Thursday, 18 September 2014

Master classes in communication: Lisa Jardine's Point of View

I try not to miss an episode of "A Point of View" which is usually broadcast at 8.45am on Sundays on Radio 4. But when Lisa Jardine, is the guest presenter, I make sure that I am by the radio, and if I can't make it, I download the podcast. The format is simple, the presenter reads an audio essay in 10 minutes, no more: no less. Other presenters include journalists, thinkers, academics, politicians etc. - I should also say that the Australian author and journalist Clive James comes a close second to Professor Jardine. Why do I enjoy Lisa Jardine's broadcasts so much? It could be because she happens to be the daughter of Jacob Bronowski, whose book and TV series, "The Ascent of Man" has stayed with me as an influence ever since I watched the series as a 15 year old schoolboy. No, it is because her use of language and choice of anecdotes, make her my favourite media communicator. As Professor of Renaissance Studies at University College London, she brings enormous insight into the legends of Science: iconic figures such as Isaac Newton and Robert Boyle. Her towering intellect combined with a life, lived rich in experience and through her encounters with some of the greatest minds of the last half century, have endowed her with a rich, cultural reservoir which she dips into regularly to enrich her essays. And this is why I want to encourage you all to download her Points of View (or PoV)!

The last PoV I tuned into was entitled "The Horror of War". I don't intend to dissect the broadcast as an amateur literary critic, but suffice to say that in 10 minutes, she manages to engage you, inform you, entertain you and leave you moved by the sincerity of her views and values, with a remarkable eloquence and economy of language. By contrast, apart from a few exceptions such as the mesmerising language of the journalists on Radio 4's "From Our Own Correspondent", the many hours I spend wading through the academic literature, the essays I from students at all levels, I feel that language skills have been eroded to the point of functionality, at best. And to find ourselves at this point, when our ability to communicate our Science, has perhaps never been so critical. For example, the need to explain the key principles of antibiotic resistance is seen to be a National priority: hence the Longitude Prize. But how many times have I heard "experts" in the media giving at best muddled and at worst, downright incorrect explanations of the mechanisms that give rise to resistant populations of bacteria. I don't think John F Kennedy would have had a problem both in recognising the importance of such an issue and then effectively communicating it.

If we are to provide students with the training needed to carry out incisive experimental Science, or indeed the tools for contributing to theoretical Physics, then we must also impress upon them the need to respect the significance of communication and dissemination. I am not suggesting that we need to get back to Shakesperian values, but I do think that Lisa Jardine's Points of View broadcasts could be used as a framework for teaching such skills. They provide not only superb examples of spoken communication, but are wonderful examples of perfectly crafted essays. 

Saturday, 13 September 2014

Epigenetics: all fingers and thumbs: Molecule of the Month for September

I was trying to find a context for this month's choice for molecule of the month, to avoid accusations of self indulgence (I work on these enzymes)! My choice is the family of enzymes responsible for modifying the genome in many organisms that forms a major part of the Biological phenomenon called "epigenetics" or increasingly, "epigenomics". Epi simply means on top of, and so epigenetics is something that modifies the phenotype of a gene. Think of it like seasoning your food: chips without salt and vinegar, or coffee without milk! For some, like me, black coffee is fine as it is, but some need milk or even cream, before they can enjoy it. The study of epigenetics really came to prominence around 25 years ago when despite considerable experimental challenges, scientists including Timothy Bestor and Adrian Bird began to develop a molecular framework for understanding DNA methylation in higher organisms. The methylation of DNA is found in most organisms (but not all!), sometimes the adenine is modified and in other organisms the cytosine. In some organisms, both nucleotides can be modified. In bacteria, methylation of the genome is part of a mechanism that protects the DNA from attack by restriction endonucleases, enzymes that cleave double stranded DNA in two. These enzymes formed the basis for the development of molecular cloning in the 1970s and '80s in particular (enter Rich Roberts in the search field for more on this). 

The methylation of cytosine bases in DNA not only provides bacteria with a primitive immune system (I should emphasis that the role of methylation and its evolutionary emergence is not as simple as this, but a discussion of this would be a distraction here), it is also at the heart of gene regulation and genomic regulation in vertebrates. After Tim Bestor identified the first vertebrate DNA methylase (DNA MT1), several more have been discovered, but it is clear from work in his lab and that of "transgenic" scientists like Rudolf (Rudi) Jaenisch in the USA, that methylation drives a number of fundamental processes during development. What is fascinating about the enzymes (such as DNA MT1) is that the methylation chemistry is carried out by a structure that is very similar in organisms as evolutionary distinct as microbes and humans. The conservation of mechanism is also preserved in the genome and can be visualised by simple BLAST searching. Therefore, when Rich Roberts and Xiaodong Cheng (and colleagues) determined the 3D structure of the cytosine-specific DNAMTase from Haemophilus haemolyticus (M.HhaI) around 20 years ago, it proved to be an excellent model for understanding the molecular basis of DNA methylation in all Life. 

The structure I want to discuss is the complex of M.HhaI with its DNA duplex,
caught in the act of methylation, before the enzyme leaves the product. This was achieved by the combination of chemical synthesis and Molecular Biology to facilitate X-ray crystallography. If you look closely you will see that the enzyme wraps around most of the DNA double helix, but remarkably, the target Cytosine base is flipped out. This means that the catayltic (active) site can now readily transfer the methyl group from the cofactor S-adenosyl-L-methionine (one of two methyl donors in Nature: what is the other?), to the target base. The reaction over, the enzyme pops the modified base back and goes on its way. 

At first glance this seems like a very elaborate mechanism, but without giving you chapter and verse, what has emerged since this landmark study, is that many enzymes that repair or modify DNA, have been shown to use base flipping as a means of reaching the parts that they would otherwise find difficult to reach. (It is possible to unwind the strands to access the bases, but this leaves the DNA vulnerable to degradation and requires greater molecular sophistication). It seems that Nature has found ways of capturing flipped bases, during a natural "breathing" phenomenon, or proteins have developed that readily push out the target base, suggesting that this is a primitive molecular function. Enzymes that repair the damage of sunlight (where Thymine bases that lie next to each other can spontaneously fuse) utilise base flipping as do enzymes that repair mismatches in the otherwise faithfully replicated DNA helix.

The crystal structure of the flipped base was made possible by the use of a fluorinated version of the cytosine, incorporated into the short synthetic DNA molecule, mimicing a drug that is used to treat a number of diseases: 5-fluorouracil. This combination of synthetic chemistry, X-ray crystallography and molecular biology (to engineer recombinant protein expression) is a wonderful example of multi-disciplinary Science. Moreover, while the catalytic questions can be analysed using the model of M.HhaI, Bestor and many others have now developed ways of tracking DNA MTase by fusing it with GFP and establishing its role with other genome modifiers in modulating the genome in a diverse number of ways (see top RHS, the fluorescence of PCNA, a marker of human DNA replication, colocalizes with DNMT1).

Returning to the fingerprints of the title, one Y13 student is asking the question, why do we have different fingerprints, and why indeed do identical twins also have non-identical prints? This is at the heart of epigenetics, when presumably differences in local concentrations of small molecules re-programme the genotype to produce a new phenotype. It was actually over 60 years ago that the famous mathematician, Alan Turing, proposed a simplified model, referred to as the reaction-diffusion system in which he proposed that morphogenesis resulted from the coming together of environmental chemistry and genetics (often referred to as chemical biology). Simple physical laws underpin complex biological events (see top LHS). The field of epigenetics is emerging as an important direction for anti cancer drug discovery and for me, illustrates how serendipity (searching for a molecular understanding of an interesting aspect of nucleic acid biochemistry) can have a major impact on medicine. 

Finally, if you think this is interesting, one of the recent acquisitions in the Institute of Integrative Biology's Centre for Genomic Research in our sponsoring institute, the University of Liverpool, is a new generation gene sequencer manufactured by Pacific Biotechnology. Already Rich Robert's group (see Rich talking recently about the work, RHS) at New England Biolabs have shown that this methodology can not only read the As, Cs, Gs and Ts of DNA, but the MeCs and MeAs, and with it will be a new era of methylome analysis as we unlock the link between our genes and our environment across entire genomes. Exciting times for us all I think ! 

Sunday, 7 September 2014

Understanding partnerships with our partners at the UTC

At the UTC, we are here to listen to our partners, the future employers and educators of our students, and to embed their values into the enrichment opportunities for our students. We are all delighted at the recent announcement by RedX Pharma that they have signed a lucrative "deal" with Astra Zeneca a company that has its origins in Merseyside and Sweden, but whose reach is now firmly global. From its origins in the pioneering days of the Chemical Industry, Imperial Chemical Industries (ICI), formed from the union of a diverse array of chemical manufacturers, was split into a number of separate entities, one of which, Zeneca merged shortly after (in 1999) with the Swedish drug company Astra, to produce one of the most successful pharmaceutical companies of the last decade right here in the North West (AZ has bases all over the world, but Alderley Park was, until recently a significant centre of operations in the drug development world). The announcement of the "deal" between AZ and RedX Oncology (where many of our students have enjoyed challenging and fulfilling placements over the year) can only be excellent news for the UTC and the region in general. It is a story, that has its origins over many years of pioneering start-ups, collaborations, mergers, acquisitions and it is mirrored by the partnerships and interactions that take place between molecules in the body that have been targeted for therapy.

Photo of Liverpool Life Sciences University Technical College students wearing Redx Pharma lab coats while they workYou may recall Phil Ingham's blog earlier in the year, in which he described the hedgehog pathway drug discovery programme that he has been involved in (which has led to the new anti cancer drug Vismodegib). Molecules in this "domain" of cellular and developmental biology have also provided a focus for efforts at RedX oncology and AZ. The Hedgehog pathway (as Phil discussed earlier: search for Phil Ingham in the Google Blog Search field, RHS) involves a cascade of interactions, or partnerships, which modulate the function of the downstream protein(s) leading to the triggering of a major cellular and sometimes tissue changes. These pathways are at fault in some diseases, or can be redirected to help restore otherwise "broken" biological functions. One of the characteristics of signalling pathways of this kind is that the proteins are often in tiny quantities, are difficult to work with because they tend to be insoluble and/or unstable in vitro: the fact that they are also chemically modified by enzymes (we refer to this as post-translational modification, or PTM for short), makes them challenging in terms of analysis. Nevertheless, as we have learnt over the last 30 years in particular, the road leading to an understanding of cancer (through work on the molecular biology of oncogenes and tumour suppressors) is paved with major challenges. However, the opportunity for UTC students to play a part, however small, in this important journey, with the support of partners like RedX Pharma is one of the reasons why the UTC vision is so powerful for young scientists.

Tuesday, 2 September 2014

Malaria, Cancer, Alzheimer's, Influenza, Measles, Ebola, AIDS, Cystic Fibrosis.....How do we decide what to investigate?

As you start your new year at the UTC, you will be no doubt be aware of the theme that will pervade the first half term: the Global Challenge of Malaria. I am sure that most of you will have a picture in your mind of African villagers dealing with a health crisis in challenging circumstances. I wont think of the prospect of catching malaria while you sleep in your own bed, but you might wonder if you are likely to catch measles from a classmate, or more likely the flu or a cold. We know that certain diseases are restricted to some parts of the world (by restricted I should really say that they are much more prevalent), some are dangerous to infants and some, like Alzheimer's disease are rarely found in adults under the age of 60. It is really important that you develop a perspective on the "significance" of a health problem. This is the theme of this Blog: I want you to be able to decide for yourselves with evidence, which areas of Medicine and Science are important. I also want to alert you to the ways in which new discoveries arise, the impact they might have on the quality of our own and the lives of others across the world. I also want you to understand why sometimes we need to investigate things out of pure curiosity, since it is from this route that many of our current technologies arose in the first place. However, ultimately, research costs money and it is the tax payer that decides how much money we invest in research. And as Benjamin Franklin said: "In this world nothing can be said to be certain, except death and taxes".

The scale of a health problem often dictates the priority given to research and financial investment. As a new University lecturer, a Head of Department will have recruited you partly because you have impressed at interview, but increasingly because you are working on a problem that is seen to be fundable. So what are the priorities of the UK funding agencies? Life Sciences in Universities and Research Institutes in the UK are funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), the Natural and Environmental Research Council (NERC) and the Wellcome Trust. There are differences in their priorities but they all agree that Human and Animal Health are a priority, with new antibiotics and resistance mechanisms, together with ageing research, receiving a great deal of attention. Cancer Research is the primary focus of Cancer Research UK (CRUK), with different Research Centres specializing in the various forms of cancer, eg lung cancer, bowel cancer, pancreatic cancer etc. You will notice that I haven't mentioned malaria or ebola. This is where the challenge of obtaining funding becomes more complex. 

The history of Tropical Disease Research in the UK is an interesting one, and one in which Liverpool has been centre stage. Over 100 years ago, shipping merchants who relied on the health of their crew for their business successes, identified "tropical diseases" as a major threat. In those days Britain's influence was just as global as it is today, but it was in the context of the British Empire, which required a radically new solution for protecting the health of commonwealth citizens, and in particular the various professionals and troops who governed countries that became lucrative sources of produce and raw materials for the increasingly industrialised "West". This led to the foundation of the Liverpool and then London Schools for studying and developing methods for preventing and treating rare, Tropical Diseases. These institutions were also critical in supporting the health of the armed forces during the two major (and many minor) wars of the last century.Today, they play a key role in both educating and providing advice to international organisations such as the World Health Organization as well as controlling the global spread of such diseases, in the context of international travel which is now commonplace in the West. In short the stability of the population of the world as a whole isn't a National issue, it is global.

We mustn't just consider research funding at academic institutions. What are the economic factors behind the growth of the Pharmaceutical sector into one of Britain's largest employers and most successful businesses? (I have touched on this issue elsewhere on these pages, and at my Molecules to Market Blog page). Clearly, just like any other "for-profit" business, a drug company must make sufficient money from the whole process of drug discovery from sales, and this is determined by the cost of development, meeting the regulatory requirements (through clinical trials) and subsequently marketing the drug at a suitable price. Given that the cost of bringing a drug to market can be several billion dollars, the pharmaceutical industry is in many ways a challenging one. It may not surprise you to learn that the focus for new drugs is driven by market size and ability of that population to pay for such high cost new drugs. It is thanks to major interventions by high profile advocates like Bill Gates, that diseases like malaria are now on the agenda of drug companies who would otherwise see malaria treatment as a high risk market.

So research into diseases is driven in part my national and international agenda in different ways and in addition, we rely on the drug companies to find ways of short circuiting the discovery and development phases, in order to keep their costs down. What room is there for serendipity in Life Science research? In respect of diseases, the work on ebola, that I discussed in my previous blog illustrates how a disease caused by a potent virus has begun to unearth new concepts in fundamental molecular biology. The disease affects a very small number of individuals annually, and is a very minor cause of death in comparative terms. It would therefore be unlikely to receive the same kind of funding as cancer research. Nevertheless, I think the work on ebola illustrates that if your ideas are sound and creative, it is still possible to attract the necessary funding, in the right environment, to make important, non-mainstream, fundamental discoveries. It is important for you as our future scientists that you are as well informed as possible, not only about how to do experiments, but why they should be done and to be aware of the forces that drive scientific discovery and remember as Louis Pasteur said: "Chance favours only the prepared mind".