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Contingency Planning in the Cell Affirms Design

Photo credit: Rémi Walle, via Unsplash.

There are accidents in biology that don’t always happen but might happen. When they do, systems are invariably in place that fly into action and do what needs to be done. The blood clotting cascade, one of Michael Behe’s illustrations in Darwin’s Black Box, is such a system. A person might go for years without a cut or scratch, but the contingency plan is there anyway, just in case. As Behe showed, it is irreducibly complex. Here are some recently elucidated examples of contingency planning within the cell itself.

Collagen: The N-Glycan Enigma

Collagen is the most abundant protein in the human body. When collagen fibers are assembled, there’s a polysaccharide that usually sits idly by. It is called N-glycan, and its role has remained elusive for decades. Now, scientists have figured out what it’s there for. Rasia C. Li et al., publishing in PNAS, announced that “Collagen’s enigmatic, highly conserved N-glycan has an essential proteostatic function.” The team figured that this member must have a function because it is highly conserved in all domains of life despite the energetic cost of maintaining it. With that knowledge, they searched for its elusive purpose.

By assaying N-glycan function under conditions of impaired collagen folding, we show that, although the N-glycan is dispensable under normal conditions, it is essential for collagen folding and secretion under conditions that challenge proteostasis. Such environments are commonly encountered during development, tissue repair, and disease. [Emphasis added.]

Glycosylation refers to the affixing of a sugar to a protein, making it a glycoprotein. Since N-glycan for collagen only plays minor roles outside the cell in the extracellular matrix and is not always essential inside the cell’s endoplasmic reticulum (ER), the team had to figure out why it’s there. Rather than dismiss it as junk they figured it might be functional in certain circumstances.

We hypothesized that the function of the N-glycan might be apparent only in the right proteostatic context. In particular, we speculated that N-glycan–mediated access to the ER’s lectin-based chaperone network could be essential when procollagen folding is challenged, such as in the context of misfolding-prone C-Pro domain mutations and/or ER stress.

To find out, they generated a procollagen variant to see what N-glycan would do when confronted with a folding challenge.

Cumulatively, these observations address the N-glycan enigma, unveiling the context-dependent essentiality of procollagen’s conserved N-glycan to enable proper folding and trafficking of procollagen in challenging proteostasis environments.

This molecule’s function, therefore, demonstrates contingency planning. Collagen fibrils often fold properly without its help. When folding is about to go awry, though, N-glycosylation calls in chaperones that rush in like spotters for a gymnast, making sure the growing collagen fibril doesn’t hurt itself and the organism. 

A 2017 textbook on the Essentials of Glycosylation spends several pages describing the synthesis of N-glycans. It takes a lot of cellular machinery to construct these players! “The biosynthesis of N-glycans is most complex in mammals,” the three authors say. There are processes to make the nascent molecule, then there are early processing steps, late processing steps and maturation steps. These occur in two cellular compartments: the Golgi and the endoplasmic reticulum. 

N-Glycan synthesis begins on a lipid-like polyisoprenoid molecule termed dolichol-phosphate (Dol-P) in eukaryotes. Following synthesis of an oligosaccharide that contains as many as 14 sugars, the N-glycan is transferred “en bloc” to protein. This synthetic pathway is conserved in all metazoa, plants, and yeast…. N-Glycans affect many properties of glycoproteins including their conformation, solubility, antigenicity, activity, and recognition by glycan-binding proteins…. Defects in N-glycan synthesis lead to a variety of human diseases.

See also Dr. Lianchun Wang’s slide show of N-glycan synthesis for a visual look at the “complicated biosynthesis” of these molecules. 

Photosynthesis and Quantum Quenching

When sunlight is adequate, leaves are happy. Their photosynthetic antennae direct the energy into the photocenters for conversion to food molecules. On some days, though, there can be too much of a good thing. Like sunburned beachgoers, plants can burn, too, but they lack the ability to run to the shade. There’s a contingency plan for that situation. 

In PNAS, Jacob S. Higgins et al. describe how “Photosynthesis tunes quantum-mechanical mixing of electronic and vibrational states to steer exciton energy transfer.” Plants know their QM (quantum mechanics) well enough to employ it like an overflow valve, steering excess energy into the quenching center.

Photosynthetic light-harvesting antennae transfer energy toward reaction centers with high efficiency, but in high light or oxidative environments, the antennae divert energy to protect the photosynthetic apparatus. For a decade, quantum effects driven by vibronic coupling, where electronic and vibrational states couple, have been suggested to explain the energy transfer efficiency, but questions remain whether quantum effects are merely consequences of molecular systems. Here, we show evidence that biology tunes interpigment vibronic coupling, indicating that the quantum mechanism is operative in the efficient transfer regime and exploited by evolution for photoprotection. Specifically, the Fenna–Matthews–Olson complex uses redox-active cysteine residues to tune the resonance between its excitons and a pigment vibration to steer excess excitation toward a quenching site.

It’s marvelous that evolution “exploited” this QM capability, isn’t it? How many mutations did it take to get that right?

DNA’s Repair Toolkit

To end this article, there’s a graphic worth looking at. Chinese scientists at the Peking University Health Science Center examined the critical pathways that cells use to avoid cancer or genomic instability. A chart of five repair pathways was posted by Medical Xpress, under the headline, “Understanding the DNA repair toolkit to chart cancer evolution.”

The chart shows five repair systems that protect DNA from damage. These are contingency planning systems that are ready and waiting to step in, like EMTs, when things go wrong during cell division or transcription. There are five systems they discussed:

  • Mismatch repair fixes mutations that insert the wrong base
  • Nucleotide excision repair comes to aid when DNA structural damage occurs
  • Base excision repair fixes bases that become separated from the strand
  • Double-stranded break repair solves the complex situation when both DNA strands become separated
  • Interstrand crosslinks repair helps when drugs block replication and transcription

When these systems work properly, they can prevent cancer and drug resistance. Many life-threatening diseases are prevented by these five pathways. When the pathways themselves fail, though, it can be bad news for the organism. The Chinese team felt that systematizing our knowledge about these pathways and the specific consequences of “pathway damage” can help oncologists know which avenues provide the best therapies for specific cancers.

Another Example of Foresight 

Contingency planning is another example of foresight, defined as “care or provision for the future; provident care; prudence,” and oversight, defined as “supervision; watchful care.” Both concepts fit perfectly with intelligent design but defy blind processes like evolution. The results of good foresight and oversight are health and well-being. The outcomes of breakdowns in contingency planning systems (caused by chance processes like mutations) are disease and death. 

Design-theoretic science is better poised to discern the foresight and oversight required for contingency planning systems. Understanding that these systems are designed for a purpose leads to practical results. Scientists can approach them with hypotheses about ways to fortify them to promote health.