Evolution of a scientific discipline…


Research bloggingTHE recent issue of Trends in Biochemical Sciences contained an interesting perspective piece from Alexander Shneider, PhD and CEO of CureLab in Massachusetts. He describes a revision, or alternative focus, of Thomas Kuhn’s (1962) theory of scientific (r)evolution. In this Shneider identifies four-stages of evolution through which a scientific disciple must pass to maturity:

Stage 1. The introduction of new objects / phenomena, with an accompanying language to adequately describe such phenomena.

Stage 2. Development of a ‘tool box’ of methods / techniques to probe the objects / phenomena; with advancements in methodologies helping to identify and understand the degree to which other phenomena fall into the realm of this new science.

Stage 3. The stage at which most of the specific knowledge is generated, with the majority of research publications being published, often focussing on the application of new research methods to objects / phenomena. Scientists may re-describe their subject matter using refinements from stage 2, in the same way that with the advent of molecular biology, biologists might re-describe old subject matter from this new context; thus creating new insights, new answers and new questions.

Stage 4. A seeming steady-state for a discipline, where the knowledge gained from earlier stages is is maintained and passed on, often with practical application; often with new means generated to present the information. Whilst ground breaking new discoveries are not necessarily made, this does not preclude crucial revisions to the role of this discipline within scientific environment.

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On the origins of life…

Research bloggingTODAY’S edition of Nature (14 May 2009) features a landmark paper from researchers at the University of Manchester School of Chemistry that describes the synthesis of a pyrimidine ribonucleotide from simple chemicals, which may have existed on an early Earth. The research by Matthew Powner, in the laboratory of John Sutherland, represents a major stepping stone in support of the ‘RNA World’ theory, which describes the origins of life as passing through a stage in which RNA was the sole mediator of inheritance and catalysis, i.e. no DNA or proteins.

You can learn more about RNA World theory at the Exploring Origins website, or via resources on the website of Jack Szostak, one of the pre-eminent leaders in the field who also presents an accompanying perspective in this edition.

Whilst RNA is certainly a versatile molecule, with one form or another capable of breaking itself apart, joining itself to other RNA molecules, promoting formation of peptide linkages (the primary links of proteins) and templating its own self-replication, a major limiting point has existed regarding the origins of the necessary precursors for the RNA itself, i.e. ribonucleotides. Since the late 60’s, chemists studying prebiotic chemistry have focussed on trying to identify conditions in which these ribonucleotides would spontaneously assemble from their constituent parts: a nucleobase (which can be adenine, guanine, cytosine or uracil), a ribose sugar and phosphate. However, this approach was based on the assumption that these sub-units would assemble first, before combining to form the ribonucleotides. Unfortunately, no realistic conditions have been found in which a nucleobase would join to a ribose sugar.

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Re-awakening ancestral genes…

Research bloggingHUMANS, as we know, are the product of tens of thousands of genes, but hidden elsewhere in your DNA are genes that are no longer functional; these vestigial genes are known as pseudogenes, and they are ancestral remnants from an earlier point in our evolution. In many cases they are simply inactivated duplicates of a current functional gene. In other cases they are genes that have been cut out, reversed and stitched back in; in this position, some believe they may act to regulate the correctly oriented ‘functional’ version of the gene. Alternatively, they may be ancestral genes encoding functions that have become inactive beacuse they are ultimately not necessary for survival. Now, what if we could turn on one of these ancestral genes? One that could actually help protect us from a modern day infection?

In the recent edition of PLoS Biology is an interesting study that describes the re-activation of just such a dormant human pseudogene, retrocyclin, and its potential use as a defensive barrier against infection with HIV-1 (a strain of the Human Immunodeficiency Virus that causes AIDS). Retrocyclin is theta-defensin, which are naturally produced, circular chains of 18 amino acids (a peptide). I have previously research blogged about the application of other such antimicrobial peptides.

Active, functional theta-defensins have only so far been identified in the old world monkeys: the Rhesus Macaque and Olive Baboon; in Humans and other primates, they exist as pseudogenes. At some point in evolutionary history, our ancestors started inheriting a genetic mutation, all be it one that exists at 100%. The Human version of the gene, retrocyclin, is inactive in Humans because of a premature ‘stop’ signal, which makes the cell abandon the production of the peptide too early.

Retrocyclin can be synthesised chemically in a lab, and in this manner that the authors of this paper (from laboratories at the University of Central Florida and UCLA) have previously shown that it is capable of inactivating HIV-1, thereby preventing its entry into cells; in fact, they have also shown that it can similarly prevent entry of Herpes Simplex Virus type I (responsible for coldsores) and type II (responsible for genital warts).

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The dead zone…

rb2IMAGINE that you’re walking along a path in the middle of a prairie, minding your own business. As you’re walking, you find yourself getting out of breath; you find you’re unable to exert yourself as you can’t seem to breath fast enough. Pretty soon you start becoming slovenly, slow moving, dulled; there’s something wrong with the air, there’s not enough oxygen; you’re in the ‘dead zone‘. You try to move away from where you are, but you don’t know where the bad air started. Before long, it’s too late.

A similar experience may happen to deep ocean fish. They need oxygen too, they just manage to get it from the water, but there’s a problem. A report in the April 17th edition of Science, by Peter Brewer and Edward Peltzer (Monterey Bay Aquarium Research Institute, Moss Landing) describes how ‘Ocean “dead zones” [defined as regions where normal respiration is greatly limited and the expenditure of effort is physiologically constrained], devoid of aerobic life, are likely to grow as carbon dioxide concentrations rise.’ In order to understand what their report is about, we need a little background.

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Targeting antibiotics…

rb1INHERITANCE, the process by which some of your parents DNA is repackaged in the agreeable form of you, can be described as ‘vertical gene transfer’, i.e. the passage of information down a lineage. However, this is not the only means by which DNA information can travel.

I once spent six years conducting research into the mechanisms by which resistance to antibiotics can be spread within, and between, bacterial species. Much of this focussed on horizontal gene transfer (HGT), specifically the transfer between bacteria of DNA packages called ‘plasmids’, which can contain a full set of instructions on how to resist an antibiotic. Unlike inheritance, HGT is more akin to you reaching out and placing your hand on your cousin and acquiring their ginger hair, or nose shape.

This is of course a very serious issue, in fact it has never been more serious. The subject of HGT is a key topic in many aspects of biological sciences, and I’ve blogged about some of the interesting aspects of such DNA information transfer before.

In the past 10 years or so, an oft’ discussed topic of conversation at the scientific conferences I’ve attended has been the development of targeted antimicrobials. This is a move towards being able to ‘take-out’ (in the mafia sense) those specific bacterial species that are causing a particular infection/disease, but without providing a selective pressure to develop resistance to the drug on this, and neighbouring, bacterial species.

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The strength of great apes…

The next time you’re down the pub, engaging your favourite Chimpanzee in an arm wrestle, I want you to reflect on a few things (besides the absurdity of wrestling an Ape).

As you take up the strain, know that the fine-tuned positioning and slow, steady building of muscle force you exert is due to the greater amount of grey matter that you posses in your spinal cord; motor neuron nerves cells that connect to muscle fibres and regulate muscle movement. The huge surplus of motor neurons you possess allows you to engage smaller portions of your muscles at any given time. A Chimpanzee, by comparison, has fewer motor neurons, thus each neuron triggers a greater number of muscle fibres, resulting in a greater proportion of muscle activation.

Reflect on how this finely tuned, incremental strength allows you to engage in tensing your muscle for a longer period. It is this fine motor control that allows you to do delicate tasks, like be victorious on the Nintendo Wii or replace the RAM in your laptop, and you know that if the RAM chip stubbornly refuses to slot back into place, you can gently exert greater and greater precise force until it does.

Finally, as the arm wrestle begins in earnest, reflect on two last things: one, your brain limits the degree of your muscle activation in an attempt to prevent damage to the fine motor control components of your muscles; and two, a Chimpanzee has no such limitation. So as the Chimpanzee tears off your arm easily and beats you over the head with it, think to yourself that rather than engaging in an arm wrestle with a Chimp, which has four times your strength, try sitting at home playing your Nintendo Wii instead, the precise motions for which it seems we are supremely evolved.

Inspired by Alan Walker’s (Professor of Anthropology at Penn State) research article ‘The strength of Great Apes and the speed of Humans’; free to read in the recent issue of the journal Current Anthropology.

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Ozone again…

In today’s Daily Mail, the spurious ‘Good Health’ section features an article entitled, ‘How a shot of ozone can beat backache’. Ozone is something of a buzz word in the alternative therapy/naturopathy circles, where O2 (oxygen) is seen as an amazing cure all (rather than a potential damaging oxidiser), thus O3 (ozone) is king. Ben Goldacre, of the Bad Science blog, has written numerous times about pseudo-scientific ozone treatments.

The difference in this case is that the evidence comes from an 8,000 person meta-study led by Kieran Murphy, MD, at the University of Toronto, analysing results published in similar European treatments, and as such has some degree of validity. Dr Murphy, who performs oxygen/ozone treatments, recently pioneered a medical device for minimally invasion introduction of an oxygen/ozone delivery device to the lumbar discs (the fluid filled spongy spacers between the bones of your spine).

Importantly however, there was a lack of randomised, blinded trials, and there was no control (placebo) group, so it’s difficult to conclude whether any improvements were specifically due to the ozone injections. The placebo effect can be powerful, especially in treatments that involve injections or ‘medical theatre’ (the degree of organisation and preparation before a procedure); Ben Goldacre also writes about such effects.

In January, researchers at the same institution (the University of Toronto) published the results of an 8-week, 3-visit, triple-blinded, randomised controlled clinical trial involving 44 subjects, looking at treatment of hypersensitive teeth with ozone injections. They found that treatment resulted in reduced pain sensation, but that this was indistinguishable from the placebo, demonstrating the patient’s expectation of cure from an invasive practice, or ‘medical theatre’.

Without such controls, it is difficult to conclude whether such therapies are truly effective, though the power of placebo cannot be discounted as having some benefit if it is able to reduce pain.

Fortunately, in the Mail’s article they did offer one paragraph to a Professor of muskuloskeletal medicine at the University of Leeds who welcomed new innovation, but also suggested that the lack of appropriate randomised controlled trials needs to be addressed.