William Haseltine misrepresents molecular biology and calls for a paradigm shift

William Hasletine is a well-respected molecular biologist with an outstanding track record dating back to the time when he was a graduate student under Jim Watson and Wally Gilbert where he studied the regulation of gene expression in bacteria (Ph.D. in 1973). This is why I was surprised to see his recent article in Forbes where he seems to have fallen hook-line-and-sinker for postgenomics gobbledygook. It looks like Haseltine is losing the ability to think critically as he concentrates more on technology and public policy.

A New Dogma Of Molecular Biology: A Paradigm Shift by William A. Haseltine

Regular readers of this blog will know exactly what's in the article because we've seen it all before. You know he's going to tell us that the old Central Dogma of Molecular Biololgy is wrong, wrong, wrong, and the latest discoveries have revealed that lots of non-coding DNA has a function that the old fuddy-duddies—like his old mentor Wally Gilbert—never suspected. He'll close with a call for a whole new paradigm to replace the mistaken views described in the textbooks.

You are right. That's exactly what he does.

The previous paradigm was given in what is called the central dogma.

          DNA --> RNA --> Protein --> Phenotype

The dogma was enshrined in Jim Watson’s 1965 epic textbook The Molecular Biology of the Gene.

In case you don't know why this is wrong, let me count the ways.

1. The real Central Dogma is "once information has passed into protein it cannot get out again." This is very clear from the two papers that Crick wrote and I'm pretty sure that Haseltine read them when he was younger because he was also a postdoc in David Baltimore's lab and the main point of Crick's second paper was to point out that the discovery of reverse transcriptase did not refute the Central Dogma. Many people have pointed this out over the past 50 years including me. Books have been written about the real Central Dogma. Just last week Matthew Cobb published an article explaining why Francis Crick Was Misunderstood.
2. The Watson version of the Central Dogma is not correct (see above). All Haseltine had to do was to read the Wikipedia article on the Central dogma of molecular biology in order to learn this important fact. It seems like this is the least he could have done since his entire article is based on the premise that his (and Watson's) version is correct.
3. No version of the Central Dogma states that "phenotype" is required.

There's more. All of the people who whine about the Central Dogma go much farther than Watson or Crick ever implied. The whiners seem to think that the key part of the Central Dogma is that the only role of DNA is to code for proteins. Haseltine falls into this trap since he writes about the fact that lots of heritable traits map to regions outside the coding DNA as though that were a big surprise.

It shouldn't have been a surprise to him because he worked on regulatory sequences as a graduate student. Also, I'm pretty sure he once knew about origins of replication, centromeres, telomeres, and genes for tRNA and ribosomal RNA. He must have forgotten that he was more knowledgeable about the core concepts of molecular biology when he was younger.

Guess what's coming next? Right! Junk DNA.

Another revelation has also emerged from genomic studies. Recent studies reveal that animal and plant cells copy the great majority of DNA into RNA. Humans copy at least 70% of our genome into RNA, vastly more than the 2% specifying protein. Previously, non-protein coding DNA was related to a trash heap called "junk DNA". Additionally, many variants that affect heritable traits occur in other non-protein-coding regulatory regions, including RNA transcription start, stop, and splicing sequences.

This shows you that not only does he not understand junk DNA but he also doesn't understand pervasive transcription. Genes occupy 45% of our genome because they contain large introns and introns are part of genes. Introns are mostly junk.

The remaining transcripts are very likely to be junk RNA because they are present in very low amounts and they aren't conserved. We have plenty of evidence that spurious transcription is a very real phenomenon—in spite of the fact that the work was done by old fuddy-duddies working under the "old" paradigm. [see Most lncRNAs are junk]

What about the The Deflated Ego Problem? That's also a common theme among the postgenomic paradigm busters. Did he forget about that? ... Nope.

A third anomaly has been apparent for some time. Very simple organisms possess versions of the great majority of the twenty thousand proteins similar to those of complex animals, including us. How do we account for the complexity of most multicellular organisms and ourselves?

There are seven ways of solving this imaginary problem of the lack of genes [see The Deflated Ego Problem]. Haseltine picks regulatory sequences and regulatory RNAs as his solution. Simple organisms apparently don't have very many regulatory sequences or regulatory RNAs but complex organisms have lots of them and that explains why we don't have more protein-coding genes than those simple organisms.

We are now in the midst of a very exciting revolution defining what role this new view of DNA and the plethora of RNAs play in defining our biology. A consensus is now emerging as a new biological theory. Whereas our twenty thousand proteins perform the necessary functions for life, it is the RNA, made mostly from the "junk DNA," that controls when and where proteins are made.

I describe this new paradigm as the DNA/RNA Dogma, a description that assigns equal importance to both DNA and RNA, a focus on the control of protein expression as a key to understanding Mendelian inheritance. The DNA/RNA Dogma offers a more comprehensive and accurate picture of Mendel’s genes and our complexity.

The new dogma now reads.

DNA <—> RNA —> Control —> Protein —> Phenotype

The insertion of the word "control" denotes our rapidly expanding knowledge of the role RNA plays in controlling when, where, how many, and in what form proteins are made.

Right. The only problems with that paradigm shift are: (1) the old fuddy-duddies like me—and the younger version of him—always knew about control and regulation, and (2) there aren't anywhere near as many regulatory RNA genes as he imagines.¹

One of the regular Sandwalk readers (Diogenes) coined the term "paradigm shaft" for this type of argument. A paradigm shaft is when you construct a false paradigm then show that it is wrong and congratulate yourself for being among the first to recognize a revolutionary paradigm shift.

Reports of the death of the standard models of molecular biology are greatly exaggerated.

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1. We knew about non-coding genes in the 1960s. They are covered in the first edition of Watson's book (1965). We learned about regulatory RNAs in the 1970s and the number of different kinds of non-coding genes expanded in the 1980s without anyone calling for a paradigm shift. We don't know how many different regulatory genes there are in the human genome but the best estimate of well-characterized examples is no more than 1000. Higher estimates of tens of thousands are nothing more than unfounded speculation. It's true that there are many more non-coding genes than we knew about 50 years ago but that's only surprising to those who thought that all non-coding genes were ruled out by the Central Dogma.