As many of us commence our holiday festivities toasting the year’s end while earnestly drawing up personal lists of events that have shaped our lives, I would like to take a brief look at three achievements in the biological sciences- two historical and one more recent- that have struck me as nothing short of momentous in their significance. The first is the publication of a book which today continues to be an outstanding and extremely readable overview of the state of research in the genetics of animal embryology. The second is a landmark study that has brought into sharp focus the molecular mechanisms through which specific epigenetic factors modulate animal behavior. The third is the functional characterization of recBCD- a DNA-unwinding protein complex that plays a crucial role in bacterial recombination. I consider the scientists involved in each of these achievements to be pioneers- ‘podium grabbers’ who have performed medal-winning science in their respective fields of expertise.
I begin with accomplished Drosophila biologist Peter Lawrence who in his 1992 volume The Making Of A Fly: The Genetics Of Animal Design detailed with inimitable clarity how the patterning of body plans during embryogenesis is dependent on ‘positional information’ – the program through which cells recognize their positions within the body and differentiate accordingly. As Lawrence so eloquently described, individual cells recognize their positional coordinates through the activities of complex proteins called morphogens that form highly specified concentration gradients across the embryo.
Morphogens tend to be transcription factors that exert their effects by activating gene-specific promoters. In all there are four independent morphogen systems that determine embryonic patterning: (i) the anteroposterior bicoid protein gradient, (ii) the posterior Nanos protein gradient, (iii) the torso protein terminal system that defines the head and tail areas and (iv) the dorsoventral system which relies upon the activation of a cellular receptor called Toll. These four systems determine the fate of cells by acting as triggers for specialization. Strikingly each system exhibits a high degree of specification. That is, particular genes are only activated above defined morphogen concentration thresholds. Indeed dramatic experiments have shown just how disastrous variations in these thresholds can be to development.
The hierarchical nature of morphogenetic activation is the overarching feature of Lawrence’s narrative. Gradient built upon gradient supply the different levels of genetic interpretation while so-called ‘gap genes’ play a critical role in the development of thoracic and abdominal body regions. Lawrence has written the story of embryogenesis in a language that debutant biologists can easily understand. His enviable ability to weave factual detail with the relevant experimental work makes The Making Of The Fly in every sense unique.
Beyond embryogenesis, the post-natal experiences of animals contribute to the shaping of long term behavior- a factor which I now consider in my second medal-winning choice. It has long been known that events during the early life of rodents have a marked effect on mental and physical health in adulthood. In particular mood and cognitive abilities can be adversely altered following prolonged periods of infant-mother separation. Animals experiencing such a maternal deficit during their early days later suffer from extreme hypersensitivities to stress-inducers. Now a group at the Max-Planck Institute Of Psychiatry in Germany has drawn a direct link between such behavioral anomalies and the methylation state of well-defined regions of DNA.
More specifically, infant-mother separation has been shown to cause a reduction in methylation of enhancers for the arginine vasopressin (AVP) hormone gene increasing the expression of AVP and ultimately disturbing brain endocrine hormone function. The resulting phenotypic changes are nothing short of remarkable- a significant loss of memory and decreased mobility in affected mice. Encouragingly these changes can be partially reversed using AVP receptor agonists- a finding that could have important medical ramifications given that these same enhancer regions are to be found across species including humans.
“This is the first study to depict a molecular mechanism by which stress early in life can cause effects later in life” McGill University epigeneticist Moshe Szyf noted in an interview with The Scientist magazine. The so-called hypomethylation of the AVP enhancer region was specific to an area of the brain that is intimately involved in stress related hormone release. The Max-Planck group further characterized the methylation-state interpretation enzymes, notably a protein called MeCP2, that couple DNA methylation to transcriptional repression. MeCP2 in particular represses transcription of AVP by binding to well-defined methylated regions of DNA. In animals suffering from maternal deficit, such a repression is reversed.
Nanomachines such as those that regulate transcription and DNA replication are ever-present throughout nature. A hot favorite of mine, the bacterial recombination recBCD complex, is also my third and final medal-winning choice. Andrew Taylor and Gerald Smith from the Fred Hutchinson Cancer Center in Seattle have brought the recBCD complex to life by showing how recB and recD operate as motors that allow the entire complex to travel along vast stretches of DNA. If either recB or recD de-couples from its DNA track the other is still there to guide the complex along in much the same way that an airplane with one engine down keeps flying albeit at a greatly reduced efficiency.
The recBCD complex epitomizes the general picture of a bacterial cell with all its components interacting in the most exquisite fashion to achieve highly specified functions. It is clear from Taylor and Smith’s work that essential cellular processes require multi-component machines that mirror in concept and exceed in precision those that are used in our own designs. Coupling systems that resemble cable cars, monorail trains and tramways work in the cell ensuring that important cargo arrives where it is needed at exactly the right time.
So there we have it- a selection of biology ‘faves’ to ring in the holiday season. Between bites of turkey and forkfuls of ham we should spare a moment for those lab-bound researchers who have given us much food for thought in their daily ventures. After all, there remain many unanswered questions beyond the already-solved enigmas of science. As Lawrence himself cautioned, “there are glimpses of clarity- enough to see the immensity and beauty…and enough to know that there is still a long and challenging journey ahead”.
Further Reading
Peter Lawrence (1992) The Making of a Fly- The Genetics Of Animal Design, Blackwell Scientific Publications, London
Chris Murgatroyd, Alexandre V Patchev, Yonghe Wu, Vincenzo Micale, Yvonne Bockmuehl, Dieter Fischer, Florian Holsboer, Carsten T Wotjak, Osborne F X Almeida & Dietmar Spengler (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress, Nature Neuroscience, published online 8 November 2009; doi:10.1038/nn.2436
Jef Akst (2009) Early Stress Alters Epigenome, The Scientist, Posted on 8th November, See http://www.the-scientist.com/blog/display/56139/
A.F. Taylor, Gerald Smith (2003) RecBCD enzyme is a DNA helicase with fast and slow motors of opposite polarity, Nature Volume 423, pp. 889-893