I expect the following collection to be the first in an occasional series of brief notes and comments relating (mostly) to the current literature of molecular biology.
Hox genes in motion: who’s moving whom? Back in the days when DNA contained “all the instructions for making a human being”, it was the linear sequence of DNA that somehow carried a “code” for, among other things, the form of organisms — or, to put that last phrase more fittingly, “the forming processes in organisms”. It’s never been easy to see how this code might work. So when particular sequences known as “Hox genes” were eventually discovered playing a role in serially producing the body segments of insects and the vertebrae of (for example) humans, there was great enthusiasm.
As these things always go, however, a progressively complex story began to unfold. It might have been expected that countless other factors would be found to be involved; but what is generally not expected — and yet always turns out to be true — is that there is no single locus of control. The Hox genes, far from being at the head of a chain of instructions, are managed in a highly patterned fashion by cellular and organismal processes as a whole. This pattern of activity, in fact, looks very much like the kind of forming activity biologists wanted to explain with Hox genes in the first place, except that it occurs at a finer level of observation. All of which illustrates the general truth that you can never find fixed structures to explain a forming activity. Rather, the structures are what precipitate out of — and subsequently get caught up in and functionally defined by — the activity.
Well, none of this is really new, at least for anyone with an eye out for the life of the organism. But I couldn’t help noticing a particular irony in an otherwise not especially noteworthy paper entitled “Hox in Motion: Tracking HoxA Cluster Formation During Differentiation” (Rousseau et al. 2014*). The paper amounts to one drop in the flood of current literature dealing with the organization and movement of chromosomes within the three-dimensional space of the cell nucleus. The irony lies in the fact that now — and the paper is one instance of this — researchers are exploring how the Hox loci on the chromosomes must themselves be brought into proper movement and spatial order in order to play their changing roles as cells differentiate.
In other words, key DNA “instructional elements” supposedly dictating certain forming processes of the organism cannot even take their limited place within a wider pattern of activity without themselves being brought into proper form according to the needs of the context.
It’s about time biologists explicitly acknowledged that their own distinctive understanding, aided as it may be by physical and chemical investigations, is — crucially, and whatever else it may be — an understanding of the play of form.
DNA vs. Metabolism. I have mentioned before that, with the slow loosening of the biologist’s fixation upon genes, we’ve started to hear other candidates suggested as the decisive “controllers” of cells and organisms. For example, the leading epigenetics researcher, Australian John Mattick (2009)*, has called RNA, not DNA, the real “computational engine of the cell”. Now we have an article in Bioessays entitled “From the Selfish Gene to Selfish Metabolism”.
Written by Victor de Lorenzo, a Spanish systems and synthetic biology researcher, the article calls for “a conceptual change in which metabolism [“rather than DNA”] has the leading position in the chain of command”. I will not burden you with details of his argument, beyond this generality: organisms, he suggests (and he is working mostly with bacteria) must scavenge for energy sources from the environment to drive their metabolism, and their success or lack of success in this figures in natural selection. When they are doing poorly, they tend to produce reactive oxygen species, which encourage genetic mutations and novelty. In this way the metabolism may secure for itself more effective enzymes and other proteins.
That’s all very interesting, but apparently old habits die hard. So when a biologist begins to doubt DNA as First Cause, he feels obligated to put something else at the head of the “chain of command”. This is nonsense, of course, and in fact, despite such dubious language, de Lorenzo does a fair job of acknowledging along the way that causal relations work in many directions. (We could, however, do without the gratuitous “selfish metabolism”.)
Those who point out the diverse “controlling” virtues of RNA or proteins (see “Shattering the Genome”) or membranes or molecular transport processes in the cell or, now, metabolism are really demonstrating how all aspects of the organism are woven together in a seamless tapestry. There is no causal chain, and no head honcho. De Lorenzo nicely brings out the importance of metabolic threads in the fabric of life (how, one wonders, could this ever have been doubted?) — and yet he shows how metabolic factors are still systematically ignored in places where they are evidently central, thanks to the preoccupation with DNA.
One particularly worthwhile section of his paper looks at the results of synthetic biology over the past three decades or so. He refers to the “recombinant [genetically engineered] DNA” hype of the mid-1980s, when it was thought that genetically engineered microorganisms would clean up all sorts of man-made pollutants, giving us a clean environment. The idea was to take genetic elements from some organisms and put them into others — especially bacteria — that could multiply explosively and were expected to perform the desired tasks more efficiently. But the expectation proved “naïve”; de Lorenzo notes that “the recombinant strains maintained their non-natural phenotypes [collection of traits] only under the very controlled selective conditions of the laboratory”. When released into the “wild”, the organisms typically lost their carefully engineered features — further testimony to the innate wisdom of the organism in managing its own DNA.
Similar problems, he continues, have afflicted more recent efforts to engineer organisms according to a “man-made blueprint aimed at programming new-to-nature properties — for example, oscillators, toggle switches, light-sensing features and many others. But, again, it is now common knowledge that such devices operate for a limited period of time, after which they often succumb to noise and mutations”.
De Lorenzo is here making the general point that the rest of the organism does not take its marching orders from DNA; rather, “the physiology of the host, of which metabolism is the key component, has a say in whether the directions from DNA are to be implemented or not. This becomes yet more manifest when the DNA-encoded instructions are aimed at changing the biochemical regime of cells: metabolism itself is most difficult to manipulate”. He then gives examples testifying to the “extraordinary robustness of the cell biochemistry against perturbations coming from DNA”.
“Perturbations coming from DNA”! The paper might be treasured just for that one phrase. Yes, old, slavish habits die hard, but signs of a progressively liberated thinking are springing up like blades of grass beneath a massive and rusting mechanical wreck.
And for a brief comic interlude .... A humorous (or not-so-humorous) counterpoint to the immediately foregoing note is provided by a response to an online article from Smithsonian Magazine (Interlandi 2013)*. The article concerns the groundbreaking work by Washington State University biologist Michael Skinner on the epigenetic inheritance of health problems by later generations when a forebear has been exposed to certain toxins. The anonymous respondent said the following (quoting in full):
This is why we need to develop advanced nanotechnology/biotechnology tools so that we can fix our defective cells and also, this capability will enable us to reverse and fix all aging/disease in our existing cells too (be sure so support Aubrey de Gray’s SENS project and the Mprize projects, both which are tax deductible in the US, they support leading scientists here in the US, plus new, young gerontologist researchers . . . they have some world class Nobel prize winning board members), remember, Aubrey says that it would only take about 1 billion, spent over 10 years to cure aging, (probably less time to do this), we spend world-wide about 10 billion per day on the worlds war machines ... such a waste, when our society needs much more nano-tech/biotech research to cure all diseases, aging, recycle all our waste, make new items with 3d nano-printers etc.
I wonder whether those many scientists who are quick to complain about the ignorance of “science deniers” would be equally quick to urge the scientific community to accept its share of responsibility for the ignorant worship of “science idolators”?
Trying to see the organism whole. The journal Cell has just come out with a special issue celebrating forty years of publication. The editorial (“Pulling It All Together”) introduces the issue this way:
Hundreds of pathways, thousands of cell types, tens of thousands of molecules, megabytes of data, and seemingly infinite biological networks — the study of life has perhaps never been more daunting. What ever happened to the explanation from Miller-Urey’s experiment on life’s origins, involving just four compounds, or the simple (okay, merely seemingly simple) unidirectional flow from DNA → RNA → protein? One can hardly study biology within the confines of a single textbook anymore, owing to its vast stratifications and marriage with multiple other disciplines. Each field seems to be paving its own frontier explaining what it takes to be a living organism. (Marcus et al. 2014*)
The editors then ask, “Are there common threads, weaving through seemingly dissimilar fields, integrating and perhaps even explaining some of the most pressing questions about the processes that define a living organism?” The special issue takes up several themes in addressing this question, one of which the editors summarize this way: “If much of the understanding over the last forty years has been centered on the ‘how’ or the ‘what’ of a process, looking at all levels of analysis, we see that there is a convergence of appreciation for a new paradigm, the ‘where’”. The idea — put forward almost as if it were a surprise — is that
biology needs the ‘where’ to work as much as it needs the other nuts and bolts. Indeed, it turns out that defining the location of a process is as important as knowing its constituent factors and how they interact with one another. This is true whether the location is in a particular tissue, cell type, subcellular compartment, or even a region of the genome.
The “where” (without which the “how” or “what” can hardly be spoken of) is indeed an integrating question, for there is nowhere a “where” except in relation to many other “wheres’ — that is, except in relation to a coherent context. And the context extends beyond genome, cell, and tissue to embrace the entire organism in its environment.
The unifying threads the editors are looking for are found in the unity of the organism as a whole. Biologists, it appears, are being invited to come full circle, having for a long while been captivated by “controlling” molecules such as DNA, but now on the verge of realizing that nothing makes sense except in the light of the whole organism.
de Lorenzo, Victor (2014a). “From the Selish Gene to Selfish Metabolism: Revisiting the Central Dogma”, Bioessays, vol. 36, pp. 226-35. doi:10.1002/bies.201300153
Marcus, Emilie, Elena Porro, Robert Kruger et al. (2014). “Pulling It All Together”, Cell vol. 157 (March 27), pp. 1-2. doi:10.1016/j.cell.2014.03.022
Mattick, John S. (2009). “Has Evolution Learnt How to Learn?” EMBO Reports vol. 10, no. 7, p. 665. doi:10.1038/embor.2009.135
Rousseau, Mathieu, Jennifer L. Crutchley, Hisashi Miura et al. (2014). “Hox in Motion: Tracking HoxA Cluster Conformation During Differentiation”, Nucleic Acids Research vol. 42, no. 3, pp. 1524-40. doi:10.1093/nar/gkt998
Interlandi, Jeneen (2013a). “The Toxins That Affected Your Great-Grandparents Could Be in Your Genes”, Smithsonian Magazine (Dec.). [Website doesn’t supply page numbers.] http://www.smithsonianmag.com/innovation/the-toxins-that-affected-your-great-grandparents-could-be-in-your-genes-180947644/.
Regarding the importance of movement, location, and structure (form) for the chromosome, see The Dynamic Chromosome and The Complex Performance of the Three-Dimensional Chromosome.
For a large collection of notes about the many startling variety of means by which the organism decides what to make of its genes, see this technical (but eminently browsable) distillation of some of the literature on gene regulation: How the Organism Decides What to Make of Its Genes.
And here you can find more about the centrality of form, not as what needs explaining in biology, but as what does the explaining: The Paradox in “Explaining” Form.
This document: BiologyWorthyofLife.org/comm/ar/2014/lit-notes1_17.htm
Steve Talbott :: Symptoms: Notes from the Biological Literature (1)