This relationship (lungfish-tetrapods) was firmly established recently by comparing the genome of the Australian lungfish (Neoceratodus forsteri) with that of tetrapods (Meyer et al., 2021). The other possibility had been ceolacanth-tetrapods. Coelacanths and lungfish are related—they form the class Sarcopterygii (lobe-finned fish).
Santi Garcia-Vallvé has reviewed my book in the journal Mètode. It's written in Catalan but Santi was kind enough to send me a translation.
OUR GENOME HAS NOT YET SPOKEN ITS LAST WORDWhat's in Your Genome? 90% of Your Genome Is Junk. Laurence A. Moran. Aevo University of Toronto Press (UTP). May 2023. 392 pages.
What's in Your Genome? exposes a variety of topics and concepts in molecular biology, genetics, and evolution that have been misunderstood by scientists and the general public. Many of these concepts are widely accepted, despite ongoing debate about them. Although the author, Larry Moran, has exhaustively discussed most of these issues on his blog "Sandwalk: Strolling with a sceptical biochemist", discussing them in a book allows for a more in-depth investigation.
One of these recurring themes is Francis Crick 's 1957 proposal of the Central Dogma of Molecular Biology. In his book Molecular Biology of the gene, James Watson adapted this concept by summarizing in a figure the flow of genetic information from DNA to RNA and then to proteins. This version was widely adopted, and many scientists now assume that it was the original definition. However, Crick claimed that once the information had been transferred to the proteins, it could not be returned to nucleic acids. Other controversial topics discussed in the book include the number of genes encoded in the human genome, the concept of Junk DNA and the prevalence of alternative splicing in the transcription of the human genome. Larry takes a certain viewpoint on all these problems, as evidenced by the title of the book, but he also presents arguments from all sides. Throughout the book, he argues that scientists must present evidence in support of and against their findings, as well as contextualise their discoveries in light of the knowledge of the subject. Thus, the first chapters of the book describe in depth the basic ideas of genetics, genetics and evolution that are required to understand the arguments that he will present later, showing also when and how they were discovered.
This is a highly recommendable book that pushed us to think about how research findings are explained and the importance of placing them in their proper context. The media frequently looks for stunning headlines and there is growing demand to assess the social impact of a project, article or scientific project. However, if we exaggerate our findings, we risk exacerbating further diminishing the general lack of interest in scientific news. Everyone is responsible that this does not happen.
Santi Garcia-Vallvé is an associate professor in the Department of Biochemistry and Biotechnology at Rovira i Virgili University (URV) in Tarragona, Spain, and a member of the Chemoinformatics and Nutrition research group."
... anything found to be true of E.coli must also be true of Elephants.
Jacques Monod (1961)
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.
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.
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]
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
"for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone"Vincent du Vigneaud (1901-1978) was an American biochemist who was awarded the Nobel Prize in Chemistry in 1955 for his work on biological molecules containing sulfur, especially methionine cystine, and biotin. The prize was for solving the structure of the peptide hormone oxytocin and synthesizing an active molecule. (See Monday's Molecule #244.) From 1938 to 1967 Vigneaud's lab was at Cornell Medical College in New York City.Here's part of the Presentation Speech.
THEME:
Nobel LaureatesUnderneath the brain, there is a small, well-protected gland, the pituitary gland. In man it is about as big as a bean. There are secreted several hormones, that is, substances which regulate important physiological functions. spite of its small size, the pituitary gland is made up of several distinct parts with different functions. We are interested here in the posterior lobe, which contains two substances called oxytocin and vasopressin. The former stimulates the contractions of the uterus and also the lactation, the latter raises the blood pressure and regulates the function of the kidneys. As early as in 1933, when rather impure preparations from the posterior lobe were used in experiments, du Vigneaud found a high percentage of sulphur, which seemed to be correlated to the physiological activity.
Using the experimental methods, which the development of science has put at his disposal and making the best of his own intimate knowledge of the organic chemistry of sulphur, du Vigneaud has step by step forced his way. Both hormones were isolated in a state of purity, and it was found that they are built up from amino acids in the same way as proteins, but with a far lower molecular weight. Such compounds are, as distinguished from real proteins, called polypeptides. The nature of the amino acids and their positions in the molecule could be determined. The sulphur is present in cystine. The two hormones have a very similar structure; both contain eight amino acids, connected to a chain, which at one point is closed to a ring. The molecule has some resemblance to a figure six or nine, where the loop contains five amino acids and the “tail” three. Two sulphur atoms, linked to each other, form a part of the ring.
The design of the molecule was thus known. It remained to build it up by synthesis and check the correctness of the design. That was perhaps the most difficult part of the work. The interest was first concentrated on the synthesis of oxytocin. Step by step the amino-acid chain was built up with the two sulphur atoms in the proper positions, one at the end of the chain and the other near the middle. At last the ring was closed by formation of a bond between the sulphur atoms. Now followed the most thrilling moment, the testing of the chemical properties and the physiological activity; perhaps there had been some mistake after all. It turned out, however, that the synthetic polypeptide was identical with the natural product.
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
Email your answer to me at: Monday's Molecule #244. The first one with the correct answer wins. I will only post the names of winners to avoid embarrassment. The winner will be treated to a free coffee and donut at Tim Hortons if you are ever in Toronto or Mississauga (Ontario, Canada).
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
In order to win you must give your correct name. Anonymous and pseudoanonymous players can't win.
Comments are closed for at least 24 hours.
UPDATE: The winner is Santi Garcia-Vallve who correctly guessed that the molecule is the peptide hormone oxytocin. Santi lives in Spain so he won't be able to collect his coffee and donut anytime soon.
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.
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.
"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.
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.
"for their discoveries concerning the regulation of cholesterol metabolism"Michael S. Brown and Joseph L.Goldstein won the Nobel Prize in 1985 for discovering the low-density lipoprotein (LDL) receptor, a cell surface protein that binds lipid-protein complexes containing cholesterol. (See Monday's Molecule #243.)Here's part of the Press Release.
THEME:
Nobel LaureatesMichael S. Brown and Joseph L. Goldstein have through their discoveries revolutionized our knowledge about the regulation of cholesterol metabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood. They found that cells on their surfaces have receptors which mediate the uptake of the cholesterol-containing particles called low-density lipoprotein (LDL) that circulate in the blood stream. Brown and Goldstein have discovered that the underlying mechanism to the severe hereditary familial hypercholesterolemia is a complete, or partial, lack of functional LDL-receptors. In normal individuals the uptake of dietary cholesterol inhibits the cells own synthesis of cholesterol. As a consequence the number of LDL-receptors on the cell surface is reduced. This leads to increased levels of cholesterol in the blood which subsequently may accumulate in the wall of arteries causing atherosclerosis and eventually a heart attack or a stroke. Brown and Goldstein’s discoveries have lead to new principles for treatment, and prevention, of atherosclerosis.
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
Email your answer to me at: Monday's Molecule #242. The first one with the correct answer wins. I will only post the names of winners to avoid embarrassment. The winner will be treated to a free coffee and donut at Tim Hortons if you are ever in Toronto or Mississauga (Ontario, Canada).1
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
In order to win you must post your correct name. Anonymous and pseudoanonymous commenters can't win.
Comments are closed for at least 24 hours.
UPDATE: The winner is Mikkel Rasmussen who correctly guessed that the protein is the extracellular domain of the low-density lipoprotein (LDL) receptor. Sadly, Mikkel lives in a faraway country that doesn't have a Tim Hortons so he won't get to enjoy a honey cruller or chocolate dip donut.1. I still owe some previous winners. If you are one of them, then you should email me to set up a time and place.
2. The figure is from Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M. S., Goldstein, J. L., and Deisenhofer, J. (2002) Structure of the LDL receptor extracellular domain at endosomal pH. Science, 298(5602), 2353-2358. [doi: 10.1126/science.1078124
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.
Sancar was born in Turkey in 1946 and got his MD degree from the Faculty of Medicine of Istanbul University. He then went on to get a Ph.D. with Claud S. Rupert at the University of Texas at Dallas in 1977. The Rupert lab worked on DNA repair and Sancar's thesis topic was the photoreactivating enzyme in E. coli. The photoreactivating enzyme was an enzyme that repaired DNA damage.
Sancar eventually secured a position at the University of North Carolina, Chapel Hill where he worked on excision repair and on photoreactivation. He is best known for his study of the mechanism of photolyase, the enzyme that repairs thymine dimers. [see Monday's Molecule #242] Photolyases are present in bacteria, protozoa, fungi, plants, and most animals. The gene for photolyase has been lost in placental mammals.
THEME:
Nobel Laureates
Aziz Sancar’s fascination with life’s molecules developed while he was studying for a medical degree in Istanbul. After graduating, he worked for a few years as phycisian in the Turkish countryside, but in 1973 he decided to study biochemistry. His interest was piqued by one phenomenon in particular: when bacteria are exposed to deadly doses of UV radiation, they can suddenly recover if they are illuminated with visible blue light. Sancar was curious about this almost magical effect; how did it function chemically?Claud Rupert, an American, had studied this phenomenon and Aziz Sancar joined his laboratory at the University of Texas in Dallas, USA. In 1976, using that time’s blunt tools for molecular biology, he succeeded in cloning the gene for the enzyme that repairs UV-damaged DNA, photolyase, and also in getting bacteria to over-produce the enzyme. This work became a doctoral dissertation, but people were hardly impressed; three applications for postdoc positions resulted in as many rejections. His studies of photolyase had to be shelved. In order to continue working on DNA repair, Aziz Sancar took up a position as laboratory technician at the Yale University School of Medicine, a leading institution in the field. Here he started the work that would eventually result in the Nobel Prize in Chemistry.
By then it was clear that bacteria have two systems for repairing UV damage: in addition to light-dependent photolyase, a second system that functions in the dark had been discovered. Aziz Sancar’s new colleagues at Yale had studied this dark system since the mid-1960s, using three UV-sensitive strains of bacteria that carried three different genetic mutations: uvrA, uvrB and uvrC.
As in his previous studies of photolyase, Sancar began investigating the molecular machinery of the dark system. Within a few years he had managed to identify, isolate and characterise the enzymes coded by the genes uvrA, uvrB and uvrC. In ground-breaking in vitro experiments he showed that these enzymes can identify a UV-damage, then making two incisions in the DNA strand, one on each side of the damaged part. A fragment of 12-13 nucleotides, including the injury, is then removed.
Aziz Sancar’s ability to generate knowledge about the molecular details of the process changed the entire research field. He published his findings in 1983. His achievements led to an offer of an associate professorship in biochemistry at the University of North Carolina at Chapel Hill. There, and with the same precision, he mapped the next stages of nucleotide excision repair. In parallel with other researchers, including Tomas Lindahl, Sancar investigated nucleotide excision repair in humans. The molecular machinery that excises UV damage from human DNA is more complex than its bacterial counterpart but, in chemical terms, nucleotide excision repair functions similarly in all organisms.
So, what happened to Sancar’s initial interest in photolyase? Well, he eventually returned to this enzyme, uncovering the mechanism responsible for reviving the bacteria. In addition, he helped to demonstrate that a human equivalent to photolyase helps us set the circadian clock.
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It's been a while since the last Monday's Molecule on May 19, 2014 but I think it's time to revive that tradition. I'll show you a molecule and you have to guess what it is without searching the internet. In other words, you have to recognize it immediately or it doesn't count. Email your answer to me at: Monday's Molecule #242. The first one with the correct answer wins. I will only post the names of winners to avoid embarrassment. The winner will be treated to a free coffee and donut at Tim Hortons if you are ever in Toronto or Mississauga (Ontario, Canada).1
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
Today's molecule (right) looks very complicated but I'm not going to ask you to give me a complete chemical name. The simple common name will do but you have to briefly explain it's biological significance and why it's always discussed in biochemistry textbooks.
In order to win you must post your correct name. Anonymous and pseudoanonymous commenters can't win.
Comments are closed for at least 24 hours.
UPDATE: The winner is Elie Huvier who pointed out that the molecule is a thymine dimer with a cyclobutane ring. Thymine dimers are mutations caused by ultraviolet light, which causes photodimerization of adjacent stacked pyrimidines in DNA. Elie Huvier was the first one to identify the molecule and describe its significance.
1. I still owe some previous winners. If you are one of them, then you should email me to set up a time and place.
