The Conspiracy of Epigenome?

How does this conspiracy of genes work? said Eric Lander to describe the latest epigenome project to New York Times reporter Gina Kolata. Conspiracy seems like a curious choice of word, because we are unsure which definition applies here.

1. An agreement to perform together an illegal, wrongful, or subversive act.

2. A group of conspirators.

3. Law - An agreement between two or more persons to commit a crime or accomplish a legal purpose through illegal action.

4. A joining or acting together, as if by sinister design: a conspiracy of wind and tide that devastated coastal areas.

We would have had to scratch our heads less, if Lander used ‘conspiracy of epigenome’ instead. Nothing managed to derail this expensive boondoggle over the last four years, including powerful critics of the scientific principle behind it, fraud allegation against the leader, public humiliation of its sister project ENCODE, NIH cost-cutting and protest of the scientists, and so on. What appears even more puzzling is that despite all those prior events, the ‘leaders’ of the epigenome project ended up making the same mistakes as ENCODE. Don’t these clowns learn anything?

Speaking of history of the epigenome project -

1. When the original project was launched, Mark Ptashne, Oliver Hobert and Eric Davidson disputed the scientific validity of the project using very strong words (Questions over the scientific basis of epigenome project). In the field of gene regulations, each of them is important in his own right. Oliver Hobert works on gene regulatory mechanisms of neural system, and his 2011 Cell paper - ‘Transgenerational Inheritance of an Acquired Small RNA- Based Antiviral Response in C. elegans’ shows one rare example of epigenetic mechanisms in animals. Eric Davidson is among the most respected developmental biologists, who works on gene regulatory mechanisms in early embryo. Mark Ptashne was the first scientist to demonstrate DNA-protein binding, in his 1967 paper “Specific Binding of the ? Phage Repressor to ? DNA”. Criticism from even one of them would be enough to raise eyebrows about a scientific project, but the epigenome project mysteriously managed to survive all three.

They were not the only ones. Ptashne et al wrote -

A letter signed by eight prominent scientists (not including us), and an associated petition signed by more than 50, went into these matters in greater detail, and expressed serious reservations about the scientific basis of the epigenome project.

2. In another unexpected blow, Manolis Kellis, the leader of the epigenome project, was accused of fraud by Berkeley mathematician Lior Pachter (check here and here). In the scientific world, a fraud allegation is far more serious than someone’s scientific theory being called wrong, yet nothing happened in this case. Given that Pachter is a very good and well-respected scientist, why was his case completely ignored?

3. ENCODE, its sister project, was publicly shamed for its media splash and hyped up claims by respected population geneticist Dan Graur. (Check “On the immortality of television sets: function in the human genome according to the evolution-free gospel of ENCODE”). The ENCODE-backers called Graur’s ‘tone’ rude, but respected scientists like Gary Ruvkun said that he was too gentle and used even stronger words. Here is the comment Ruvkun left in Graur’s blog.

I have enjoyed your devastating critiques of Encode and ModEncode. I forwarded your On the immortality of television sets to dozens. But you are too gentle here. I get Nature now for free, since I review quite a bit for themit is a sign of the decline of journals and the decline of the science that they publish that they now give it away to their reviewerssort of like the discounted subscriptions for magazines which sell high end merchandise if you live in the right zip code. So, I was well rested today and decided to give the 5 papers of the modEncode a chance to blow me away. Not one interesting finding. Not one. Worse than junk food, which at least satisfy in the moment. Hundreds of millions of dollars on genome scale observations of transcripts and transcription factor binding. Grind up a whole animal and look at the average of hundreds of cell types pooled together. A few weak correlations between this and that transcription factor. A few differentially spliced mRNAs. I would say that about 1% of the modEncode budget was appropriate for getting better transcript annotation, but the rest was misguided genomics. A waste of research dollars! The so-called brain trust of the NIH does not understand the difference between big science that is foreverthe thousands of genome sequences that are precise to one part in a billion and will be used for the rest of timeand big science datasets that will simply fade away because they are so imprecise and uninteresting to anyone, like RNA seq. On the other hand, the good news about projects such as these is that the hundreds of authors on those papers are distracted from serious science, and the bizarre sexiness of these papers attracts other marginal intellects to those fields, and thus fields that are important becomes much less competitive, ignoring the bloated budgets of these Soviet- style five-year plans.

4. ENCODE made a big climb-down from its position that 80% of human genome was functional. Given that it was supposed ENCODE’s earth-shattering discovery, ENCODE appeared to have discovered nothing and ended up being the most expensive ‘resource paper’. The statistical paper backing ENCODE’s primary claim was strongly disputed by Nicolas Bray and Lior Pachter.

Ward and Kellis (Reports, September 5 2012) identify regulatory regions in the human genome exhibiting lineage-specific constraint and estimate the extent of purifying selection. There is no statistical rationale for the examples they highlight, and their estimates of the fraction of the genome under constraint are biased by arbitrary designations of completely constrained regions.

Note the name Kellis there? He is the leader of the epigenome project.

5. After the huge waste of $350M by ENCODE, scientists are up in arm against all such expensive its huge price tag of $350M. The controversy section of ENCODE’s wiki page is now bigger than every other section, and you cannot imagine what scientists say in private.

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Despite all these, the $250M epigenome project came out with another media splash and public claim of major discovery, as if ENCODE never happened. Reuters reports -

Scientists unveil map of ‘epigenome,’ a second genetic code

A second genetic code???? Please note that these articles are usually handed by university’s internal team to the reporters. So, we should not blame the reporters for misunderstanding science.

If you do not believe it, here is the leader of the project showing he is no better.

“A lifetime of environmental factors and lifestyle factors” influence the epigenome, including smoking, exercising, diet, exposure to toxic chemicals and even parental nurturing, Kellis said in an interview. Not only will scientists have to decipher how the epigenome affects genes, they will also have to determine how the lives people lead affect their epigenome.

Why not add victims of holocaust and slavery as well, like the paper mentioned in this post. Needless to say, not a single claim is backed by any science. We have gone through many of the relevant studies, and they were often based on poor-quality association studies of 30 or 40 persons and no further study of causal mechanism.

The article further says -

“The only way you can deliver on the promise of precision medicine is by including the epigenome,” said Manolis Kellis of the Massachusetts Institute of Technology, who led the mapping that involved scientists in labs from Croatia to Canada and the United States.

Given that ‘precision medicine’ and ‘epigenome’ are both vaporwares, there is no doubt that one will help with delivery of the promise of the other.

In this entire media circus, the only truth is spoken by Anshul Kundaje (emphasis ours) -

But while the researchers are confident that their discoveries will be revelatory, they also see a long road ahead. They will find circuits, another author, Anshul Kundaje, an assistant professor of genetics at Stanford said. But, he added: Making sense of them is a whole different story.

In other words, nobody understands what is going on, but they all agree that they made a major discovery (‘second genetic code’). Apart from resorting to conspiracies, as Lander did, can anyone provide a sane explanation of how this freak show is sustained?