Philip Ball strikes back

Philip Ball believes that we are in the middle of a revolution in our way of thinking about how life works. His ideas are complex but part of his case involves molecular biology and how things work at the molecular level. Ball believes that the old view of molecular biology placed far too much emphasis on coding DNA and ignored all the other functional regions of genomes. He also says that most of our genes specify non-coding RNA instead of mRNA and implies to his readers that a very large fraction of our genome is functional (i.e. not junk).¹

In order to build the case for revolution, he tries to demonstrate a paradigm shift in our view of molecular biology by showing a huge gap between the understanding of previous generations of molecular biologists and the post-genomic view. I believe he is wrong about this for two reasons: first, he misrepresents the views of older molecular biologists and, second he misrepresents the discoveries of the past twenty years. I tried to explain why he was wrong about these two claims in a previous post where I discussed an article he published in Scientific American in May 2024: Philip Ball says RNA may rule our genome.

Philip Ball responded to my criticism in a comment under that article.

Older molecular biologists were really stupid

I said ...

Ball begins with the same old myth that writers like him have been repeating for many years. He claims that before ENCODE most molecular biologists were really stupid. According to Philip Ball, most of us thought that coding DNA was the only functional part of the genome and most of the rest was junk DNA.

In the comment section of my earlier post, Philip Ball says,

I’m sorry to say that Larry’s commentary here is dismayingly inaccurate.

Let’s get this one out of the way first:

“He claims that before ENCODE most molecular biologists were really stupid.”

I have never made this claim and never would – it is a pure fabrication on Larry’s part. I guess this is what John Horgan meant in his comment to Larry: credible writers don’t just make up stuff.

I admit that Philip Ball never said those exact words. I'll leave it to the readers to decide whether my characterization of his position is accurate.

I stand by the statements I made although I admit to a bit of hyperbole. Ball has said repeatedly that the molecular biologists of my generation were wedded to the idea that coding regions were the only important part of the genome and he often connects that to the Central Dogma of Molecular Biology. He also claims that the experts in molecular biology dismissed all non-coding DNA as junk. Here's how he puts it in another article that he published recently in Aeon: We are not machines.

Only around 1-2 per cent of the entire human genome actually consists of protein-coding genes. The remainder was long thought to be mostly junk: meaningless sequences accumulated over the course of evolution. But at least some of that non-coding genome is now known to be involved in regulating genes: altering, activating or suppressing their transcription in RNA and translation into proteins.

I interpret that to mean that older molecular biologists, like me, didn't know about functional non-coding DNAs such as centromeres, telomeres, origins of replication, non-coding genes, SARs, and regulatory sequences in spite of the fact that thousands of papers on these sequences were published in the 30 years that preceded the publication of the first draft of the human genome sequence. This is not true, we did know about those things. I don't think it's too much of an exaggeration to say that Philip Ball thinks we were really stupid.

Here's what he says in his book, "How Life Works" (p. 85) when he's talking about the beginning of the human genome project.

Even at its outset, it faced the somewhat troubling issue that just 2 percent or so of our genome actually accounts for protein-coding genes. The conventional narrative was that our biology was all about proteins, for each of which the genome held the template. ... But we had all this other DNA too! What was it for? The common view was that it was mostly just junk, like the stuff in our attics: meaningless material accumulated during evolution, which our cells had no motivation to clear out.

Again, his claim is that in 1990 at the beginning of the human genome project the experts in molecular biology thought that non-coding DNA was mostly junk (98% of the genome). I have repeatedly refuted this myth and challenged anyone to come up with a single scientific paper arguing that all non-coding DNA is junk. I challenge Philip Ball to find a single molecular biology textbook written before 1990 that fails to discuss regulation, non-coding genes, and other non-coding functional elements in the human genome.

The truth is that the molecular biology experts concluded in the 1970s that we had about 30,000 genes and that 90% of our genome is junk and 10% is functional. That 10% consisted of about 2% coding DNA (now thought to be only 1%) and 8% functional non-coding DNA. So the "conventional narrative" was that there was a lot more functional non-coding DNA than coding DNA.

The human genome is full of genes for regulatory RNAs.

"Ball is one of the most meticulous, precise science writers out there. He is the antithesis of hypey, "dumb-it-down" reporting. He is MUCH more credible than you are, Laurence."

John Horgan July, 2024The title of the article I was discussing is "Revolutionary Genetics Research Shows RNA May Rule Our Genome." In that article Ball says that ENCODE was basically right and there are many more non-coding genes than protein-coding genes. I pointed out that Ball mentions some criticism of this idea but only to dismiss it. I said that "[Ball] wants you to believe that almost of all of those transcripts are functional—that's the revolution that he's promoting." Philip Ball objects to this statement ...

This too is sheer fabrication. I don’t say this in my article, nor in my book. Instead, I say pretty much what Larry seems to want me to say, but for some reason he will not admit it – which is that there is controversy about how many of the transcripts are functional."

Ball states that "ENCODE was basically right" when they claimed that 75% of our genome was transcribed and he goes on to say that ...

Dozens of other research groups, scoping out activity along the human genome, also have found that much of our DNA is churning out 'noncoding' RNA.

He says that ENCODE has identified 37,000 noncoding genes but there may be as many as 96,000. After making these definitive statements, he mentions that there are "still doubters" but then discuss why these discoveries are revolutionary. Later on he quotes John Mattick suspecting that there may be more that 500,000 non-coding genes.

Toward the end of the article, after discussing all kinds of functional RNAs, he brings up the Ponting and Haerty review where they say that most lncRNAs are just noise. He also mentions that the low copy number of non-coding RNAs raises questions about whether they are functional but immediately counters with the standard excuses from his allies.

Ball closes the article with ...

Gingeras says he is perplexed by ongoing claims that ncRNAs are merely noise or junk, as evidence is mounting that they do many things. "It is puzzling why there is such an effort to persuade colleagues to move from a sense of interest and curiosity in the ncRNA field to a more dubious and critical one," he says.

Perhaps the arguments are so intense because they undercut the way we think our biology works. Ever since the epochal discovery about DNA's double helix and how it encodes information, the bedrock idea of molecular biology has been that there are precisely encoded instructions that program specific molecules for particular tasks. But ncRNAs seem to point to a fuzzier, more collective, logic to life. It is a logic that is harder to discern and harder to understand. ut if scientists can learn to live with the fuzziness, this view of life may turn out to be more complete.

What's remarkable about the quote from a leading ENCODE worker (Gingeras) is that he is "puzzled" by scientists who are dubious and critical about claims in the ncRNA field. Isn't that what good scientists are supposed to do? Isn't that exactly what we did when we successfully challenged the dubious claims about junk DNA made in 2012?

There is no doubt in my mind that Philip Ball has fallen hook-line-and-sinker for the ENCODE claims that our genome is buzzing with non-coding genes. He only brings up the counter-arguments to dismiss them and pretend that he is being fair. Nobody who was truly skeptical about the function of transcripts would write an article with the title, "Revolutionary Genetics Research Shows RNA May Rule Our Genome."

However, as Ball points out in other comments, he does have a sentence in his book where he mentions that perhaps only 30% of the genome is functional. He says in the comment that what he believes is that the amount of functional DNA lies somewhere between 10% and 30%. That's not something that he mentions in the Scientific American article but, if he's being honest, it does mean that I was unfair when I said he believes that "almost of all of those transcripts are functional" but I only know that from what he now says, not from the published article.

If I were to take Philip Ball at his word—as expressed in the comment—then he must believe that most of the ENCODE transcripts are junk RNA. That's not a belief that you get from reading his published work.² Furthermore, if I were to take him at his word, then he must believe that there are some reasonable criteria that must be applied to a transcript in order to decide whether it has a biologically relevant function. So, when he says that ENCODE identified 37,600 non-coding genes he must have these criteria in mind but he doesn't express any serious skepticism about that number. We all know that there's no solid evidence that such a large number of transcripts are functional but that doesn't bother Philip Ball. He thinks we are in the middle of an RNA revolution.

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1. In commenting to my previous post, Ball says he believes that somewhere between 70% and 90% of our genome is junk but he doesn't say this in the Scientific American article. Instead, he says that scientists were surprised to learn that 75% of the human genome is transcribed implying that there's a lot of function. He goes on the say that "ENCODE was basically right." But what the ENCODE publicity campaign actually said was that junk DNA is dead and there's practically no junk DNA. If Ball really believes that up to 90% of the genome is junk then to me this means that ENCODE was spectacularly wrong not "basically right."

2. Ball says that 75% of the genome is transcribed. If Ball believes that as little as 10% may be functional then he must believe that less than 10% is transcribed to produce functional RNAs since he has to allow for regulatory sequences and other functional DNA elements. Let's say that 8% is a reasonable number. Ball seems to be willing to admit that 67% of the genome might be transcribed to produce junk RNA.

Philip Ball writes about molecular mechanisms of evolution

It's been almost a year since I commented on an Nature article by Philip Ball [see DNA: Nature Celebrates Ignorance]. Here's part of what I wrote back then ...

The main premise of the article is revealed in the short blurb under the title: "On the 60th anniversary of the double helix, we should admit that we don't fully understand how evolution works at the molecular level, suggests Philip Ball."

What nonsense! We understand a great deal about how evolution works at the molecular level.

The worst thing about the Nature article was the misuse of the Central Dogma of Molecular Biology. The second worst thing was the "revelation" that genes are regulated by regulatory sequences as if that was a new discovery. (He mentions the ENCODE results.)

Philip Ball's new book: "How Life Works"

Philip Ball has just published a new book "How Life Works." The subtitle is "A User’s Guide to the New Biology" and that should tell you all you need to know. This is going to be a book about how human genomics has changed everything.

SEED and the Central Dogma of Molecular Biology - I Take Back My Praise

On October 1, 2007 I praised SEED magazine for being one of the few science magazines to correctly define the Central Dogma of Molecular Biology. Here's what I said two months ago.

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One of my pet peeves is the misuse of the term "Central Dogma of Molecular Biology" [Basic Concepts: The Central Dogma of Molecular Biology]. Most people define it as the flow of information from DNA to RNA to protein. Many then go on to declare that the Central Dogma has been overthrown because of reverse transcriptase, alternative splicing, microRNA, epigenetics, or whatever.

This month's issue of SEED has a tear-out summary (cribsheet) of "Genetics." In one of the boxes titled "The Central Dogma of Molecular Biology" there's a drawing of the major pathways of information flow [Cribsheet #12]. The caption says.

There are nine ways information can theoretically flow between DNA, RNA, and protein. Of these, three are seen throughout nature, DNA to DNA (replication), DNA to RNA (transcription), and RNA to protein (translation). Three more are known to occur in special circumstances like viruses or laboratory experiments (RNA to RNA, RNA to DNA, and DNA to protein). Flows of information from protein have not been observed. The trend is clear: information flow from DNA or RNA into protein is irreversible. This is known as the "central dogma," and forms the foundation of molecular biology.

Yeah! As far as I know this is the only popular magazine to get it right.

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I take it all back.

This month's issue has an article by Philip Ball outlining another revolution in molecular biology that overthrows the Central Dogma of Molecular Biology. This time it's microRNAs that have done the dirty deed [Redefining Genes].

Philip Ball is a London (UK) based freelance science writer with a Ph.D. in Physics. He has written 10 books on science and many articles for the news section of Nature. Philip Ball blogs at homunculus.

Here's what he says on page 29 of the current newsstand issue of SEED.

For nearly 50 years, the central dogma of molecular biology has been that genetic information is contained within DNA and is passed by rote transcription through RNA to make proteins. ...

The central dogma is being eroded, and it now appears as if DNA's cousin, the humble intermediary RNA, plays at least an equal role in genetics and the evolution of the species.

Philip Ball then gives two recent examples of work showing the involvement of noncoding RNA in gene expression. Then comes the revolution ...

These and a host of other recent findings are rewriting the textbooks of molecular biology. They are beginning to show not only that RNA is more fundamental to genetics than once believed, but also that it can directly affect evolution and elucidate the differences between species. The result is a story that looks a lot messier, but potentially a lot more interesting, than anyone ever guessed.

This is deeply insulting to all biochemists and molecular biologists. What in the world must people like Ball be thinking of us when he writes such nonsense? Does he really believe that for over half a century we have been slavishly adhering to the dogma that genes only make proteins? I know lots of scientists who think the Central Dogma refers to the general pathway of information flow (DNA → RNA → protein) but I never met a biochemist or a molecular biologist who thought that this pathway ruled out genes whose final product was RNA.

That idea is total nonsense, of course, and Philip Ball would know this if he only bothered to read any of the textbooks of molecular biology. Not only have we been teaching about ribosomal RNA, and transfer RNA for 40 years, we've also covered all of the small RNAs involved in splicing, telomeres, signal recognition particle, RNAse P etc. etc. Does he think we're completely ignorant of the Nobel Prizes awarded to Sidney Altman and Tom Czech in 1989 "for their discovery of catalytic properties of RNA"?

Furthermore, we've been teaching about regulatory RNAs for almost as long. The classic examples are the antisense RNAs in bacteriophage λ, attenuation in the trp operon and small RNAs that control the initiation of DNA replication at plasmid origins.

If you were to believe Philip Ball, molecular biologists have clung to his version of the Central Dogma of Molecular Biology in spite of all these counter-examples. Only now are they waking up to the fact that some genes make RNA as their final product. How stupid is that?

Science writers have a special obligation when writing for a general audience. Not only do they have to explain things in simple language but they have to be accurate as well. Pert of being accurate in science is having enough knowledge of the subject to be able to sort out the hype from reality. Philip Ball does not know anough about molecular biology to make that call. He should have read the cribsheet.

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DNA: Nature Celebrates Ignorance

Some freelance science writer named Philip Ball has published an article in the April 25, 2013 issue of Nature: Celebrate the Unknowns.

The main premise of the article is revealed in the short blurb under the title: "On the 60th anniversary of the double helix, we should admit that we don't fully understand how evolution works at the molecular level, suggests Philip Ball."

What nonsense! We understand a great deal about how evolution works at the molecular level. Perhaps Philip Ball meant to say that we don't understand the historical details of how a particular genome evolved, but even that's misleading.

I've commented before on articles written by Philip Ball. In the past, he appeared to be in competition with Elizabeth Pennisi of Science for some kind of award for misunderstanding the human genome.

SEED and the Central Dogma of Molecular Biology - I Take Back My Praise
Shoddy But Not "Junk"?

Let's look at what the article says ...

Intelligent design creationists think junk DNA is a placeholder for ignorance

Paul Nelson is a Senior Fellow of the Discovery Institute—the most important source of intelligent design propaganda. Paul and I have been disagreeing about science for many years. He is prone to interpret anything he finds in the scientific literature as support for the idea that scientists have misunderstood their subject matter and failed to recognize that science supports intelligent design. My goal has always been to try and explain the actual science and why his interpretations are misguided. I have not been very successful.

The photo was taken in London (UK) in 2016 at a meeting on evolution. It looks like I'm holding my breath because I'm beside a creationist but I assure you that's not what was happening. We actually get along quite well in spite of the fact that he's wrong about everything. :-)

Philip Ball says RNA may rule our genome

Philip Ball is on a roll. He has published a new book plus several articles in popular magazines and he has appeared in a bunch of podcasts and YouTube videos. The message is all the same, he claims that it's time for a revolution in biology.

Ball's ideas are complicated and I won't go into all of them in this article. Instead, I want to focus on one of his more scientific claims; namely, the claim that genomic data has overthrown the fundamental principles of molecular biology. Let's look at his recent (May 14, 2024) article in Scientific American: Revolutionary Genetics Research Shows RNA May Rule Our Genome.¹

The subtile of the article is "Scientists have recently discovered thousands of active RNA molecules that can control the human body" and that's the issue that I want to discuss here.

Philip Ball doesn't understand sloppy genomes

... anything found to be true of E.coli must also be true of Elephants.
                                                         Jacques Monod (1961)

This version of the famous statement by Jacques Monod comes from 1961 but he said similar things much earlier and other scientists even predate Monod's earliest use of the phrase (Friedman, 2004). He echoed this same idea in Chance and Necessity (p. 102)

The diversity of types remained even so, and there was no getting around the fact that a great many macroscopic structural patterns, radically unlike one another, coexist in the biosphere. A blue alga, an infusorium, an octopus, and a human being—what had they in common? With the discovery of the cell and the advent of cellular theory a new unity could be seen under this diversity. But it was some time before advances in biochemistry, mainly during the second quarter of this century, revealed the profound and strict oneness, on the microscopic level, of the whole of the living world. Today we know that from a bacterium to man the chemical machinery is essentially the same, in both its structure and its functioning.

Monod was making a case for life as a chemical process and he reflected the view of the 'phage group who were studying bacteria and bacteriophage. He argued that all living things would consist of the same basic chemicals such as lipids, nucleic acids, proteins, and carbohydrates. He also assumed that all living things would have similar networks of metabolic enzymes and contain similar pathways. These enzymes would be regulated by similar mechanisms, such as allosteric regulation, and they would be composed of the same 20 amino acids. He expected all living cells would have similar mechanisms for capturing energy and they would obey the fundamental laws of thermodynamics.

He assumed that the genetic code would be universal and that the process of protein synthesis would be essentially the same in all species. He assumed that the fundamentals of transcription and DNA replication would be the same in all species. He imagined that the basic principles of gene regulation that were worked out in bacteria would apply to eukaryotes. This included the action of transcription factors and more unusual regulatory molecules such as the regulatory RNAs discovered in 'phage and bacteria. He expected that genes, regulatory sequences, origins of replication, and other important genetic elements would be found in the DNA molecules of the genome.

This theme of unity of life at the microscopic level was very important but it did not mean that all living things would be identical. Monod was a firm proponent of evolution and since evolution depended on the random occurrence of mutations the actual history of life is unpredictable. There's nothing profoundly upsetting about the fact that elephants have trunks and E. coli doesn't because that's not the point.

I'm sure that Monod was not upset to learn that some genes had introns or that eukarotic chromatin is more complicated than the DNA-protein complexes found in bacteria. He would not have been shocked to learn that many eukaryotes have more functional RNAs than E. coli or bacteriophage λ. Junk DNA was not a problem for someone who understood evolution.

I think Monod reflected the dominant view of most knowledgeable biochemists and molecular biologists of the 1960s and 1970s.

Over the next 50 years we learned a lot more about complex eukaryotes and the dominant theme at the molecular level is that they contain lots of junk DNA and lots of overly complex structures that only make sense in light of evolution. There's a lot of sloppiness in eukaryotes, including genomes full of transposon fossils, aberrant transcription, pseudogenes, inefficient splicing, and promiscuous enzymes. A lot of this sloppiness was apparent in the 1970s, including the fact that junk DNA must contain thousands of ineffective transcription factor binding sites. We learned in the 1980s that some structures, such as the spliceosome, could only have arisen by evolution since no designer in their right mind would have built such a thing.

I would be quite proud to have served on the committee that designed the E. coli genome. There is, however, no way that I would admit to serving on a committee that designed the human genome. Not even a university committee could botch something that badly.                                                          David Penny

I got this quote from Dan Graur who credits it to David Penny as a personal communication. Graur used it in his scathing criticism of ENCODE researchers after they declared the death of junk DNA (Graur et al., 2013). The meaning is clear. The E. coli genome is compact and carries all the information needed to ensure the survival and evolution of the bacterium. It has one copy of most protein-coding genes, two copies of ribosomal RNA genes, and a minimal number of tRNA genes. The regulatory sequences are just big enough for efficient transcription under the appropriate conditions. Many genes are clustered in operons to save space. There's only one origin of replication and one terminator sequence. There's only one chromosome and it is efficiently segregated to each daughter cell after DNA replication and cell division. There are only a small number of regulatory RNA genes in E. coli.

The human genome is a mess. 90% of it is junk and it requires complicated features like centromeres and telomeres. There are 100,000 origins of replication and tens of thousands of pseudogenes. The protein-coding genes are full of useless introns and they take up 40% of the genome even though the functional parts only occupy 1%. Every cell has thousands of incorrectly spliced transcripts. The genome is littered with fossil transposons and viruses and many of them still have partially active promoters churning out junk RNA. Useless transcription factor binding sites and chromatin alterations are ubiquitous. The abundance of junk DNA means that you need tens of thousands of copies of every transcription factor just to make sure the right genes are regulated. A large part of the genome is transcribed but the vast majority of those transcripts are useless junk.

This is why David Penny would not be proud to have served on the committee that designed the human genome. Neither would I, and that's why I spent so much time explaining sloppy genomes in my book. The idea of a sloppy genome is a difficult concept to grasp so I devoted the final chapter (Chapter 11) to the art of coping with this issue.

Now let's look at how Philip Ball handles this information on pages 116-117 of his book How Life Works.

These differences in the relative proportions of coding and non-coding DNA for simpler and more complex organisms reflect fundamental distinctions in how these organisms work. The problem has been delightfully, if inadvertently, stated by theoretical biologist David Penny. "I would be quite proud to have served on the committee that designed the E. coli genome" he has said. "There is, however, no way that I would admit to serving on a committee that designed the human genome. Not even a university committee could botch something that badly."

I'd suggest that can be rephrased: "I can understand how the E. coli genome works. I cannot make any sense of how the human genome works." So the corollary of Penny's comment is rather profound: how E. coli works is not how humans work. But his quip betrays an understandable frustration that the workings of the human genome are inscrutable to us. And I fear that the remark carries the same bias as that which leads us to insist that a foreign language we find difficult to learn is unnecessarily perverse and even absurd.

This shift in perspective challenges a famous statement by Jacques Monod: "What is true for E. coli is true for the elephant." In fairness, Monod had in mind here the notion of how DNA encodes proteins—for indeed it does so in (roughly) the same way in bacteria as in pachyderms, insofar as it uses the same genetic code. But the implication in Monod's comment is that this is what really matters in the same spirit as Crick's Central Dogma. We can now see that Monod's quote is misleading in an important sense, because what matters for E. coli is not the same as what matters for an elephant. The bacterium has a genome dedicated mostly to making proteins. The elephant has a genome dedicated mostly to making noncoding RNAs with regulatory functions. To truly understand how the elephant—and the human—works, we need to untangle the mechanisms governing this regulation.

As Morris and Mattick say,

It appears that we may have fundamentally misunderstood the nature of the genetic programming in complex organisms because of the assumption that most genetic information is transacted by proteins. This may be largely true in simpler organisms, but is turning out not to be the case in more complex organisms, whose genomes appear to be progressively dominated by regulatory RNAs that orchestrate the epigenetic trajectories of differentiation and development.

Or as biochemist Danny Licatalosi and neuroscientist Robert Darnell put it, biological complexity "has RNA at its core."

I think this is an excellent illustration of the differing viewpoints of Philip Ball and many biochemists and molecular biologists. David Penny and the rest of us don't disparage the human genome because we don't understand it. Quite the contrary. We think we DO understand evolution and the basic principles of molecular biology and that's why we recognize a sloppy genome when we see it. Philip Ball just can't get his head around the fact that we aren't ignorant of functional non-coding RNAs ... we just don't believe Mattick and ENCODE when they claim, without evidence, that the human genome is full of non-coding genes modulating some sophisticated regulation of the protein-coding genes.

Not only does such a model lack support but it doesn't make any sense. Why would all the 10,000 or so housekeeping genes require such regulation in humans and not in yeast? Why would evolution have selected for regulatory RNAs acting on the genes for the glycolytic enzymes? What kind of selective advantage would there have to be in order to evolve a regulatory RNA gene that could tweek expression by a few percent?

"Ball is one of the most meticulous, precise science writers out there. He is the antithesis of hypey, "dumb-it-down" reporting. He is MUCH more credible than you are, Laurence."

John Horgan July, 2024Philip Ball even wants to twist the Monod quote to fit his agenda on the importance of proteins. That's not what Monod meant. But let's think about this for a minute. The biochemists of the last century discovered a complex network of metabolic pathways with reactions that were catalyzed almost exclusively by protein enzymes. That hasn't changed. It's true of E. coli and it's true of elephants.

They also discovered that the expression of genes, especially at the level of transcription, was mostly controlled and regulated by proteins; namely, RNA polymerase and transcription factors. That hasn't changed. The expression of elephant and human genes is also regulated by transcription factors and RNA polymerase. Hundreds of studies of particular mammalian genes have demonstrated beyond a doubt that we can explain most regulation by such a model.

That doesn't mean that proteins are the only players in regulation. Over the past several decades we've discovered a variety of regulatory RNAs and we now know that there are more of these non-coding genes in humans than in bacteria. We don't know how many but so far the number of well-characterized examples amounts to fewer than 2000 genes and probably less than 1000. Note that I said "well-characterized" examples and that means that the individual RNA molecule has been studied and its biologically relevant function has been confirmed. That's not the same as a genomics study that simply identifies candidate transcripts that may or may not have a function.

Proteins still play the most important functional roles in metabolism and gene expression but they are not the only players. We've known that for 50 years. The only thing that's changed is that there may be as many as two thousand non-coding genes in humans and only a dozen or so in E. coli and the human genome may be a lot more sloppy than bacterial genomes. That's not a paradigm shift.

Note: Philip Ball was an editor at Nature and that's ironic because it's the failure of Nature editors to do their job in 2012 that got us into the mess we're in today. The editors not only allowed ENCODE researchers to make exaggerated claims about junk DNA but they actively supported and participated in the publicity campaign that sold those false claims to the general public. Nature editors have never apologized for their behavior in 2012; in fact, one of them, Magdalena Skipper, has been promoted to editor-in-chief. [The 10th anniversary of the ENCODE publicity campaign fiasco]

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Friedman, H.C. (2004) From Butyribacterium to E. coli: An Essay on Unity in Biochemistry. Perspectives in Biology and Medicine 47:47-66. doi: 10.1353/pbm.2004.0007

Graur, D., Zheng, Y., Price, N., Azevedo, R.B., Zufall, R.A. and Elhaik, E. (2013) On the immortality of television sets:“function” in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution 5:578-590. doi: doi: 10.1093/gbe/evt028

How do proteins move around amidst the jumble of molecules inside a living cell?

I've been reading Philip Ball's book on "How Life Works" and I find it increasingly frustrating because he consistently describes things that he's "discovered" that biochemists like me must have missed. Here's an example from pages 231-232.

He presents a cartoon image of a cell showing that it's full of all kinds of molecules packed closely together, then he says,

Shoddy But Not "Junk"?

Philip Ball is a freelance science writer based in London (UK). He frequently writes for Nature. His latest article is a review of a recently published paper by John Avise [What a shoddy piece of work is man]. Apparently Avise has just published a paper in PNAS where he points out that our genome does not look like it was designed. It's an attack on Intelligent Design Creationism and Adaptationism.

I can't find the paper but I have read Avise's book, Inside the Human Genome so I'm familiar with his thesis—and I agree with it.

The purpose of this posting is not to review the points that John Avise makes but to comment on one of the points made by Philip Ball. At the end of his Nature review he says,

However — although heaven forbid that this should seem to let ID off the hook — it is worth pointing out that some of the genomic inefficiencies Avise lists are still imperfectly understood. We should be cautious about writing them off as 'flaws', lest we make the same mistake evident in the labelling as 'junk DNA' genomic material that seems increasingly to play a biological role. There seems little prospect that the genome will ever emerge as a paragon of good engineering, but we shouldn't too quickly derogate that which we do not yet understand.

THEME

Genomes & Junk DNA

I just gave a talk on junk DNA where I explained to my audience the nature of the scientific controversy. We know for a fact that our genome is littered with pseudogenes of all sorts and we know for a fact that more than 50% of our genome is repetitive DNA of one kind or another. A good hunk of that is degenerative transposons and fragements of transposons [Junk in your Genome: LINEs]. Another large hunk is Alu sequences: fragments of an ancient primate transposon derived from 7SL RNA [Transcription of the 7SL Gene].

We also know a great deal about introns and that knowledge leads to the conclusion that most intron sequences are dispensable. it's part of the junk in our genome. We know about the genetic load argument [Genetic Load, Neutral Theory, and Junk DNA] and we know about the C-Value Paradox. Most scientists who study the problem of junk DNA know about The Onion Test.

My point is that it's extremely misleading to suggest that our identification of junk DNA is based on a lack of understanding. That's simply not true. There are some very good scientific reasons for maintaining that most of our DNA is junk based on over 40 years of work on genome organization.

Yes, it's true that there have been some scientific challenges questioning the conclusion of those studies. There is a group of scientists who claim that vast amounts of our genome serve some mysterious purpose that's only vaguely defined. It could be regulation of some sort or even an entire new class of RNA-encoding genes that make us human.

These claims make the debate over junk DNA a scientific controversy but they certainly haven't succeeded in disproving the hypothesis. None of the recent claimants can explain pseudogenes and degenerative transposons, which make up more than half of our genome. None of the opponents can refute the genetic load argument.

Science writers like Philip Ball can be forgiven for not delving into the problem. It's easy to fall for the latest articles that purport to show function for a large part of what we call junk DNA. After all, those anti-junk proponents don't do their homework either and they gloss over all the data that contradicts their "new" hypothesis.

My point is that the idea of junk DNA is alive and well in spite of what modern science writers seem to think. It's just not true that today's scientists think we made a big mistake in the past by calling it junk DNA. This is still very much a scientific controversy and it's too soon to tell how it will pan out.

Personally, I think the evidence in favor of a large amount of junk in our genome is persuasive and I'd be very, very surprised if a significant amount of it turns out to be functional. I wish science writers would stop behaving as though the issue had been resolved and junk DNA is dead.

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Philip Ball's view of alternative splicing

Genomics is a powerful tool that allows you to collect massive amounts of data that can point the way to new understanding. But it can also be abused when the results are overinterpreted. We saw an extraordinary example of this in 2012 when ENCODE made unsubstantiated claims that were quickly challenged.

I'm reminded of the caution from Sydney Brenner who warned us about genomics (Brenner, 2000) and the warning in Dan Graur's harsh critique of the 2012 ENCODE claims (Graur et al., 2013) where they said ...

The Editor-in-Chief of Science, [Bruce Alberts,] has recently expressed concern about the future of "small science," given that ENCODE-style Big Science grabs the headlines that decision makers so dearly love. Actually the main function of Big Science is to generate massive amounts of easily accessible data. The road from data to wisdom is quite long and convoluted. Insight, understanding, and scientific progress are generally achieved by "small science." ...

Guess what happens when Nature asks EES proponents to write reviews of books by other EES proponents?

There are a bunch of people who think that evolutionary theory needs to be extensively revised. They focus their attacks on a particular (incorrect) version of the Modern Synthesis and they promote a new version called the Extended Evolutionary Synthesis (EES).

Most EES proponents have very little in common except that they see themselves as revolutionaries. They each have their own little hobbyhorse that is presumably being suppressed by classical evolutionary biologists. Some of them belong to a cult called The Third Way (of Evolution). They are very good at promoting their point of view through whatever means it takes to get attention. The media loves them.

Scientific Authority and the Role of Small RNAs

A few weeks ago I criticized Philip Ball for an article he published in Nature: DNA: Nature Celebrates Ignorance. Phil has responded to my comments and he has given me permission to quote from his response. I think this is going to stimulate discussion on some very interesting topics.

The role of small RNAs is one of those topics. There are four types of RNA inside cells: tRNA, ribosomal RNA (rRNA), messenger RNA (mRNA), and a broad category that I call “small RNAs.”

The small RNAs include those required for splicing and those involved in catalyzing specific reactions. Many of them play a role in regulating genes expression. These roles have been known for at least three decades so there haven’t been any conceptual advances in the big picture for at least that long.

What’s new is an emphasis on the abundance and importance of small regulatory RNAs. Some workers believe that the human genomes contains thousands of genes for small RNAs that play an important role in regulating gene expression. That’s a main theme for those interpreting the ENCODE results. Several prominent scientists have written extensively about the importance of this “new information” on the abundance of small RNAs and how it assigns function to most of our genome.

Popular science books aren't fact-checked

Michael Marshall is a science journalist. He published a short essay in New Scientist where he laments the fact that popular science books may contain lots of errors. The title of the original article was Getting the facts right but the online version is Readers deserve beter from popular science books. The blurb is the same for both versions.

"There is a dirty secret in publishing: most popular science books aren't fact-checked. This needs to change, says Michael Marshall."

Most of you won't be able to read the article because it's behind a paywall but here's a few paragraphs that should stimulate discussion.

No, the problem is much simpler, and it is a dirty secret of non-fiction publishing: most books aren’t fact-checked. If an author makes a mistake or misinterprets a study, nobody stops them.

In journalism, fact-checking practices vary widely. New Scientist has two layers of editors, who each ensure readability and accuracy. Others are even stricter: fact-checkers at The New Yorker re-report entire stories. Non-fiction publishing is far more relaxed. Often, there is no fact-checking at all: editors offer guidance on readability, but take factual claims on trust. The UK publishers of my book The Genesis Quest did this (though my US publishers, a university press, recruited anonymous peer reviewers).

It is easy to see why this has happened. Nuance is difficult to sell. If your book has a counterintuitive thesis, or simply promotes a moral panic, it is easier to market. Non-fiction authors who are rigorous and careful can’t compete. That’s why shops are flooded with books about one neat trick for a better life or how everything you know is wrong. But without fact-checking, these books might as well be scrawled in crayon. Publishers must do better.

For the record, my book was sent out to reviewers and I got back some very helpful comments that caused me to make some serious changes. I also sent it to some of my colleagues and they corrected quite a few errors.

The last part of Marshall's essay is something that I've been worried about for many years, "Non-fiction authors who are rigorous and careful can’t compete."

Note: I inserted an image of Philip Ball's latest book because it's a recently published popular science book. I have no idea whether it was fact-checked or not. (But I have my suspicions.)

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Monday's Molecule #135: Winner!

 
Yesterday's molecule was the type II reaction center from the photosynthetic purple bacterium Rhodobacter spaeroides.

When light shines on the special pair of chlorophyll molecules known as P870, a single electron is boosted to a high energy level by absorbing a photon. This electron is transferred to an adjacent bacteriochlorophyll a heme group in a typical oxidation reaction. The single electron then travels down the electron transport pathway to a bacteriopheophytin heme and then to a quinone molecule that's part of the pathway.

In the final step, the electron reduces another quinone bound to the "mobile" site. This reduction is mediated by an iron atom (red ball). Quinol (QH₂) is released after two electrons have been transferred sequentially. The quinol molecule carrying two electrons then diffuses to a cytochrome bc complex that pumps protons across the membrane. The creation of a proton gradient drives the synthesis of ATP.

The electron deficient P870 chlorophylls are re-supplied with electrons from cytochrome c, which gets them from the chytorchrome bc complex in a cyclic reaction [see A Simple Version of Photosynthesis].

Purple bacteria are strict anaerobes—oxygen is poisonous to them so their The purple bacteria version of photosynthesis does not involve the splitting of water and generation of O₂. This is an important point since many students think that water (H₂O) is the only possible electron donor in photosynthesis. In fact, the ability to oxidize water evolved much later.

It's much better to think of photosynthesis as a light-activated oxidation-reduction system where there are several possible electron donors and acceptors.

The type II reaction center molecules are embedded in a membrane-spanning protein complex whose structure has been solved [see Nobel Laureates: Deisenhofer, Huber, and Michel]. In the version shown here, the electron donor is cytochrome c, which binds to the top part of the molecule on the exterior surface of the membrane.

Photosynthesis is a complex example of an electron transfer reaction. Rudolph A. Marcus was awarded a Nobel Prize for his work on understanding this type of chemical reaction.

This week's winner is Philip Johnson of the University of Toronto. He blogs at Biocurious. While Philip was the first to get the right answer, an honorable mention has to go to Wibowo Arindrarto from Jakata, Indonesia for the best answer.

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Your task for today is to identify the molecules with the question marks and explain (briefly) what's going on.

There's a Nobel Prize associated with the type of reaction that you're seeing here. Focus on the red arrows. The prize wasn't for this particular reaction although it is depicted in the Nobel Lecture as an example of the type of reaction that was being described. Name the Nobel Laureate.

The first person to describe the reaction and name the Nobel Laureate wins a free lunch. Previous winners are ineligible for six weeks from the time they first won the prize.

There are only three ineligible candidates for this week's reward: Alex Ling of the University of Toronto, and Markus-Frederik Bohn of the Lehrstuhl für Biotechnik in Erlangen, Germany, and Maria Altshuler of the University of Toronto

I have an extra free lunch for a deserving undergraduate so I'm going to continue to award an additional prize to the first undergraduate student who can accept it. Please indicate in your email message whether you are an undergraduate and whether you can make it for lunch.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule(s) and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Prizes so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow.

Comments will be blocked for 24 hours. Comments are now open.

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Theme: Genomes & Junk DNA

Junk in Your Genome

Transposable Elements: (44% junk)

      DNA transposons:
         active (functional): <0.1%
         defective (nonfunctional): 3%
      retrotransposons:
         active (functional): <0.1%
         defective transposons
            (full-length, nonfunctional): 8%
            L1 LINES (fragments, nonfunctional): 16%
            other LINES: 4%
            SINES (small pseudogene fragments): 13%
            co-opted transposons/fragments: <0.1% ^a

^aCo-opted transposons and transposon fragments are those that have secondarily acquired a new function.

Viruses (9% junk)

      DNA viruses
         active (functional): <0.1%
         defective DNA viruses: ~1%
      RNA viruses
         active (functional): <0.1%
         defective (nonfunctional): 8%
         co-opted RNA viruses: <0.1% ^b

^bCo-opted RNA viruses are defective integrated virus genomes that have secondarily acquired a new function.

Pseudogenes (1.2% junk)
      (from protein-encoding genes): 1.2% junk
      co-opted pseudogenes: <0.1% ^c

^cCo-opted pseudogenes are formerly defective pseudogenes those that have secondarily acquired a new function.

Ribosomal RNA genes:
      essential 0.22%
      junk 0.19%

Other RNA encoding genes
      tRNA genes: <0.1% (essential)
      known small RNA genes: <0.1% (essential)
      putative regulatory RNAs: ~2% (essential) Protein-encoding genes: (9.6% junk)
      transcribed region:  
            essential 1.8%  
            intron junk (not included above) 9.6% ^d

^dIntrons sequences account for about 30% of the genome. Most of these sequences qualify as junk but they are littered with defective transposable elements that are already included in the calculation of junk DNA.

Regulatory sequences:
      essential 0.6%

Origins of DNA replication
      <0.1% (essential) Scaffold attachment regions (SARS)
      <0.1% (essential) Highly Repetitive DNA (1% junk)
      α-satellite DNA (centromeres)
            essential 2.0%
            non-essential 1.0%%
      telomeres
            essential (less than 1000 kb, insignificant)

Intergenic DNA (not included above)
      conserved 2% (essential)
      non-conserved 26.3% (unknown but probably junk)

Total Essential/Functional (so far) = 8.7%
Total Junk (so far) = 65%
Unknown (probably mostly junk) = 26.3%

For references and further information click on the "Genomes & Junk DNA" link in the box

LAST UPDATE: May 10, 2011 (fixed totals, and ribosomal RNA calculations)

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November 11, 2006
Sea Urchin Genome Sequenced

The sea urchin genome is 814,000 kb or about 1/4 the size of a typical mammalian genome. Like mammalian genomes, the sea urchin genome contains a lot of junk DNA, especially repetitive DNA. The preliminary count of the number of genes is 23,300. This is about the same number that we have in our genomes. Only about 10,000 of these genes have been annotated by the sea urchin sequencing team.