Friday, March 16, 2012

John Mattick Wins Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research

Shame on the Human Genome Organization (HUGO). It has awarded a prestigious prize (US $10,000) to John Mattick, director of the Centre for Molecular Biology and Biotechnology at the University of Queensland in Brisbane, Australia. Here's the report from the Sydney Morning Herald.

Making something of junk earns geneticist top award

WHEN Sydney geneticist John Mattick suggested junk DNA was anything but rubbish he was challenging an assumption that had underpinned genetics for 50 years.

''The ideas I put forward 10 years ago were quite radical but I thought I was right,'' Professor Mattick said.

He was. And tomorrow he will become the first Australian honoured with the Chen Award for distinguished academic achievement in human genetic and genomic research, awarded by the Human Genome Organisation.

For decades after James Watson and Francis Crick discovered DNA was a double helix, scientists believed most genes were the written instructions for proteins, the building blocks of all body processes. The assumption was true for bacteria but not complex organisms like humans, said Professor Mattick, the new executive director of the Garvan Institute.

In humans, more than 95 per cent of the genome contains billions of letters that do not make proteins, called non-coding DNA. ''When people bumped into all this DNA that didn't make proteins they thought it must be junk,'' he said. But Professor Mattick felt it was unlikely that useless material would survive hundreds of millions of years of evolution.

He found that the non-protein-coding sections of DNA had a function, to produce RNA.

"The obvious and very exciting possibility was that there is another layer of information being expressed by the genome - that the non-coding RNAs form a massive and previously unrecognised regulatory network that controls human development.''

Many scientists now believe this RNA is the basis of the brain's plasticity and learning, and may hold the secret to understanding many complex diseases.
Mattick is one of the most prominent, non-creationist, opponents of junk DNA. He has published numerous papers and articles promoting the idea that most of our genome contains genes for regulatory RNA molecules. Here's a summary of his view as posted on his lab website [Mattick Lab].
The central hypothesis/heuristic of the Mattick Lab is that the majority of the genomes of complex organisms is devoted to an RNA regulatory system, and that this was the enabling platform for the evolution and development of complex multicellular organisms.

The central challenge in biology is to understand how our genome (which consists of two copies inherited from our parents, each containing 2.9 billion base pairs)1 encodes the information that directs our development from a single fertilized cell to a precisely sculptured organism of around 100 trillion differentiated cells, and how that information underpins the differences between individuals and species, including their cognitive capacity.

The human genome contains around 25,000 genes encoding proteins2, less than rice and only 20% more than a simple worm comprised of just 1,000 cells. Most of the proteins encoded in the human genome have recognizable equivalents in other mammals and other animals, indicating that these organisms share a relatively common set of functional components. These protein-coding sequences account for less than 1.5% of the human genome, leading to the questions - what, if anything, is the function of the remainder of the sequences in the genomes of higher organisms and are they somehow related to our complexity?

These non-protein-coding sequences occur within genes (intervening sequences or “introns”) and between genes (“intergenic sequences”) a significant proportion of which (around 45%) are the descendents of past molecular invasions (transposons). These sequences are often lumped together and referred to as "junk DNA", because they do not code for protein, despite the fact that many if not most of these sequences are in fact expressed as non-protein-coding RNAs, which account for around 98% of all genomic output in humans. Indeed the prevailing assumption, based on bacterial molecular genetics and genomics, is that genes are generally synonymous with proteins, and genetic information is transduced by proteins, which comprise the structural and functional (analog) components of cells, and are also the primary agents by which the system is regulated.

We are working on the alternative hypothesis that the majority of the genomes of complex organisms is devoted to the regulation of development and that most of this information is transacted by noncoding RNAs. Both logic and the available evidence suggest that these RNAs form a highly parallel digital network that integrates complex suites of gene expression and controls the programmed responses required for the autopoeitic development of multicellular organisms. If this is correct, our current conceptions of the genomic information content and programming of complex organisms will have to be radically reassessed, with implications well beyond biology.
It's certainly true that this is a radical idea. Is he right? The Sydney Morning Herald seems to think that Mattick's views have won the day and I assume the Human Genome Organization believes this as well. Here's an excerpt from the press release issued by Mattick's employer [Professor John Mattick wins prestigious HUGO Chen Award].
The Award Reviewing Committee commented that Professor Mattick’s “work on long non-coding RNA has dramatically changed our concept of 95% of our genome”, and that he has been a “true visionary in his field; he has demonstrated an extraordinary degree of perseverance and ingenuity in gradually proving his hypothesis over the course of 18 years.”
I'm pretty sure that there's no more than a handful of biochemists/molecular biologists who believe Mattick. They know that lots of noncoding DNA has a function—a fact that's been in the textbooks for almost fifty years—but they do not believe that most of our genome encodes functional regulatory RNAs. It's simply untrue that Mattick has proved his hypothesis over the past 18 years. Just the opposite has happened.

Theme

Genomes
& Junk DNA
Most knowledgeable, intelligent, biochemists know that at least half of our genome is littered with pseudogenes and defective transposons and viruses. That's junk by any reasonable definition. They know that functional noncoding DNA makes up about 8% of the genome and when you add in the exons the total comes to no more than 10% [What's in Your Genome?].

Much of the remaining 40% is probably junk but that's still a debatable point. (Half of it is introns.) What's not debatable is whether all of this DNA contains genes for regulatory RNAs. Nobody (to a first approximation) believes that except for a few people who hand out prestigious awards. I don't recognize any of the people on the Chem Award Review Committee as experts in the study of genomes and genome evolution but maybe that's because I'm not an expert either.

I've written about Mattick several times over the past few years, usually to show why he is so wrong. For example, here's a post from July 2007: Junk DNA in New Scientist.
Most articles on junk DNA eventually get around to mentioning John Mattick who has been very vocal about his claim that the Central Dogma has been overturned and most of the genome consists of genes that encode regulatory RNAs (Mattick, 2004; Mattick, 2007). This article quotes a skeptic to provide some sense of balance and demonstrate that the scientific community is not overly supportive of Mattick.
Others are less convinced. Ewan Birney of the European Bioinformatics Institute in Cambridge, UK, has bet Mattick that of the processed RNAs yet to be assigned a function - representing 14 per cent of the entire genome - less than 20 per cent will turn out to be useful. "I'll get a case of vintage champagne if I win," Birney says.
Under the subtitle "Mostly Useless," Pearson correctly summarizes the scientific consensus. (I wish she had used this as the title of the article. The actual title is somewhat misleading. Editors?)
Whatever the answer turns out to be, no one is saying that most of our genome is vital after all. "You could chuck three-quarters of it," Birney speculates. "If you put a gun to my head, I'd say 10 per cent has a function, maybe," says Lunter. "It's very unlikely to be higher than 50 per cent."

Most researchers agree that 50 per cent is the top limit because half of our genome consists of endless copies of parasitic DNA or "transposons", which do nothing except copy and paste themselves all over the genome until they are inactivated by random mutations. A handful are still active in our genome and can cause diseases such as breast cancer if they land in or near vital genes.
One of the most annoying things about Mattick is the way he distorts the meaning of the Central Dogma of Molecular Biology and the history of genome studies. It's simply not true that the Central Dogma means what he thinks it means in his 2003 paper. And it's simply not true that biochemists thought that all genes encoded proteins—at least not in the past 50 years [Basic Concepts: The Central Dogma of Molecular Biology].
The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of genetic regulatory systems in animals and plants may be incorrect. (Mattick 2003)
It's also annoying that Mattick equates "noncoding DNA" with "junk DNA." It seems like he never heard of functional noncoding sequences like centromeres, telomeres, regulatory sequences, origins of replication, etc and he assumes that most biochemists were just as ignorant back in the 1970s. Of course they weren't ... and they also knew about genes for ribosomal RNA and transfer RNA so the idea that all noncoding DNA was considered junk is, how shall it put it?, ... stupid.

This lack of rigor in his arguments does not inspire confidence.

One of the issues in the debate concerns the fraction of our genome that is transcribed to produce functional RNA molecules. My colleagues at the University of Toronto claim that much of the observed transcription is junk RNA that's due to aberrant (error-prone) transcription. Mattick has challenged their results in the scientific literature and that debate is one of the reasons why there's still a scientific controversy over the exact amount of functional RNAs [Pervasive Transcription]. If most of those scattered little bits of very low abundance RNAs are junk RNAs then Mattick is wrong and HUGO has made a huge mistake. As I said above, I think the majority of biochemists now think that only a fraction (less that 20%) of our genome is devoted to making functional regulatory RNAs.

Returning to rigor, Mattick is famous for the silly figure (right) in his 2004 Scientific American article. I first wrote about it in 2007 [Genome Size, Complexity, and the C-Value Paradox], pointing out the obvious flaws. Ryan Gregory liked it so much he coined a new term for such figures: Dog Ass Plots! Ryan was the one who alerted me to the award from HUGO to John Mattick and all he does on his blog is post the press release and the famous Dog Ass Plot as though nothing more need be said [Making something of junk earns geneticist top award.]!

Ryan is probably right but I couldn't resist saying a few more things. :-)


[Hat Tip: Ryan Gregory: Making something of junk earns geneticist top award.]

1. It's actually 3.2 billion base pairs [How Much of Our Genome Is Sequenced?] but why should anyone working on genomes cares about such quibbles?

2. It's actually closer to 20,500 [How Much of Our Genome Is Sequenced?] but we all know how hard it is to update a lab website. The number he gives was true five years ago and that's probably close enough for an expert in the human genome.

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939.

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am. 291:60-7.

Mattick, J.S. (2007) A new paradigm for developmental biology. J. Exp. Biol. 210:1526-47. [PubMed Abstract]

25 comments:

  1. That's appalling, but an even worse offense is the hijacking of the term "Hugo Award".

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  2. Perhaps his Hugo comes from these people http://www.thehugoawards.org/

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  3. I couldn't resist also posting the following in the comments to my post.

    --------

    ”When people bumped into all this DNA that didn’t make proteins they thought it must be junk,” he said. But Professor Mattick felt it was unlikely that useless material would survive hundreds of millions of years of evolution.

    ————-

    “But being junk doesn’t mean it is entirely useless. Common sense suggests that anything that is completely useless would be discarded.”
    – Comings (1972), the first in depth discussion of “junk DNA”

    ————-

    “This is what I emphasized earlier, that this DNA must have a functional value since nothing is known so widespread and universal in nature that has proven useless.”

    - Yunis, in the discussion following Ohno’s 1972 presentation in which the term “junk DNA” was introduced

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    1. I don't understand why people like John Mattick feel the need to lie about the history of their field. Is it because it makes them look so much better if they can prove that everyone else was stupid?

      If so, it usually backfires.

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    2. While clearly your views on the science differ, which you’re entitled to—and with all respect to you—some remarks in this discussion are, to be polite, leaning towards ad hominem. I can’t help noticing, for example, that here you’re relying on what it likely to be a casual remark or ‘gloss’ to a journalist* to make your case, which you have juxtaposed against more formal presentations. The two have very different settings and contexts.

      Personally, if you object to his science wouldn’t you be better to stick to the published science and not media stories? Certainly calling someone a liar on this basis strikes me as unwise.

      (Please don’t throw at me that it’s wrong anyway, you’d be missing my point. There are an awful lot “maybe”s with the use of quotes in media; it could just be an unfortunately choice of sound bite by the journalist/editor when viewed by those more familiar with the wider background. It could be an unfortunately spur-of-the-moment gloss, it happens.)

      --
      * Best as I can tell this has originated from the Sydney Morning Herald.

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    3. "While clearly your views on the science differ, which you’re entitled to—and with all respect to you—some remarks in this discussion are, to be polite, leaning towards ad hominem."

      I don't think you know what "ad hominem" means. It is not a synomym for "saying something bad about a person" and it is not a synonym for "impolite." I am criticizing Mattick's ideas, which I find to be quite silly and irrational. Saying that Mattick is stupid and irrational because of what he writes and draws is not an ad hominem fallacy.

      "I can’t help noticing, for example, that here you’re relying on what it likely to be a casual remark or ‘gloss’ to a journalist* to make your case, which you have juxtaposed against more formal presentations. The two have very different settings and contexts."

      If you follow the links to my other postings you will see that Mattick has presented his distorted view of history in many publications.

      "Personally, if you object to his science wouldn’t you be better to stick to the published science and not media stories? Certainly calling someone a liar on this basis strikes me as unwise."

      I assume you are not familiar with Mattick's writings in his scientific publications and in his articles in science magazines. Here's something that he wrote for Science just last year.

      These observations suggest that we need to reassess the underlying genetic orthodoxy, which is deeply ingrained and has been given superficial reprieve by uncritically accepted assumptions about the nature and power of combinatorial control. As Nobel laureate Barbara McClintock wrote in 1950: “Are we letting a philosophy of the [protein-coding] gene control [our] reasoning? What, then, is the philosophy of the gene? Is it a valid philosophy?” … There is an alternative: Human complexity has been built on a massive expansion of genomic regulatory sequences, most of which are transacted by RNAs that use generic protein infrastructure and control the epigenetic mechanisms underpinning embryogenesis and brain function. I see the human genome not simply as providing detail, but more importantly, as the beginning of a conceptual enlightenment in biology.

      I am very familiar with Mattick's ideas. I'm not just talking about something he said only once to a journalist last week. You might have considered doing a little research before posting a comment like that.

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    4. Please, I don’t need to be lectured - perhaps the lecturer in you is coming out? ;-)

      Seriously - no offence meant in saying this, but you appear to be rushing to defend the wrong thing. I wrote with reference to a few comments here, on this thread, not your previous writing, and in particular in reference to the passage quoted from the Sydney Morning Herald and subsequent remarks.

      The remark to the journalist / ‘gloss’ I referred to is that that Gregory Ryan quoted, not you. (Your response is worded as if I wrote about something in your article.)

      I know very well what ad hominem means. Likewise, I am well aware of your previous writing on the subject and your views. As I think I made clear, I have no problem with people having different points of view on the science. I think understandably enough I don’t appreciate you trying to imply that I don’t know this or that nor do I think it’s helpful. I didn’t question your understanding of, or views on, the science.

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  4. Ha! Of course it doesn't survive hundreds of millions of years of evolution. Junk DNA can be recognized because it accumulates changes at the neutral rate, including deletions. If there were nothing replenishing junk DNA, it would eventually all disappear. Lucky for the junk we know of processes that do indeed replenish it.

    Reminds me of a typical creationist argument: Salt is being added to the oceans by runoff from the land in an amount sufficient to produce the current concentration in only 20,000 years [from memory; it's within an order of magnitude]; therefore the earth can't be more than 20,000 years old.

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    1. If there were nothing replenishing junk DNA, it would eventually all disappear.

      I'm not sure that's entirely true. The principal mechanism of loss would presumably be excisions during misalignment in meiosis. But every such misalignment produces two gamete products, one longer and one shorter. So in a purely neutral scenario, a population could not purge itself of its junk by this means. It could drift out, but just as likely not. Add into that the fact that the shorter gametes will be more frequently deleterious (since excision is more likely to do damage), and you have a bias against shortening. Interacting with these factors we have the cost of the 'extra' DNA, but this is only assumed to be significant. For a multicellular organism, it's the material cost of adding this fractional extra DNA to a soma, which is already a pretty expensive suit (but which presumably pays for itself). Even in a single-celled organism, shortening will only be selected if the advantage in the current population is significant. The genomes that could shed it all might be lean, but the kind of generational shredding available is unlikely to produce a significant advantage to offset the cost.

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    2. The DNA in question is small modules with significant sequence-similarity to each other. This type of sequence is subject to intrachromosomal crossing over, the result of which depends on the relative orientation of the recombining sequences. If the sequences have the same orientation, then one copy of the repeat and all intervening sequence is excised as an episomal circle. So long as the degree of sequence identity is sufficiently high to permit recombination, this is a potentially rapid mechanism of deletion.

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    3. There are a great many mechanisms for deletion as well as a great many for insertion. The point is that if we assume there are no insertions and also that there are some deletions, all junk DNA must eventually disappear.

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    4. Are you familiar with Prof Mattick's following work? It elaborates on this very elegantly.
      http://www.ncbi.nlm.nih.gov/pubmed/17690206

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  5. If, as Mattick is implicating, non-coding functional DNA was unknown before him why would Brosius and Gould have published "On "genomenclature": A comprehensive (and respectful) taxonomy for pseudogenes and other "junk DNA" back in 1992 though I am not sure if their article wasn't originally planned for the April 1st issue.

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  6. Interesting that his lab wiki does not allow comments. Guess they don't want people to know the truth.

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  7. Mr. Moran, your article misleadingly labels the Chen Award as the "HUGO Award." As you may know, the Hugo Award is presented annually by the World Science Fiction Society for excellence in science fiction and fantasy. "Hugo Award" is a registered service mark of the World Science Fiction Society. One of the other comments above indirectly touches upon the confusion caused by mislabeling. Could you please re-title your piece to remove this confusion?

    Kevin Standlee
    Chairman
    World Science Fiction Society
    Mark Protection Committee

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    1. I changed the title from "wins HUGO award" to "wins Chen award" but only reluctantly. Most of my readers are intelligent enough to have gotten the connection between Mattick winning this prize and winning a prize for science fiction and they know the difference, as well as the similarity. It's true that I was deliberately playing on the similarity of names.

      The very first sentence of my article explains that this is an award from the Human Genome Organization (HUGO). Do you honestly believe that science fiction fans are so stupid that they will be confused or are you just irony deficient?

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    2. Mattick simply wants to win the Thomas Kuhn award!Perhaps he is in secret communication with James Shapiro.

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  8. Alan Miller: Let's remember that we're assuming there is no process that lengthens junk DNA -- that would be "replenishment". If there were only processes that either shortened it or left it the same, it's mathematically certain that it would eventually disappear given sufficient time. Selection against it is unnecessary. Selection against any losses that aren't neutral -- presumably those that include non-junk sequences -- merely delays the eventual result if there are any losses that are neutral.

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  9. Do you honestly believe that science fiction fans are so stupid that they will be confused or are you just irony deficient?

    Larry -

    It is likely that Mr. Standlee is not irony deficient but rather that the best policy on these sorts of things, legally speaking, is to be seen to object to all unauthorized uses. The alternatives (to never defend the tradename or trademark, and thus lose the right to do so when a truly objectionable misuse occurs; or to "pick your spots," thus taking more time and thought to exercise possibly faulty judgment in each individual case) are probably worse for the WSFS.

    Lawyers - just helping to make the world a better place. :-)

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  10. this DNA must have a functional value since nothing is known so widespread and universal in nature that has proven useless

    Exactly, like nipples on guys! Oh, wait....

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  11. John reckons that retrotransposons are thr 'hobos' of the cell. I reckon that they are the aristocracy as we wouldn't be here without them. As reverse transcription is much simpler than forward transcription it had to have come first. In the primordial soup primitive rna polymers and peptides interacted with each other then cooked up reverse transcription to make DNA so they'd have a permanent archive to draw on, then mutate these genes to make new genes. I believe that this is how drug resistance occurs in cancer cells, as there seems to be retrotransposon activity in cancer cells.

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  12. Atheists get more and more terrified each day.

    Its truly laughable, yet sad, to see this constant display of willful disbelief in the obvious.

    You,re done, cooked, its been over for 30 years but you havnt got the memo. Science--your god, had so hoped to prove the appearance of design just that--- but instead found the Math shows without question that it is overwhelming more designed than what we clearly see with our own eyes.

    Its time for the obscenely ludicrous multiverse idea to supplant Biology-- as it has Physics. Many biologist have already jumped ship to wacko multiverse--but that's where weirdos who deny reality need to live anyway.

    So it turns out that pathologically biased and darkened intellect of atheists has led them to their own fairy tale world where everything happens. Wow, thats scientific ! Did it ever occur to you that because all of human history has believed in a Creator and you have not ....that your mind might be demented? Because this denial of the facts is hobo's eating their own poop kind of nuts.

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  13. ruly Anonymous you are indeed terrifying.
    It is no real surprise that people in such technical enterprises as Astrophysics go slightly into the realm of imagination with the likes of multiverses. I suppose that might also be an excuse for Mattock, who is a fellow Australian, so I should support him i.e. genetics is complex and technical and it is no wonder I suppose that there are some ideas "out there".
    However, the junk DNA thing seems to have only moved slightly forward in the 20 years since I did my biology degree, with a smattering of molecular genetics. I am however glad that some of the other new knowledge is considerable, and I look forward to the pursuit of science ironing out these debates in the near future.
    That is what my "pathologically biased and darkened intellect" which is apparently "demented" and lacking "reality" since I don't believe in a creator being, says to me will happen.
    Thus Mattock and his ideas, although drawing an interesting connection between of development and RNA, will be superceded by new information.
    However new information is not of interest to Anonymous and co, or really any information at all, which truly is a terrifying indictment of the state of education in western society.
    I look forward to the "light from above" shining on molecular genetics in the next 20 years. Especially since there is no light whatsoever from the Seen-the-Light peddlers.

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  14. ""Whatever the answer turns out to be, no one is saying that most of our genome is vital after all. "You could chuck three-quarters of it," Birney speculates."

    What happened to Birney between this and the 80% functional claim of ENCODE?!? I'd love to get some frank answers.

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