodness and glory have grown as I contemplate almost every aspect of creation in each new scientific study.

One thing that continues to amaze me is the staggering complexity of all things biological. Whether we’re looking at things as “simple” as genes and their regulatory elements, or basic life-supporting components such as photosynthesis, nitrogen fixation, or DNA replication, life is not simple by any measure.

It’s easy to miss life’s complexity. Daily routines don’t allow for much reflection, and biological complexities don’t fit into five-second soundbites. Admittedly, many of us are tempted to check out when topics become too detail-oriented. Additionally, scientific experimentation necessitates that we simplify complex systems and isolate various mechanisms in order to study individual components in cause-and-effect relationships. The detailed findings that reach peer-review publication are often reductionistic and further simplified by science writers and then given a provocative (and sometimes inaccurate) “hook” for the general public. We often have to look past the headlines—and sometimes beyond the detailed but limited findings—to appreciate the underlying complexities.

Complexity upon Complexity Everywhere We Look

I was impressed by three articles in Nature‘s December 6, 2018 issue, which reminded me of the near fathomless depths of complexity contributing to life’s staggering complexity.1 In the first article, researchers identify a mechanism involved in regulating repair of damaged DNA that depends on a specific protein called cyclin-dependent kinase 12 (CDK12). This article drew my attention to the extreme complexities of transcription and DNA damage responses employed in all cells to maintain genome integrity.

Mission Critical: DNA Repair

Our DNA is in constant need of repair. Cells are continually bombarded by various forms of ionizing radiation and they encounter other kinds of environmental stress (smoke, chemicals, UV light, etc.). Even normal cellular metabolism produces potentially damaging byproducts such as reactive oxygen species. Replication of DNA for cell proliferation results in DNA damage as well. Estimates suggest that every cell may experience 100,000 DNA damage events per day!2

Some of these events result in base modifications and damage to only one strand of the DNA double helix. Some damage leads to double-stranded breaks (DSB) in cellular DNA. Thankfully, cells contain complex systems for repairing DNA damage. Two main mechanisms of DNA repair allow for homologous recombination (HR) and non-homologous end-joining (NHEJ) at the sites of DSBs. HR maintains genomic integrity by utilizing sister chromatids to provide an unbroken and undamaged template for DNA repair. HR is a primary mechanism for repair when these sequences are most accessible (in S and G2 of the cell cycle).3 NHEJ, which is less rigorous in maintaining DNA sequence integrity, joins damaged ends together and sometimes introduces deletions (or insertions) at the site of repair. NHEJ functions through all stages of the cell cycle and is a major mechanism for post-mitotic repairs and for generating critical diversity in immune system proteins.4

Because DNA is the substance of heredity and the template for cellular processes, maintaining genomic sequence integrity is critical and requires myriad supporting players. More than 50 proteins are involved in DNA damage response (DDR), with some estimates of tens of thousands of copies of each.5 More recent omics studies estimate that thousands of gene products participate in DDR.6 The proteins serve a variety of functions that are highly spatially and temporally orchestrated. DDR takes place in intracellular foci described as highly dynamic giga-dalton (a billion atomic mass units) structures that can assemble and disassemble within minutes and are capable of simultaneously repairing multiple DNA lesions.7

“DNA repair is carried out by a plethora of enzymatic activities that chemically modify DNA to repair DNA damage including nucleases, helicases, polymerases, topoisomerases, recombinases, ligases, glycosylases, demethylases, kinases and phosphatases. These repair tools must be precisely regulated because each in its own right can wreck havoc on the integrity of DNA if misused or allowed to access DNA at the inappropriate time or place.”

—Alberto Ciccia and Stephen Elledge

HR and NHEJ are not simple processes. The choice of which one is utilized depends on multiple factors, of which many, if not most, remain unidentified. As it turns out CDK12 may be one contributing regulator favoring implementation of HR repair. But in order to understand how CDK12 may be contributing to HR, we need to understand another layer of complexity, that of cellular transcription.

Transcribing DNA to RNA

Transcription is the rewriting of DNA into RNAs which serve as regulators of cellular processes and templates for protein production. Transcription involves another myriad of players, highly orchestrated, within a process that takes place remarkably fast and continually within every cell.8 In eukaryotic cells, RNA polymerase II (Pol II) transcribes DNA into pre-mRNAs. The 12-component Pol II complex in mammals does not act alone in initiating, elongating, or terminating transcription. Pol II requires several general transcription factors for binding the DNA promoter and recruiting the Pol II complex to the DNA promoter. Many additional proteins and protein complexes are needed for Pol II elongation and termination.9 Furthermore, many more proteins are involved in co-transcriptionally and post-transcriptionally modifying pre-mRNA transcripts into mRNAs.

CDK12 and HR Repair

One of the 12 subunits of Pol II, RPB1, serves many critical functions in transcription and processing of mRNAs. CDK12, the star of the first article, functions to phosphorylate (post-translationally modify) RPB1 at a specific site (Ser-2 residue in the C-terminal heptad repeat).10

In the Nature report, the researchers present data that demonstrates that CDK12-dependent phosphorylation of Pol II contributes to Pol II’s transcription elongation and results in an increase in full-length mRNAs that encode many of the HR repair proteins. Without this phosphorylation event, transcription in many HR repair genes (and others) is prematurely terminated at internal poly-adenylation (IPA) sites located in introns upstream of the 3′-most exon. If transcription terminates at IPAs, full-length pre-mRNAs are not transcribed, and full-length HR proteins are not produced.

The researchers “conclude that the primary role of CDK12 is to suppress IPAs genome-wide and to promote expression of distal (full-length) isoforms.”11 This effect impacts multiple genes, but it seems CDK12 has a more profound effect on HR repair genes. “Our data suggest that the cumulative effect of multiple, high-sensitivity IPAs in HR genes accounts for the downregulation of their full-length isoforms. . . We propose that the combined effect of strong downregulation of multiple gene products within the same functional pathway causes the HR-deficient phenotypes observed upon CDK12 loss.”12

That means when CDK12 is present, Pol II elongation continues to the distal polyadenylation site in many genes, and specifically results in a functional HR repair pathway. These findings demonstrate a role for CDK12 in the phosphorylation of Pol II that regulates the production of essential HR repair proteins and suggests that regulation of CDK12 may be one factor affecting the selection of HR (over NHEJ) in a system of staggering complexity.

Complexity’s “Wow” Factor

In the second and third Nature articles (which I won’t unpack here), additional layers of complexity for sustaining and propagating life are brought to the fore. Just briefly, the second article highlights complex spatial and mechanotransductive signals that affect cell fate during development and differentiation. Mechanical signals like stretching and confinement affect cellular processes and cellular development and ultimately cell fates (in this case, pancreatic cell type) of pluripotent and multipotent stem cells.13 In the third article, researchers examine the maintenance and protection of the methylation status of oocyte genomes necessary for proper progression of embryogenesis. That is, they look at the effect of DNA modifications (not affecting the DNA sequence) and the regulation of those modifications by at least three critical proteins: Stella, UHRF1, and DNMT1.14 Each of those proteins, in turn, serves various critical roles at different stages and in different cell types. The signals, molecules, and mechanisms regulating these functions are astoundingly complex and only partially understood but are critical for proper development and life.

These three very different studies all contribute to the fundamental complexities required for sustaining and propagating all animal life. I look at these biological processes in sheer wonder and awe at the complexities involved in fundamental processes for sustaining and propagating life. It comes as no surprise that many of the mechanisms and molecular players are highly conserved within various organisms—from yeast to human beings. These functions are critical for sustaining and propagating life—so, of course, living organisms share these critical functions.

Our ability to apply basic research findings from yeast, flies, and mice for human care and creation care is a magnificent byproduct of God’s providence in creating life according to shared molecular archetypes and fundamental processes. These and other fundamental, common features (such as the DNA code) point to God’s goodness and his providence in caring for creation and human well-being. These shared features do not (or need not) point to shared ancestral origins. Their discovery requires no broad evolutionary narrative. And to imagine that they come from unaided naturalistic processes requires broad speculations as to how these staggering complexities may have originated—speculations that never include specifics on how complex, interdependent networks of systems are established or how novel genes are produced. Reductionistic views and oversimplification (even in complex, peer-reviewed research reports) neglect underlying complexities.

When “All” Isn’t All

While reading a recent Science News article, I was struck by this tendency to over-simplify yet again. The article addresses unexpected findings of paternal mitochondrial DNA inheritance. In it, the author states, “DNA in a cell’s nucleus is inherited equally from both parents and contains all the genetic instructions for building a body.” Reading this, one probably thinks, “Well, of course it does. DNA contains all the genetic instructions for building a body.” But is it true? Is parental DNA all the instructions needed for life? Well, technically speaking, no.

As the three Nature articles above point out, the system comes preloaded with (1) not only genomes regulated by epigenetic modifications but also with regulatory RNAs often post-transcriptionally and differentially modified and expressed to varying degrees, (2) proteins with relevant and variable cellular localizations, expression levels, glycosylation statuses and post-translational modifications, and (3) cells elegantly set with various capacities for mechanical transduction signaling (including force responses to gravity and proximity-type detection that can sense, not just variable force, but directional differences). All of these molecular components bear additional information for cell development and replication and are necessary for the growth, development, and reproduction of living cells and creatures. These all (not to mention the critical role for mitochondria, which have their own DNA) carry information necessary for building a body. These components also accompany and are all necessary for accessing the genetic instructions in nuclear DNA. In scientific terms, the information in DNA is necessary but not sufficient for building a body. So “all” isn’t all.

God’s Fingerprints

I often say that the data can fit almost any scenario for life’s origins with varying degrees of plausibility. Data can fit an evolutionary narrative or a progressive creation narrative. My evolution-advocating colleagues argue that evolution explains all these features, but I really don’t see it the same as they do. I actually find the scope of evolution fairly limited and, the more I study, I see appeals to evolutionary just-so stories growing more incredulous.

These studies convince me even more that life requires life of similar levels of complexity to propagate and sustain itself. Life, it seems, only ever comes from life, and science has produced no data that supports a contradictory claim. Life comes from life always and everywhere we look.

These reports point ever more clearly to common features of mind-boggling complexity necessary for fundamental life-sustaining and propagating cellular processes. But what a remarkable testament to the glory of God. God’s providence seems clear. As scientists make these discoveries and test their viability in animals and yeast, they unlock applications for human biology and other areas of creation stewardship. As I consider these things, I am led to worship God for his glory demonstrated throughout the complex array of life’s interdependent systems and for his magnificent foresight and infinite, clever brilliance. We, and all life, are walking miracles of absurd complexities that shout often without words, “Glory to God!”

Indeed, all glory to God! And in this case “all” does mean all.

  1. Sara J. Dubbury, Paul L. Boutz, and Phillip A. Sharp, “CDK12 Regulates DNA Repair Genes by Suppressing Intronic Polyadenylation,” Nature 564, no. 7734 (2018): 141–45, doi:10.1038/s41586-018-0758-y; Anant Mamidi et al., “Mechanosignalling via Integrins Directs Fate Decisions of Pancreatic Progenitors,” Nature 564, no. 7734 (2018): 114–18, doi:10.1038/s41586-018-0762-2; Francesca M. Spagnoli, Nature: News and Views, November 28, 2018,; Yingfeng Li et al., “Stella Safeguards the Oocyte Methylome by Preventing de novo Methylation Mediated by DNMT1,” Nature 564, no. 7734 (2018): 136–40, doi:10.1038/s41586-018-0751-5.
  2. Alberto Ciccia and Stephen J. Elledge, “The DNA Damage Response: Making It Safe to Play with Knives,” Molecular Cell 40, no. 2 (2010): 179–204, doi:10.1016/j.molcel.2010.09.019.
  3. M. Lisby and R. Rothstein, “DNA Damage Checkpoint and Repair Centers,” Current Opinion in Cell Biology 16, no. 3 (June 2004): 328–34, doi:10.1016/
  4. Shruti Malu, Vidyasagar Malshetty, Dailia Francis, and Patricia Cortes, “Role of Non-Homologous End Joining in V(D)J Recombination,” Immunologic Research 54, no. 1–3 (December 2012): 233–46, doi:10.1007/s12026-012-8329-z; Mayilaadumveettil Nishana and Sathees C. Raghavan, “Role of Recombination Activating Genes in the Generation of Antigen Receptor Diversity and Beyond,” Immunology 137, no. 4 (December 2012): 271–81, doi:10.1111/imm.12009.
  5. Lisby and Rothstein, “DNA Damage,” 328–34.
  6. Kasper W. J. Derks, Jan H. J. Hoeijmakers, and Joris Pothof, “The DNA Damage Response: The Omics Era and Its Impact,” DNA Repair 19 (July 2014): 214–20, doi:10.1016/j.dnarep.2014.03.008.
  7. Lisby and Rothstein, “DNA Damage,” 328–34.
  8. Transcription does not occur in enucleated red blood cells although mRNAs and microRNAs are detected. Khan Academy, “Transcription and mRNA Processing | Biomolecules | MCAT | Khan Academy,” video, 05:31, posted June 3, 2016,
  9. T. A. Brown, “Assembly of the Transcription Initiation Complex,” chap. 9 in Genomes, 2nd ed. (Oxford: Wiley-Liss, 2002); “RNA Polymerase II Holoenzyme,” Wikipedia, last modified July 16, 2018, 15:11 (UTC),
  10. Kaiwei Liang et al., “Characterization of Human Cyclin-Dependent Kinase 12 (CDK12) and CDK13 Complexes in C-Terminal Domain Phosphorylation, Gene Transcription, and RNA Processing,” Molecular and Cellular Biology 35, no. 6 (March 2015): 928–38, doi:10.1128/mcb.01426-14; Hana Paculová and Jiří Kohoutek, “The Emerging Roles of CDK12 in Tumorigenesis,” Cell Division 12 (2017): 7, doi:10.1186/s13008-017-0033-x.
  11. Dubbury, “CDK12 Regulates DNA Repair,” 141–45.
  12. Dubbury, 141–45.
  13. Mamidi, “Mechanosignalling via Integrins,” 114–8.
  14. Li, “Stella Safeguards the Oocyte,” 136–40.