The textbooks are wrong about protein synthesis according to a press release from the University of Utah

A recent paper in Science provides evidence that when protein synthesis is stalled a protein called Rqc2 ("conserved from yeast to man") catalyzes the addition of random amounts of alanine and threonine the the C-terminus of the proteins that's about to be destroyed (Shen et al., 2015).

Here's the editorial summary of the work ...

During the translation of a messenger RNA (mRNA) into protein, ribosomes can sometimes stall. Truncated proteins thus formed can be toxic to the cell and must be destroyed. Shen et al. show that the proteins Ltn1p and Rqc2p, subunits of the ribosome quality control complex, bind to the stalled and partially disassembled ribosome. Ltn1p, a ubiquitin ligase, binds near the nascent polypeptide exit tunnel on the ribosome, well placed to tag the truncated protein for destruction. The Rqc2p protein interacts with the transfer RNA binding sites on the partial ribosome and recruits alanine- and threonine-bearing tRNAs. Rqc2p then catalyzes the addition of these amino acids onto the unfinished protein, in the absence of both the fully assembled ribosome and mRNA. These so-called CAT tails may promote the heat shock response, which helps buffer against malformed proteins

This is mildly interesting. We've known about ubiquitin ligase for decades but this is a different way of tagging proteins for destruction.

We'll have to see if this work stands up to verification but even if it does, it's not going to make it into the textbooks.

Let's see what the University of Utah Press Office has to say ...

Defying Textbook Science, Study Finds New Role for Proteins

Open any introductory biology textbook and one of the first things you’ll learn is that our DNA spells out the instructions for making proteins, tiny machines that do much of the work in our body’s cells. Results from a study published on Jan. 2 in Science defy textbook science, showing for the first time that the building blocks of a protein, called amino acids, can be assembled without blueprints – DNA and an intermediate template called messenger RNA (mRNA). A team of researchers has observed a case in which another protein specifies which amino acids are added.

"This surprising discovery reflects how incomplete our understanding of biology is,” says first author Peter Shen, Ph.D., a postdoctoral fellow in biochemistry at the University of Utah. “Nature is capable of more than we realize." ...

Mathew Cobb, writing on Jerry Coynes blog, explains why this isn't really a big deal [CAT tails weaken the central dogma – why it matters and why it doesn’t]. Let me just add that the synthesis of peptides with defined sequences in the absence of mRNA and ribosomes has been described in most textbooks since the 1980s. The best examples are the peptides involved in pepditogylcan synthesis (cell walls) and peptide antibiotics.

Here's a figure from my book.

What this means is that the statement, "... showing for the first time that the building blocks of a protein, called amino acids, can be assembled without blueprints – DNA and an intermediate template called messenger RNA (mRNA)" is simply not true.

We really, really, need to do something about university press releases.

---

Shen, P.S., Park, J., Qin, Y., Li, X., Parsawar, K., Larson, M.H., Cox, J., Cheng, Y., Lambowitz, A.M., Weissman, J.S., Brandman, O., and Frost, A. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347:75-78. [doi: 10.1126/science.1259724 ]

Guilt by association

There are many common fallacies that can easily make your argument invalid. The Intelligent Design Creationists seem to posses an uncanny ability to use each and every one of them. Here's a good example of guilt by association, heavily laced with ad hominem.

It's a documentery called The Biology of the Second Reich) by John West and colleagues. John West is one of the bigwigs at the Discovery Institute. The IDiots see this sort of propaganda as support for Intelligent Design Creationism and evidence against evolution.


The IDiots are excited about the fact that this documentary just won a prize in the "Best Documentary Short" category of the Los Angeles Cinema Festival of Hollywood! [Congratulates to John West as Biology of the Second Reich, "Best Documentary Short," Scores Big Recognition!]. I'm pretty sure the prize is based on the quality of the production and not on the accuracy of the information in the documentary. This is typical of most awards for documentaries and nonfiction books.

---

If you take away religion, you can't hire enough police

Here's a Harvard Professor, Clayton Christensen, telling us with a straight face that democracy in the USA requires religion because in the absence of religion people won't choose to obey laws. He ends with, "If you take away religion, you can't hire enough police."

It makes me wonder how much critical thinking goes on in his classes at Harvard Business School. Do Harvard students let him get away with this crap?

---

A lesson on genetic load

The genetic load argument is one of the five things you should know if you are going to participate in the junk DNA debate.

Dan Graur has written an excellent summary of the genetic load argument from the perspective of population genetics. He links to it from his blog: If @ENCODE_NIH is right, each of us should have 7 x 10⁴⁵ children.

Read it.

---

Is that really all they've got?

Last week I alerted you to seven of the top ten evolution stories according to IDiots [Is that all they've got?. Now it's time for the top three stories .... hang on to your hats.

#3. #3 of Our Top Ten Evolution Stories of 2014: Cosmos Finale Takes One Last Shot at the Privileged Planet Thesis

#2. #2 of Our Top Ten Evolution Stories of 2014: Now with More Doubt! Meyer's Landmark Is Back in a New Edition, Replying to the Critics

And the number one proof of Intelligent Design Creationism in 2014 is ....

#1. Happy New Year! Our #1 Evolution Story of 2014: New Paper from Biologic Institute, "Shared Evolutionary History or Shared Design?"

At this rate real, science will probably survive through most of 2015.

---

A physiologist thinks about evolution

Denis Noble is a physiologist at Oxford University (now Professor Emeritus). He is famous for his work on the physiology of the heartbeat and he is touted as one of the founders of systems biology.

Denis Noble wrote a book on evolutionary theory called The Music of Life. It's featured on The Third Way, a website created by James Shapiro to promote his version of a paradigm shift in thinking about evolution. All the usual suspects are represented on that site.¹

Here's how the book is described on that website ....

What is Life? Decades of research have resulted in the full mapping of the human genome - three billion pairs of code whose functions are only now being understood. The gene’s eye view of life, advocated by evolutionary biology, sees living bodies as mere vehicles for the replication of the genetic codes.

But for a physiologist, working with the living organism, the view is a very different one. Denis Noble is a world renowned physiologist, and sets out an alternative view to the question - one that becomes deeply significant in terms of the living, breathing organism. The genome is not life itself. Noble argues that far from genes building organisms, they should be seen as prisoners of the organism.

The view of life presented in this little, modern, post-genome project reflection on the nature of life, is that of the systems biologist: to understand what life is, we must view it at a variety of different levels, all interacting with each other in a complex web. It is that emergent web, full of feedback between levels, from the gene to the wider environment, that is life. It is a kind of music.

Including stories from Noble’s own research experience, his work on the heartbeat, musical metaphors, and elements of linguistics and Chinese culture, this very personal and at times deeply lyrical book sets out the systems biology view of life.

I haven't read this book and I don't intend to read it. Having listened to a lecture by Denis Noble (below) I don't think I'm going to learn anything more by buying the book.

I urge you to watch the lecture. It's the plenary lecture at the International Conference of Physiological Sciences in November, 2012. Denis Noble is the President of the International Union of Physiological Sciences. The lecture is only 30 minutes long but it gives you a good introduction to the way many scientists from outside the field of evolutionary biology are thinking about evolution (and the Central Dogma of Molecular Biology). It's not a very pretty picture.


If you want a brief summary of what's wrong with this lecture see Jerry Coyne's blog website post: Famous physiologist embarrasses himself by claiming that the modern theory of evolution is in tatters.

---

1. For more on James Shapiro see: The Third Fourth? Way
Evolution: a View from the 21st century
Reply to Laurence A Moran’s review of Evolution: A View from the 21st Century
James Shapiro Responds to My Review of His Book
James Shapiro Never Learns
James Shapiro Claims Credit for Predicting That Junk DNA Is Actually Part of a "highly sophisticated information storage organelle"
Revisiting the Central Dogma in the 21st Century.

Thinking critically about the Central Dogma of Molecular Biology

Our department is preparing to review our undergraduate courses and programs. Part of the review will be to examine our fundamental goals and objectives and determine if we are meeting them. In preparation for this exercise, I've been going over some papers that have been sitting around my office.

One of them concerns teaching the Central Dogma of Molecular Biology (Wright et al., 2014). It was just published last year. The authors have discovered that students have a "weak conceptual understanding" of information flow. Here's how they describe it in the abstract.

The central dogma of molecular biology, a model that has remained intact for decades, describes the transfer of genetic information from DNA to protein though an RNA intermediate. While recent work has illustrated many exceptions to the central dogma, it is still a common model used to describe and study the relationship between genes and protein products. We investigated understanding of central dogma concepts and found that students are not primed to think about information when presented with the canonical figure of the central dogma. We also uncovered conceptual errors in student interpretation of the meaning of the transcription arrow in the central dogma representation; 36% of students (n = 128; all undergraduate levels) described transcription as a chemical conversion of DNA into RNA or suggested that RNA existed before the process of transcription began. Interviews confirm that students with weak conceptual understanding of information flow find inappropriate meaning in the canonical representation of central dogma. Therefore, we suggest that use of this representation during instruction can be counterproductive unless educators are explicit about the underlying meaning.

Most popular Sandwalk post in 2014

Lot's of people are publishing year-end summaries of their blog activity. It got me to wondering which of my posts was the most popular in 2014.

The result was a surprise ...

August 18, 2014: John Wilkins discusses the "Demarcation Problem"

One of the most fascinating things about philosophy is the fact that philosophers still can't agree on the major issues even after debating them for hundreds of years. For example, they still can't, as a discipline, agree on whether there are good arguments for the existence of gods. Many universities have theologians who masquerade as philosophers and publish in philosophy journals....

---

What do you do in Los Angeles in February?

I've visited Los Angeles in February. There are lots of cool things you can do, like going to the beach with your granddaughter or spending a day at Disneyland. I won't be there this February and that's a shame because I'll be missing an important event [Things to do in LA in February].

Bad Biology: How Adaptationist Thinking Corrupts Science

11 a.m., Sun., Feb. 15 – Hollywood; 4:30 p.m. – Costa Mesa

In 1979, Gould and Lewontin published an important paper, “The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme”, in which they deplored the narrow focus on seeing evolution as only a process of adaptation. They further criticized the field of evolutionary biology for perpetuating this pattern of flawed thinking.

Biologist PZ Myers bemoans that their warnings have gone unheeded in some biological sub-disciplines. He’ll be discussing a few examples of bad evolutionary biology, including the “human biodiversity” movement that is little more than a collection of pseudoscientific rationalizations for racism; evolutionary psychology, which seeks to explain modern human biology with imaginary scenarios of adaptive constraints from 10,000 years ago; and the ENCODE project, which was an obvious and overt exercise in adaptive bias applied to genomic data. A common thread among these examples is an excessive reliance on adaptationist thinking and a lack of appreciation of the diversity of mechanisms underlying our evolutionary history.

Don't miss it if you are anywhere near Los Angeles this February.

---

Simulated meteorite impact produces RNA bases. So what?

A group of Czech scientists have fired a big laser at a solution of formamide and found traces of adenine, guanine, cytosine, and uracil (Ferus et al., 2014). The result is reported in an article in Science [From hell on Earth, life's building blocks]. The image is from the Science article.

Here's the abstract of the PNAS article ...

The coincidence of the Late Heavy Bombardment (LHB) period and the emergence of terrestrial life about 4 billion years ago suggest that extraterrestrial impacts could contribute to the synthesis of the building blocks of the first life-giving molecules. We simulated the high-energy synthesis of nucleobases from formamide during the impact of an extraterrestrial body. A high-power laser has been used to induce the dielectric breakdown of the plasma produced by the impact. The results demonstrate that the initial dissociation of the formamide molecule could produce a large amount of highly reactive CN and NH radicals, which could further react with formamide to produce adenine, guanine, cytosine, and uracil. Based on GC-MS, high-resolution FTIR spectroscopic results, as well as theoretical calculations, we present a comprehensive mechanistic model, which accounts for all steps taking place in the studied impact chemistry. Our findings thus demonstrate that extraterrestrial impacts, which were one order of magnitude more abundant during the LHB period than before and after, could not only destroy the existing ancient life forms, but could also contribute to the creation of biogenic molecules.

In case you don't appreciate the significance of this research, PNAS provides you with a brief summary ...

This paper addresses one of the central problems of the origin of life research, i.e., the scenario suggesting extraterrestrial impact as the source of biogenic molecules. Likewise, the results might be relevant in the search of biogenic molecules in the universe. The work is therefore highly actual and interdisciplinary. It could be interesting for a very broad readership, from physical and organic chemists to synthetic biologists and specialists in astrobiology.

The problem with all these studies is that they don't answer the most important question; what happens next?

Let's assume that the four bases were created in the atmosphere as meteorites crashed into Earth four billion years ago. Let's assume there was water in the form of early oceans or big lakes. Then what happens? Do these researchers imagine that the concentrations of these bases built up gradually over thousands of years until there were spontaneous reactions with five-carbon sugars and phosphate to form nucleotides? Then did these nucleotides assemble into short RNA molecules?

It's a very large step from demonstrating that RNA bases can be made from formamide under extreme conditions to showing that their concentrations could have been high enough to make RNA spontaneously.

We need to demand more of these researchers. If they are going to postulate that life arose in a primordial soup then it's no longer sufficient to publish one more paper on how you can make organic molecules from inorganic precursors. Enough already. That's the easy part of the hypothesis. Let's see some evidence for the hard part.

---

Ferus, M., Nesvorný, D., Šponer, J., Kubelík, P., Michalčíková, R., Shestivská, V., Šponer, J.E., and Civiš, S. (2014) "High-energy chemistry of formamide: A unified mechanism of nucleobase formation." Proceedings of the National Academy of Sciences Published online before print December 8, 2014. [doi: 10.1073/pnas.1412072111]

Is that all they've got?

This is a rather slow time for comedy so I thought I'd alert you to the Top Ten Evolution Stories of 2014 as reported by IDiots.

#10 A Stunning New Illustration of Intelligent Design in the Cell
#9 The Ham-Nye Creation Debate: A Huge Missed Opportunity
#8 State-Run Museum Covered Up Collaboration with Atheist Groups
#7 Ciliate Organism Undergoes "Scrambled Genome" and "Massive...Rearrangement"
#6 Phys.org Says the Argument for Suboptimal Design of the Eye "Is Folly"
#5 Whale Hips, Another Icon of Darwinian Evolution, Takes a Hit
#4 A Key Inference of The Edge of Evolution Has Now Been Experimentally Confirmed

I bet you can't wait for the top three to be announced over the next three days? Maybe one of them will be about scientific evidence for intelligent design and god(s).

---

How do we teach our students that basic research is important?

There's a fabulous editorial in the Toronto Star today. It's critical of the Prime Minister and the Conservative Party of Canada for the damage they are doing to science in Canada [Canada needs a brighter federal science policy: Editorial].

Here's some excerpts ...

Finding a fan of Canada’s current science policy among those who care about such things would be a discovery worthy of Banting and Best. Few if any would contend that Ottawa’s approach is sound; rather, the debate in 2014 has been over what in the world would possess a government to pursue such a catastrophic course.

According to one school of thought, the answer is simple: the Conservatives are cavemen set on dragging Canada into a dark age in which ideology reigns unencumbered by evidence. Let’s call this the Caveman Theory.

The other, more moderate view holds that Prime Minister Stephen Harper et al are not anti-science – that they at least understand the importance of research and development to their "jobs and growth" agenda – but are instead merely confused about how the enterprise works and about the role government must play to help it flourish. Let’s call this the Incompetence Theory.

The rest of the editorial describes how Stephen Harper and his Conservative buddies have directed funding agencies to concentrate on research that will be of direct benefit to Canadian for-profit companies.

It concludes with ...

Whatever the government’s motives, whatever it understands or does not about how science works, it has over the last eight years devastated Canadian research in a way that will be hard to reverse. Private sector R&D continues to lag, but in our efforts to solve that problem we have seriously reduced our capacity for primary research, squandering a long-held Canadian advantage. Meanwhile, we have earned an international reputation for muzzling scientists, for defunding research that is politically inconvenient and for perversely conflating scientific goals with business ones, thus dooming both. Our current funding system is less well placed than it was in 2006 to promote innovation and our science culture has been so eroded that we are unlikely to attract the top talent we need to compete in the knowledge economy.

Whether it was anti-intellectualism, incompetence or both that led us to this dark place, let this coming election year bring the beginning of a climb back into the light.

How can the government of Canada be so ignorant? It's because they have a huge amount of support from the general public who see all research as technology. They are only willing to support research that helps the economy.

Most people are not interested in research that simply advances our knowledge of the natural world.

What are we doing as educators to reverse this trend? Not very much, as it turns out. Many of our courses in biochemistry focus on how biochemistry can benefit medicine as though this was the only reason for learning about biochemistry.¹ Our department is discussing whether we should have undergraduate courses on drug discovery and how drugs are brought to market. We are considering a co-op program where students will spend some time working in the private sector. We are toying with the idea of creating an entirely new program that will train students to work in the pharmaceutical industry.

It's no wonder that the general public thinks of science as the servant of industry. We are not doing a very good job of teaching undergraduates about the importance of knowledge and the value of scientific thinking. In fact, we are doing the opposite. We are supporting the Stephen Harper agenda.

Don't be surprised if it comes back to bite you in the future.

---

1. We teach medical case studies in our introductory biochemistry course for science undergraduates!

How to think about evolution

New Scientist published a short article on How to think about. Evolution. It was written by Michael Le Page who contacted me a few months ago.

I think it's better than most such articles but I may be a little biased. Here's an excerpt.

What's more surprising is that even mutations that don't increase fitness can spread through a population as a result of random genetic drift. And most mutations have little, if any, effect on fitness. They may not affect an animal's body or behaviour at all, or do so in an insignificant way such as slightly altering the shape of the face. In fact, the vast majority of genetic changes in populations – and perhaps many of the physical ones, too – may be due to drift rather than natural selection. "Do not assume that something is an adaptation until you have evidence," says biologist Larry Moran at the University of Toronto, Canada.

So it is wrong to think of evolution only in terms of natural selection; change due to genetic drift counts too. Moran's minimal definition does not specify any particular cause: "Evolution is a process that results in heritable changes in a population spread over many generations."

---

Professors and stress

Last January I posted a note about how stressful the job of university professor can be [University Professor is one of the least stressful jobs in America?]. That was a followup to a previous post that I wrote in response to Forbes magazine claiming that university professor have an easy job [I Have the Least Stressful Job!!!]. (That's me on the right in the picture. If you don't think this is stressful then you ought to try dressing up like that!)

A writer for the Globe & Mail (Toronto, Canada) contacted me about an article she was writing on stress in academia. The article has been published and she got it right! [Increased pressures, class sizes taking their toll on faculties in academia. I even got quoted.

Research funds are also difficult to access. New funding rules that emphasize commercial potential, particularly in the sciences, mean that professors have to deal with the prospect of their careers being cut short if they don’t win grants to run a lab.

“My younger colleagues are having to survive in stressful situations that I never had to survive,” said Larry Moran, a professor of biochemistry at the University of Toronto. “Government policies have redirected research funds so that it’s hit and miss if you get grants. ... When you fail at this job, there aren’t a lot of other places to go,” he said.

---

Questions about alternative splicing

Alternative splicing is a mechanism where am intron-containing gene is transcribed and the primary transcript is spliced in two or more different ways to produce different functional RNAs. If it's a protein-coding gene then the idea is that different forms of the protein are produced in this way and each of them is functional.

It's important to emphasize that the products of alternative splicing must be functional because we know that splicing is error-prone and that mispliced, nonfunctional, RNAs will be quite common. Every gene will produce a bunch of these aberrantly spliced variants but that doesn't mean that every primary transcript is alternatively spliced.

It's important to distinguish between real functional alternative splicing and junk RNAs that arise from splicing errors. One of the ways to do this is to report on the concentrations of the various transcripts but that's rarely done in papers that promote alternative splicing [see: The most important rule for publishing a paper on alternative splicing].

The importance of alternative splicing is related to the debate over the importance of pervasive transcription and junk DNA since advocates of alternative splicing are often the same people who object to junk DNA [see: Vertebrate Complexity Is Explained by the Evolution of Long-Range Interactions that Regulate Transcription?]. I call this The Deflated Ego Problem because these scientists are usually looking for way to "explain" the complexity of humans in light of the fact that we seem to have the same number of genes as many other species.

If it's true that most human genes are alternatively spliced then let's see the evidence. That means actually demonstrating that different proteins with different functions are produced from the same gene. We've known for 35 years that this is possible but that's not the point. The point is whether all, or most, human RNAs are alternatively spliced. I've issued a simple challenge to those who use the alternative splice databases [A Challenge to Fans of Alternative Splicing]. So far, nobody has stepped up to the plate.

Some of the examples that are promoted in those databases make no sense whatsoever [Two Examples of "Alternative Splicing"] [The Frequency of Alternative Splicing ].

Someone raised this issue in the comments to another post and send me a link to a paper published in 2010. Here's the paper and part of the introduction.

Keren, H., Lev-Maor, G. and Ast, G. (2010) Alternative splicing and evolution: diversification, exon definition and function. Nature Reviews Genetics 11:345-355 [doi: 10.1038/nrg2776].

Splicing of precursor mRNA (pre-mRNA) is a crucial regulatory stage in the pathway of gene expression: introns are removed and exons are ligated to form mRNA. The inclusion of different exons in mRNA — alternative splicing (AS) — results in the generation of different isoforms from a single gene and is the basis for the discrepancy between the estimated 24,000 protein-coding genes in the human genome and the 100,000 different proteins that are postulated to be synthesized.

... Comparing species to see what has changed and what is conserved is proving valuable in addressing these issues and has recently yielded substantial progress. For example, new high-throughput sequencing technology has revealed that >90% of human genes undergo AS — a much higher percentage than anticipated. Such technological progress is providing more comprehensive studies of splicing and genomic architecture in an increasing number of species, and these studies have extended our evolutionary understanding.

I'd like you to answer two questions.

1. Do you believe that there are about four (4) different, functional, proteins produced on average from every human protein-encoding gene?
2. Do you believe that more than 90% of human genes produce a transcript that can be alternatively spliced, where alternative splicing is restricted to producing different functional RNAs and not just noise?

---