Tuesday, 1 December 2015

Molecule of the Month for December: Lidocaine

Lidocaine-from-xtal-3D-balls.pngLidocaine (sometimes called lignocaine or xylocaine) is a drug that was first synthesised just over 70 years ago by the Swedish chemist Nils Lofgren (for those of you of a musical bent, you may like me enjoy the beautifully understated guitar playing of the founder of Grin,  who enjoys a solo career and also accompanies both Neil Young and latterly, Bruce Springsteen. My favourite example of his guitar work is on the track Speakin' Out from the Neil Young and Crazy Horse album entitled Tonight's the Night, you can find it on YouTube). Anyway, back to drugs! Lidocaine was originally introduced as an anaesthetic 70 years ago and later became popular for treating patients presenting with a number of heart problems.The reason I decided to write about lidocaine is two-fold. The first is its extraordinary, rapid action: it is effective within two minutes after injection (fizzling out after about 20 minutes). The second is its target: a group of sodium channels. Sodium channels (as the name suggests) regulate the passage of Na+ ions across cell membranes and play a key role in nerve transmission and governing the balance of electrolytes in the body, including the heart. How can a molecule like lidocaine interfere with the function of a protein that selectively guides a small cation like Na+?  Let's find out.First of all let's look at the chemical properties of lidocaine. As indicated in the title of the post, one of the names given to the drug is xylocaine, which provides a clue to the origins of this type of compound. Chemists from the Victorian (and Wilhelmian) era were forever "brewing up" wood and coal, and extracting organic molecules. One such molecule from wood tar, was xylene (xylon is Greek for wood; ligno is incidentally Latin for wood: you know scientists are such classical scholars). The aromatic moiety of lidocaine comprises xylene: a benzene ring substituted with two methyl groups. This is linked to a short chain comprising hydrogen bond donors and acceptors of the acetamido- class (the red and blue atoms at the top LHS). For a comprehensive set of data and links to lidocaine, aspiring medicinal chemists should look at the PubChem site, which is an extraordinary resource. There are two biological targets for lidocaine: a group of fast, voltage-gated
sodium channels and, as with every drug (in mammals), one or more cytochrome P450 enzymes. I wont discuss the latter, since they were the subject of a previous MOTM post. Just pause for a moment and think of the remarkable speed with which lidocaine acts after an injection. I am immediately reminded of a conversation with Dr. Rob Harrison at the Liverpool of Tropical Medicine, as we paused in front of one of his splendid collection of snakes: the Green Mamba. Rob's life work has been devoted to understanding the science of snake bites! The Green Mamba, a particularly unsociable, venomous snake, produces a rapid acting, but lethal venom. In some cases, the infiltration of the blood stream with its cocktail of neurotoxins and cardiotoxins, can lead to death in 30 minutes! This is exactly what happens with lidocaine: well not the death bit! Which brings me to the -caine part of lidocaine. It is of course related to cocaine, the recreational drug that preceded drugs like lidocaine in surgery. Cocaine rapidly induces euphoria, but importantly for medicine, it was an early anaesthetic, or numbing agent. Lidocaine combines the anaesthetic properties of cocaine, with the cardiovascular properties of many venom toxins.

When a patient presents with a cardiac arrhythmia, (such as ventricular tachycardia (LHS) drugs like lidocaine have traditionally been employed to restore normal heart rhythm. Today, there is a different protocol associated with advanced cardiac life support (ACLS): typically through the widespread distribution and training in the use of defibrillators, the restoration of normal heart rhythm is done at the site of "attack" by trained first aiders or by paramedics. However, from a molecular physiology perspective; what's happening? Lidocaine acts to prevent conduction of impulses along the nerve fibres. Such impulses rely, as do cardiac contractions, on the proper functioning of sodium channels.

There is no crystal structure available yet of lidocaine bound to a sodium channel, but indirect binding experiments on wild type and mutant forms of such channels suggests that lidocaine makes potent interactions with the two major conformational states (open and closed) of sodium channels. In the diagram opposite,  two key residues that mediate the lidocaine interaction are shown. You can read an open access article from Dorothy Hanck at the University of Utah, here). In finishing, it seems fascinating to me that molecules such as lidocaine can have such a rapid effect on the cardiovascular system of a relatively large organism. An integral membrane channel that selectively handles a small ion, fortuitously captures molecules like lidocaine and the normal rapid electrical processes are dissipated. It also suggests to me that by investigating the properties of naturally occurring toxins, such as those found in snake venom, we may be able to understand the complexity of cardiovascular and nervous "systems", but also, we find some useful drugs. 

Wednesday, 25 November 2015

Science funding in the UK, past present and future?

This week saw the publication of the eagerly awaited "Independent Review of the UK Research Councils" by Sir Paul Nurse (Read his Biography here). You can access the document and supplementary information here. The purpose of such reviews and reports is to take stock of where we (the UK) are in respect of our "Science" (which is clearly defined right at the start as "knowledge", embracing not only traditionally viewed Science as STEM, for example). I particularly like like the quotation at the start of the document:

In the words of Robert Wilson, Director of the Fermi Lab particle accelerator – when asked by the US Congressional Joint Committee on Atomic Energy whether the accelerator in any way involved the security of the country, he replied, “It only has to do with the respect with which we regard one another … our love of culture….. it has nothing to do directly with defending our country, except to make it worth defending. 

The document gets increasingly specialised as you read through it, but I would urge anyone with an interest in educating young scientists, in the process of learning the ropes at school or University and finally anyone who wants to understand why tax payers should vote for those politicians who wish to support our Science base. 

The first ten pages include the following topics followed by a summary of the recommendations:
  • Guidelines and principles
  • Why do we do research?
  • How do we fund research?
  • The scientific approach
  • How do we decide what to research?
  • What are the best mechanisms for making funding decisions?
  • How science delivers for society 
I don't know about you, but these seem to be existential issues for all of those interested in the future of Science. Why not set up a debate amongst Science students: a great way for Science students to prepare for UCAS interviews?

Monday, 23 November 2015

Big in the Ukraine? Life Sciences in The Ukraine Past and Present

I have noticed with some interest that the audience for my Blog Posts has taken a turn for the East. In a manner similar to Tom Waites, who declared in one of his songs that he was "Big in Japan", or to the late Norman Wisdom, who was very, very big in Albania; my biggest readership currently comes from the Ukraine. And since, over the last 25 years, I have come to know and work with a number of Russian and Ukrainian scientists, I thought I would take a look at the Life Sciences in the Ukraine, past present and today. This is part of my lone campaign to increase the awareness of scientific pursuits around the world amongst students. I hope you find it as interesting to read as I have found it to write! And if you are interested in finding out more, my advice is to buy a copy of Geoffrey Smith's superb documentary "The English Surgeon" which relates the story of the relationship between the late career surgeon, Henry Marsh and the challenges of supporting clinical colleagues in the field of neurosurgery in the Ukraine. In my view, it is a masterpiece.

The first thing that surprised me, was that a year before I was born, the Ukrainian city of Odessa was twinned with Liverpool. Two great historic ports, with a shared history of wartime bombardment. Secondly, I was aware of the great tradition of Science in Odessa, but I hadn't connected George Gamow with Odessa. Gamow was an eminent physicist, who turned his mind to the challenges of Molecular Biology during the years shortly after Watson and Crick had published the double helix, and the race was on to crack the Genetic Code. [The term Genetic Code has come to be used to describe the information encoded by a genome, but as a traditionalist in such matters, I am using the Crick-Brenner definition which refers to the relationship between the sequences of bases in DNA and the unique sequences of proteins, in the form of amino acids.] Gamow's mathematical ideas have been quoted by Crick and others as incredibly influential during that golden age of Molecular Biology, when ideas, intellect and insight was in much greater supply than experimental technology! On a more whimsical note, Gamow, along with Watson and other leading lights of the day, formed a Molecular Biology discussion group, called the RNA Tie Club in 1954.

Four members of the RNA Tie club are shown on the left. Can you name them? I also like the tie design, which I believe was a responsibility of George Gamow. I think a separate post on the RNA Tie Club is in order for the future. In the meantime, back to the main topic of the post.....

The Ukraine has a population today of around 45 million and was a founding member of the Commonwealth of Independent States (the CIS), but recent conflicts have led to a stand-off. In fact the Ukraine has been at the heart of conflict over the last two hundred years. Ukraine was a significant centre of culture, commerce and industry, in the Russian Empire, during the reign of the last Czars. It was the birth place of Leon Trotsky, an important "ideological" figure in the shaping and early days of the October Revolution. Perhaps the saddest part of modern Ukrainian history came in the early 1930s, when the Soviet led collectivisation of agriculture, forced Ukrainian farmers to meet impossible targets. Failure to meet such targets led to the withholding of grain supplies by the State. As a result it is believed that maybe as many as 10 million Ukrainians died of starvation.

During World War II, the Ukrainian people faced difficult decisions of national loyalty. Do we stand side-by-side with our Russian neighbours? Or do we support the fascist invasion by Nazi Germany. Following the dismantling of the Soviet Union at the end of the last century, Ukrainian independence was restored fully, but the Orange Revolution and the political divisions which pull Ukraine East and West continue to make life for ordinary Ukrainians a real challenge. Against this backdrop, it is difficult to imagine how a country with a population around the same as Spain could have produced some world leading Science and Scientists. However, the combination of a rich cultural heritage and a subsequent, shared commitment to prioritising and encouraging access to education in both the former Soviet Union and Ukraine today, has given the Ukraine an enviable platform on which to contribute some outstanding science and young scientists.

I haven't got time to name everyone, but in the field of Genetics, Theodosius
Dobzhansky (pictured right), and later George Gamow, spring to mind as pioneers of experimental evolutionary genetics and Molecular Biology, respectively. Theodosius Dobzhansky spent his first 27 years in the Ukraine, before leaving for the USA in 1927, some three years after the death of Lenin, during the Rykov administration. Prior to his departure from the Soviet Union, Dobzhansky worked in St. Petersburg with Professor Yuri Filipchenko, where together they brought progressive evolutionary thinking to the development of sophisticated Drosophila genetics, setting the stage for Dobzhansky to become one of the century's foremost evolutionary geneticists. The expression: "Nothing in Biology makes sense, unless in the light of evolution" is attributed to Dobzhansky, and is something I constantly realise when I am teaching Molecular Biology.

George (Georgiy Antonovich) Gamow, shown right, was born in Odessa in 1904. There is a nice summary of his career in Physics, Biology and Science Communication at the University of Colorado. Like many of the great minds that shaped the pioneering phase of Molecular Biology, Gamow's thinking was
rooted in Physics. Before considering the question of the Nature of the Genetic Code, Gamow had contributed significantly not only to particle physics, but also to astronomy and the "Big Bang" theory. In 1954, two years after Watson and Crick's landmark publication of the Double Helix, Gamow proposed that the "Genetic Code" was triplet. That is, given that DNA and RNA, contain 4 types of nucleotides whilst proteins, the major products of the genome (a term that came later), contain 20; it seemed likely that triplet combinations of these nucleotides (64 in total) would form the basis of translating nucleic acid language into that of proteins. You can read the original paper here, in which Gamow and Ycas discuss the probability of a triplet code. Subsequent work by many experimental Biochemists and Molecular Geneticists, have established that the Genetic Code is indeed triplet.

There are many other great names, including a particular favourite of mine, the Biochemist Jakub Karol Parnas, who with Embden and Myerhoff, laid the foundations for Glycolysis in the Metabolic Age of Biochemistry. However, space and time pressures are bearing down, so bringing us up to date in the Ukraine, I decided to search PubMed for papers with a Ukraine affiliation. I should say this is not a comprehensive analysis, but does give a reasonable indication of levels of activity and the quality of the work, using my own interpretation of the current  "standing" of journals through impact factors etc. Secondly, I noticed from the Blog site of (@IHS4LifeScience) in which the analyst Kavita Rainova pointed to a growing investment confidence in the Ukraine in the Life Sciences sector in 2013. A number of European and American Pharmaceutical companies were set to invest in manufacturing and R & D facilities around the Ukraine, in view of the substantial market for and appetite for better drugs. The more recent problems with the Health Care Sector may have important consequences for sustainable investment, but only the politicians can resolve this!

Ukraine has around 50 more Universities than the UK (just under 150), with a population that is around 20 million less. The Universities range from the Ancient (the Ostroh Academy) to Historic, including the National University of Kyiv-Moyhla Academy and Lviv University to the Universities that include Kharkiv and Kyiv with vibrant new programmes.
At the Institute of Molecular Biology and Genetics (IMBG) of the National Academy of Sciences of Ukraine (NASU), Professor Anna V. El’skaya leads a staff of nearly 500 scientists delivering an impressive research programme covering the areas of Structural and Functional Genomics, Proteomics and Protein Engineering, Molecular and Cell Biotechnology and Bioinformatics and Computational Modelling.