It's design all the way down

Protein Quality Control Surprise: An Enzyme Can Operate a Stalled Ribosome

Evolution News & Views January 9, 2015 5:17 AM | 

 

A cell is "a well-run factory," according to scientists at the University of Utah. Its protein assembly machines -- ribosomes -- do their work reliably and efficiently most of the time. On rare occasions, though, a nascent protein stalls inside the machine. When that happens, it's a crisis that can kill the cell or lead to serious diseases.

Fortunately, the cell has a plan to rescue itself:

Ribosomes are machines on a protein assembly line, linking together amino acids in an order specified by the genetic code. When something goes wrong, the ribosome can stall, and a quality control crew is summoned to the site. To clean up the mess, the ribosome is disassembled, the blueprint is discarded, and the partly made protein is recycled. (Emphasis added.)

A surprise surfaced when the Utah researchers, in an "extensive biochemical analysis," sought to understand the steps involved in tagging the stalled protein for destruction. Stalling causes the two parts of the ribosome, 40S and 60S, to separate. Immediately afterward, two "rare" quality-control proteins, Ltn1p and Rqc2p, bind to the stalled protein in the 60S part. Ltn1p binds near the exit tunnel and attaches the usual tag for destruction, ubiquitin. (Biochemists have a sense of humor sometimes; the "RING" domain of Ltn1p stands for "Really Interesting New Gene.")

It's the other participant, Rqc2p, that plays an unexpected role: it continues assembling the stalled protein without the benefit of a template or transfer RNA! "In this case, we have a protein, Rqc2, playing a role similar to that of mRNA" (messenger RNA), researcher Adam Frost says. "I love this story because it blurs the lines of what we thought proteins could do." But what kind of information can a template-free protein add to a stalled protein? The story gets even more bizarre:

Yet this study reveals a surprising role for one member of the quality control team, a protein conserved from yeast to man named Rqc2. Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of 20 total) -- alanine and threonine -- over and over, and in any order. Think of an auto assembly line that keeps going despite having lost its instructions. It picks up what it can and slaps it on: horn-wheel-wheel-horn-wheel-wheel-wheel-wheel-horn.

Is this a factory gone berserk? No. Using design thinking, the researchers figured there must be a purpose behind the seemingly wacky process:

Like a half-made car with extra horns and wheels tacked to one end, a truncated protein with an apparently random sequence of alanines and threonines looks strange, and probably doesn't work normally. But the nonsensical sequence likely serves specific purposes. The code could signal that the partial protein must be destroyed, or it could be part of a test to see whether the ribosome is working properly. Evidence suggests that either or both of these processes could be faulty in neurodegenerative diseases such as Alzheimer's, Amyotrophic lateral sclerosis (ALS), or Huntington's.

In fact, earlier experiments have shown a link between Rqc2p and the "heat shock" response of a cell under stress. This response up-regulates the manufacture of heat shock proteins. These proteins come to the aid of a cell that gets too hot, too cold, or oxygen deprived. The heat shock proteins act as chaperones and damage-control agents. They can re-fold partially folded proteins, tag misfolded proteins, or move proteins to safe-houses in the cell. In multicellular eukaryotes, they can even target proteins for the cell surface to be recognized by the immune system.

The linkage between Rqc2p and heat shock gave the researchers a clue. The alanine-threonine tags on the stalled protein (named, whimsically, "CAT tails" for "carboxy-terminal Ala and Thr extensions") might turn on the heat shock response. In their paper in Science, they put the story together:

Integrating our observations, we propose the model schematized in fig. S13. Ribosome stalling leads to dissociation of the 60S and 40S subunits, followed by recognition of the peptidyl-tRNA-60S species by Rqc2p and Ltn1p. Ltn1p ubiquitylates the stalled nascent chain, and this leads to Cdc48 recruitment for extraction and degradation of the incomplete translation product. Rqc2p, through specific binding to Ala(IGC) and Thr(IGU) tRNAs, directs the template-free and 40S-free elongation of the incomplete translation product with CAT tails. CAT tails induce a heat shock response through a mechanism that is yet to be determined.

It wouldn't be enough, in other words, for Ltn1p to tag the bad protein with ubiquitin. All that would do is silently send the protein to the trashcan (the proteasome). No, the cell needs an alarm signal that a ribosome might have gone haywire. The CAT tails added by Rqc2p somehow inform the cell that a heat shock response team is needed to investigate.

To add the CAT tails, Rqc2p cannot rely on the failed ribosome. It also cannot rely on the messenger-RNA and transfer-RNA pathways from the genetic code in the nucleus. Without a template, it has to work autonomously, using its own active sites for alanine and threonine, and the ability to fasten them to the incomplete protein. By stitching on these extra amino acids to the stalled protein, Rqc2p sends something like an SOS message to the cell, using the actual defective protein as evidence. It's all quite elegant and unexpected.

"There are many interesting implications of this work and none of them would have been possible if we didn't follow our curiosity," says Brandman. "The primary driver of discovery has been exploring what you see, and that's what we did. There will never be a substitute for that."

That statement is pregnant with design implications, however unintended. If the researchers stopped at Darwinian ideas of random, purposeless matter in motion, would they have found this new process? It was their curiosity about "what we thought proteins could do" -- what purposeful roles they could play -- that led them to expand our knowledge of cell quality control.

So whether or not these biochemists "believe in" intelligent design -- we assume they don't -- their actions speak louder than words. By viewing the cell as "a well-run factory" with "machines on a protein assembly line," they added to a growing view that "Nature is capable of more than we realize."

Lastly, don't miss that incidental statement about the "member of the quality control team" Rqc2p being "a protein conserved from yeast to man," implying that for hundreds of millions of years, evolution had nothing to do with it.

 

Survival of the kindest?

An Evolutionary Challenge: Explaining Away Compassion, Philanthropy, and Self-Sacrifice

Denyse O'Leary January 9, 2015 11:23 AM | 

 

 

Apart from religion, no subject has vexed naturalists more than why people sacrifice themselves and their wishes, hopes, dreams, and pleasures for others. Branding both philosophy and religion and popular arts and culture for naturalism includes explaining away compassion, philanthropy, and self-sacrifice.

Redefinition is a first step. This entire group of qualities is now loosely called "altruism," a trans-species concept by which, for example, worker ants pass on their genes by serving their queen, who lays lots of eggs, instead of reproducing individually (kin selection).

Kin selection grew legs in 1955 when British geneticist J. B. S. Haldane said, we are told, that he would risk his life for two brothers or eight cousins, to preserve enough of his own genes to justify his death. Evolutionist William Hamilton described the idea mathematically, calling it inclusive fitness. His calculations have been used ever since, and were a key inspiration for Richard Dawkins's The Selfish Gene.

Altruism has been described as "an anomalous thorn in Darwin's side" and a "conundrum that Darwinians would need to solve, given their view of the ruthless struggle among living beings for survival." So, if Darwinizing the mind through altruism and kin selection succeeds, we can account for such human behavior as if we were bees or beavers, which greatly simplifies matters.

E. O. Wilson is widely hailed as the founder of sociobiology (circa 1975), which expounded these theories. Sociobiology later morphed into evolutionary psychology. But then Wilson dramatically abandoned kin selection in 2010 in a Nature paper, "The evolution of eusociality," co-authored with mathematicians. He argued that strict Darwinism (natural selection acting on random mutation) "provides an exact framework for interpreting empirical observations," dispensing with the other theories he had promoted for decades. Over 140 leading biologists signed a letter to Nature, attacking the 2010 paper. Some called his new, strictly Darwin model "unscholarly," "transparently wrong," and "misguided."

What? All this is said of a Darwin-only model, the gold standard of naturalism?

New Atheist evolutionary biologist Jerry Coyne has weighed in, saying that Wilson et al. are "wrong -- dead wrong." Curiously, he admitted, "The 'textbook' explanation, based on a higher relatedness of workers to their sisters than to their own potential offspring, no longer seems feasible. ... But we've known all this for years!" If so, he and fellow evolutionary biologists have been very economical with their accounts of the failures. How else to account for the -- to many people, incomprehensible -- uproar at the time?

Evolutionary psychologist David Sloan Wilson, defending E. O. Wilson, scolded, "This degree of illiteracy about foundational issues is an embarrassment for the field of evolutionary biology." He is perhaps telling us more than he realizes. Neuroscientist Michael Gazzaniga, attempting to defend Wilson, offered:

In the end, Mr. Wilson comes down on the side of what is called multi-level selection -- the view that evolution involves a combination of gene selection, individual selection, kin selection, and group selection. Although he says his new theory opposes the idea of kin selection, in another sense he is simply maintaining that everybody is right. Genes are being selected to benefit the individual and their kin. Genes are also being selected that encourage the individual to participate in a group.

So if Wilson thinks everybody is right, why is Wilson so wrong? As John Gray put the matter in The New Republic, the debate is "an exercise in sectarian intellectual warfare of the kind that is so often fought in and around Darwinism." The uproar shows as well how flimsy the foundations of the Darwinian naturalist account of compassion, empathy, and self-sacrifice in humans have always been.

But that account meets a deeply felt need among naturalists. Generosity, we are told by one research group, leads to evolutionary success:

"When people act generously they feel it is almost instinctual, and indeed a large literature in evolutionary psychology shows that people derive happiness from being generous," [University of Pennsylvania biology Joshua] Plotkin said. "It's not just in humans. Of course social insects behave this way, but even bacteria and viruses share gene products and behave in ways that can't be described as anything but generous."

Elsewhere, we are told that altruism is just another form of manipulation, which greatly simplifies matters. Indeed, Northeastern University philosophy professor Rory Smead offers a Darwinian explanation of spite (why, counterintuitively, it is adaptive). Yet evolution is also moral, for it punishes the selfish and mean, according to two Michigan State University evolutionary biologists, who claim to disprove an earlier theory popularized in 2012.

We also learn that moral behavior is based on primitive disgust (not rational evaluation); altruism is really a form of sexual display; altruism is really just selfishness; a child must have a selfish motive for saving her sister's life; and why we don't (usually) hurt ourselves to hurt others.

Actually, it is far from clear that altruism selects for survival of selfish genes in humans. In addition to admirable self-sacrifice, there is also "pathological altruism" (often described as co-dependency), a common life- and health-endangering problem. In any event, as Oxford physiologist Denis Noble observes, "selfish genes" have no empirical basis in science. The idea, though "one of the most successful science metaphors ever invented," as David Dobbs tells us at Aeon, does not help us understand how actual genes work.

But never mind genetics, there is still neuroscience. Human brains, we are told, are "hardwired for empathy, friendship" (or they are wired to connect -- as Forbes puts it, "Study: To the Human Brain, Me Is We"). "Our self comes to include the people we feel close to," explains one University of Virginia research team.

This likely is the source of empathy, and part of the evolutionary process, [psychology professor James] Coan reasons.

But if the researchers wish merely to defend the thesis that humans are social rather than solitary, the word "hardwired" and its connotations are comically wrong. The word derives explicitly from devices that do not evolve. If the brain is indeed evolving, then nothing is hard-wired, though some types of experience and behavior may predominate over time and be reflected in brain organization. It is not clear, though, which came first.

A media-friendly approach is to study the animal mind. A cottage industry in this field is the study of primates. The empathy chimpanzees offer is, we are told, key to understanding human engagement. That said, some researcher think that humans are not as empathetic as apes because we are less likely to engage in contagious yawning. But still others say that we can't even predict the level of altruism in apes by their degree of kinship with humans.

"Humans and callitrichid monkeys acted highly altruistically and almost always produced the treats for the other group members. Chimpanzees, one of our closest relatives, however, only did so sporadically." Similarly, most other primate species, including capuchins and macaques, only rarely pulled the lever to give another group member food, if at all -- even though they have considerable cognitive skills.

It depends, these researchers find, on "cooperative breeding." "When our hominin ancestors began to raise their offspring cooperatively, they laid the foundation for both our altruism and our exceptional cognition." Maybe. Could they be cooperative before they were altruistic? On the whole, it is not clear what we can learn from altruism in primates.

Animals do show empathy. But that's part of the puzzle. Consider the monkey who rescued his electrocuted buddy. But then tortoises have been captured on film laboriously turning other upended tortoises back onto their feet.

The nature of the difficulty is apparent when we ask ourselves, what is the tortoise thinking? It is a reptile who cannot right itself, so how does it know enough to right another tortoise? When considering empathy in chimpanzees, we assume, with some justification, that the chimp who helps or shares has mental experiences analogous to those of humans. But if the famously slow-witted tortoise has such experiences as well, then there is not only no "Tree of Intelligence," there seems to be no Tree of Empathy either. Genetic closeness to humans may not have explanatory value for humans, any more than the supposed "selfish gene" does.

For human nature, evolution appears to be an endless well from which any lesson whatever can be drawn. And "evolutionary" explanations need not be informative; they need only be fully naturalist.