In a novel form of peer review, a biologist has given an colorfully fiery critique of a genome research consortium. Here's why.
Posted 02.25.2013 at 12:59 pm
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Encode Project On the Cover of Nature
The project published around 30 papers in three leading scientific journal groups.
© Nature Sept. 6, 2012
If every new abstract read like Dan Graur’s latest contribution, people wouldn’t need any TLC reality shows--they could get all the drama they’d want from research papers. Graur’s new paper, a takedown of a much-ballyhooed genomics project, contains some of the most fiery language ever to appear in the staid, typically decorous world of scientific literature.
On the phone, Graur is just as frank: “Their data analysis is obscene,” he said. “It was horrible. This is not science.”
Here’s the story: The Encyclopedia of DNA Elements (ENCODE) project was a five-year effort involving hundreds of people who sought to unravel the functions of so-called non-coding, or “junk,” sections of the human genome. When it was published last September, scientists who led the project claimed it would upend decades of assumptions about how the genome works, causing textbooks to be rewritten. Most of the genome is biologically active, they said--it’s functional. But many evolutionary biologists were peeved by this characterization and the loose definition of the word function.
"We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten," Graur and his colleagues write in the journal Genome Biology and Evolution.
Graur, a professor of molecular evolutionary bioinformatics at the University of Houston, is the lead author of a seething response to a global consortium of genetics and bioinformatics researchers that provoked plenty of frustration from evolutionary biologists.
“Big science, like the Human Genome Project, should publish data. Small science should do the analysis.”One of the key complaints: That Encode authors are computational scientists, not biological scientists. "They're computer jocks," as Graur put it. "Big science, like the Human Genome Project, should publish data. Small science should do the analysis."
In evolutionary biology, “function” is a loaded word--an organ, a piece of DNA or a cell can perform a function that’s selected for, and a function that’s causal. Selected functions are things that confer an evolutionary advantage, while causal functions don’t, to put it very simply. In the paper, Graur uses an example of a human heart: Its evolutionary function is pumping blood through your body. A causal function is its capacity for making noise. Incidentally, that’s useful to your doctor or personal trainer, but isn’t the heart's primary function.
If you think of the human genome like a textbook, you can think of Encode as the footnotes, intended to provide insight into what all the nucleotides are doing. It annotates all of the 3.2 billion combined A, C, G and T nucleotides that make up genes and their regulatory sections. In doing this, Encode papers defined function in a loose way, to include all the things that DNA does. The research says the vast majority of our DNA participates in at least one “biochemical event” in at least one cell type, and considers this a function. But that definition is liberal at best, and it wasn't even the project’s goal, said Mike White, a systems biologist at Washington University in St. Louis who has criticized Encode’s hype but (unlike Graur) has praised its value to science. Rather, it was to comprehensively measure the biochemical features of the genome, and let scientists have a go with those measurements.
“Those features are going to help other scientists actually discover functional regions,” he said.
Genome Gradient: Wikimedia Commons
Biochemical functions include a wide range of activities, like DNA sequences that are transcribed into RNA; regions that are bound up by regulatory proteins, which might switch genes on or off; regions that are not wrapped up tightly in chromatin, which packages DNA in a cell; and so on. (For a very detailed description of these biological
Here is how Graur explained it on the phone: “Have you ever stepped on a piece of chewing gum? It binds to the sole of your shoe. But this is not the function of chewing gum, to bind to the shoe on a hot day.”
White said these activities are useful to measure because they can be associated with functions--just not necessarily associated with them. Establishing function is difficult and requires a lot more work, he said.
In his own lab, White is studying a specific regulatory protein that binds to DNA in about 10,000 places on the genome, and helps switch a gene on or off. He is trying to determine whether that binding event has to do with the gene activation, and how the proteins find their way along the genome as they’re floating around in a cell. Each of the 10,000 binding events might be functional, there might be non-specific “noisy” DNA binding as the protein takes a shotgun approach, or maybe something else is going on.
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Science, Rebecca Boyle, big data, controversy, encode, evolutionary biology, genomes, genomics, human genome projectOther biologists are also glad to use the data, though they still express frustration with how it was presented. Mick Watson, director of ARK-Genomics at the University of Edinburgh's Roslin Institute, wrote in a blog post that he disagrees with Encode's definitions.
"However, I do appreciate that science, like many other disciplines, requires, and benefits from, people with opposing views. Your view of functionality certainly opposes mine; however, at the very least, what you have achieved is to stimulate debate on the topic, which is of benefit to everyone," he wrote, adding that Graur's paper sets a bad example for young scientists.
Graur has several other problems with the research, not the least of which is its data analysis. He lamented that many of the analysts and researchers in Encode are computer scientists, not biologists. He said he felt like he had to speak up. Students, postdocs and other young researchers have since thanked him for publishing his paper, he said.
“Many people object to the tone, but actually the tone was the point. I’m a professor, I am tenured. ... Sometimes you need an old card like me to do that,” he said. “Science is about presenting hypotheses and refuting them. A lot of the people who are dealing with data and analyzing data have forgotten about that.”
White agreed that some contributors lack a background in evolutionary biology, and this may have contributed to the hype--scientists were overstating their findings. It also may have contributed to the backlash and ongoing resentment, he said.
“People resent that, when you have people coming in from a different field and they start making sweeping statements about your own field, and they don’t know anything about it and the sweeping statements are wrong,” he said.
“I’m a little surprised that a paper this angry got through without changes--it was a little over the top in terms of its outright inflammatory statements--but on the other hand, I understand the anger. A lot of us were really angry,” he said. “Now we have to see, is the data going to be useful? Are they going to start publishing real studies with this? We’ll see.”
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To summarize.
Big science like Graur still wants to crush the Copernicus's of the world.
Come on Graur, it's just a challenge to evolution, it's not like ENCODE challenges any real science.
Similar situation in climatology. Here science has been ceded to people who are digital computer based. Subsequently the domain expert, or practicing scientist is subverted by model makers.
@bagpipes: It's not fair to challenge anyone who says something controversial in the field of science to Copernicus: His views were primarily challenged by the church. But in any case, just because someone is challenged by known science doesn't make them automatically right.
Still calling parts of the genome junk show how little they actually understand. Perhaps some of it functions in a quantum fashion?
@Bropocalypse
"His views were primarily challenged by the [ruling scientific body of the day]". Correction mine.
The Sumerians did not quote previous myths. They wrote down history as the GODS told them how things are, including humans were designed by them, which does not undermine evolutional theory.
It does mean that in the natural course of evolution and outsider came to Earth and did some tweaking of the DNA of the local primates. Behold, humans were born and suddenly rather than being focus only on instincts, this new human could ponder all around himself better, make better tools, use his imagination for art and future leaps of genius of problem solving and finally communicate his ideas among his friends with a verbal and written language.
@bagpipes: You are saying the Church was a scientific body? LoL The Church was not even in agreement with plain old common sense much less science.
@killerT
At the time, yes.
But something tells me you don't really understand the difference between science and religion anyway.
Bagpipes
Many people do not see the difference between history verse myths and or religion. Often they are lumped all together and then ignored.
"Come on Graur, it's just a challenge to evolution, it's not like ENCODE challenges any real science."
Are you suggesting evolution is wrong?
Further how does encode challenge evolution as a whole? At best I can see it rectifying some assumptions made about the "junkiness" of parts of our DNA.
Just reading the abstract alone sounded more like a hit piece than professional scientific journalism. The mean spirited tone reeked of anger and bias.
As I read further, I was surprised to find the authors paraphrasing Frank Zappa. Don't get me wrong, I loved Zappa, but I think even he would have said that it would be very silly to use any of his utterances in a science journal, and especially one which seems to be more personalized than unbiased.
“Data is not information, information is not knowledge, knowledge is not wisdom, wisdom is not truth,” —Robert Royar (1994) paraphrasing Frank Zappa’s (1979) anadiplosis
Dan Graur "The human genome is rife with dead copies of protein-coding and RNA-specifying genes that have been rendered inactive by mutation. These elements are called pseudogenes (Karro et al. 2007). Pseudogenes come in many flavors (e.g., processed, duplicated, unitary) and, by definition, they are nonfunctional"
I repeat according to Gruar "by definition, they are nonfunctional"
Unfortunately this molecular biologist doesn't even seem to be aware of the current data as cited below.......
PSEUDOGENES: Are They “Junk” or Functional DNA?
Annual Review of Genetics
Pseudogenes have been defined as nonfunctional sequences of genomic DNA originally derived from functional genes. It is therefore assumed that all pseudogene mutations are selectively neutral and have equal probability to become fixed in the population. Rather, pseudogenes that have been suitably investigated often exhibit functional roles, such as gene expression, gene regulation, generation of genetic (antibody, antigenic, and other) diversity.
Pseudogenes are involved in gene conversion or recombination with functional genes. Pseudogenes exhibit evolutionary conservation of gene sequence, reduced nucleotide variability, excess synonymous over nonsynonymous nucleotide polymorphism, and other features that are expected in genes or DNA sequences that have functional roles......
Here is another paper
RNA Biol. 2012 Jan;9(1):27-32. doi: 10.4161/rna.9.1.18277. Epub 2012 Jan 1.
Pseudogenes are not pseudo any more.
Wen YZ, Zheng LL, Qu LH, Ayala FJ, Lun ZR.
Source
School of Life Sciences and Key Laboratory of Tropical Diseases and Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Abstract
Recent significant progress toward understanding the function of pseudogenes in protozoa (Trypanosoma brucei), metazoa (mouse) and plants, make it pertinent to provide a brief overview on what has been learned about this fascinating subject.
We discuss the regulatory mechanisms of pseudogenes at the post-transcriptional level and advance new ideas toward understanding the evolution of these, sometimes called "garbage genes" or "junk DNA," seeking to stimulate the interest of scientists and additional research on the subject. We hope this point-of-view can be helpful to scientists working or seeking to work on these and related issues.
Yet another.
Comp Funct Genomics. 2012;2012:424526. doi: 10.1155/2012/424526. Epub 2012 May 7.
Pseudogenes.
Tutar Y.
Source
Department of Biochemistry, Faculty of Medicine, Cumhuriyet University, 58140 Sivas, Turkey.
Abstract
Pseudogenes are ubiquitous and abundant in genomes. Pseudogenes were once called "genomic fossils" and treated as "junk DNA" several years. Nevertheless, it has been recognized that some pseudogenes play essential roles in gene regulation of their parent genes, and many pseudogenes are transcribed into RNA. Pseudogene transcripts may also form small interfering RNA or decrease cellular miRNA concentration.
Thus, pseudogenes regulate tumor suppressors and oncogenes. Their essential functions draw the attention of our research group in my current work on heat shock protein 90: a chaperone of oncogenes. The paper reviews our current knowledge on pseudogenes and evaluates preliminary results of the chaperone data. Current efforts to understand pseudogenes interactions help to understand the functions of a genome.
Conclusion.
It seems the biggest criticism in this paper is in how the the word function is used, as the definition of function is used broadly, but it also seems kind of silly to not expect such a broad definition when the findings themselves are so broad. And again just because the findings seem incongruent to how we view selection based on the modern synthesis (and or what Stewart Newman refers to as these old entrenched dogmas) it does not mean the theory should trump scientific revelation & discovery based on new and empirical data. Maybe it's the theory that needs changing. One very well known scientist once told me. Scientist don't change their minds, they just die.
Killer T
Yes the church was protecting what they thought was the accepted science of that day. It was called the Ptolemaic system). It was the church that founded and funded the first universities in Europe which taught what we now call the modern sciences which originated from the ancient antiquated Greek sciences. Most of the first scientist of this day were not only Christians, but they were also theologians. Copernicus, Kepler, Galileo were themselves theologians who challenged the same science that the church accepted, but unlike their more secular counter parts who refused to even look into Galileo's telescope, the church and its inquisitors at least allowed and even encouraged Galileo to continue his work.
His error was in publicly humiliating the same Pope that befriended and supported him. Galileo was simply told that to keep it academic and not challenge the church unless he could prove it mathematically. Galileo however made a lot of errors in his math and thought the sun caused the tides to rise. And even after he publicly humiliated the Pope in his writing of The Dialogue Concerning the Two Chief World Systems (Dialogo sopra i due massimi sistemi del mondo) 1632 He was again told to prove it mathematically or renounce it, but he could not, and heliocentrism wasn't scientifically quantified until a hundred years after his death.
He actually lived a better life style than most, even under house arrest as he was given a beautiful villa to live in with a full staff of servants, and he was eventually allowed to come and go to his lab when ever he wished, and this is were it is said that he did his best work. He remained a deeply religious man till his death and years after the incident, he admitted that he had broken his promise to not get involved in the affairs of the church and that he was treated fairly. See (the myth of Galileo.
I think it presumptuous to believe that ENCODE is complete at any point in the near future anyway, and that issues with the various scientists not having their say is a temporal issue. Over time, the gaps tend to get filled in by need. The project as a whole has the requirement of producing a real mountain of as yet imperfectly understood data in a basically correlated fashion.
Even if this project were complete to say, 100 years from now, today; it's verified compiled data is still only a work in progress. A guidepost for discovery. We must keep in mind that the science being done now in support of the project will be considered crude understanding in ten years.
ENCODE science at this stage is in fact of lesser importance than the data collection process and methods being defined in this first generation. A vast percentage of all current data will be overwritten in time, as THEMAYAN points out. Normally I'd find instant agreement with a given scientist in a scenario like this, but not this one. A tenured professor should understand this project from personal experience in education. We are still identifying valid information sources out of the huge amounts of genetic data extant now. The idea that all the scientists now working in anything related to this project all be given their head to work as they will and dot every i rather than in the method that will produce a basic, usable product in a real timeframe is unreasonable.