Guilty privates

There’s an army barracks attached to a local village that allows the public to use its heated outdoor swimming pool in the summer. I often assumed it was too much chlorine that was the problem with stinging eyes.

But, according to chemist Howard Gosling that typical swimming pool smell actually comes from compounds known as chloramines that form when chlorine reacts with any urine or sweat in the water. Nice. It’s the chloramines not the chlorine that make your eyes sting.

I’ll leave you to draw your own conclusions about why the army pool brings tears to the eyes. Maybe the CO should drop in some of that chemical that turns the water blue of there are any guilty privates swimming.

Illicit CD-ROMs

An Australian chemist friend of mine was giving a lecture recently on how Western chemists might best help their colleagues in the developing world gain access to the mountains of chemical information available without eating into their own budgets too much.

Various systems based around the Web were discussed but industrial delegates were surprisingly more than a little interested in one particular idea concerning CD-ROMs.

My chemist friend planned to set up a cheap subscription service for a monthly CD-ROM that would mirror chemistry sites on the web and so bring the internet to those scientists in poverty-struck institutes with no access. When the queue for samples of the CD-ROM had stretched to the back of the lecture hall my friend asked the next person in line why they were so keen to see the CD-ROM. The startling reply was that their employer was so scared of staff wasting time on the web that all net access was blocked – a CD-ROM could be viewed illicitly without needing a net connection.

Where there’s muck, there’s brass

Where’s there’s muck there truly is brass according to the late Benjamin Luberoff writing in Chemistry & Industry. Luberoff reported that in Sacramento, California, someone is stealing the trash. Not just any old rubbish, mind, the stuff that’s getting the attention of the local criminal fraternity, or sorority, is the tonnes of recyclables residents kindly sort and leave out for collection every week.

It’s easy to load a pickup truck with aluminium Coors cans, paper and glass, drive to the local recycling plant and pick up a few nickels and dimes in return for one’s efforts, he reckons. The local police department estimates that some $400,000 worth of recyclables are being scavenged from among the garbage of the citizenry each year.

A sizeable loss to the city coffers to add to the $250,000 they spend on disposal of old fridges and tyres. I’m waiting with interest to see the same happening in Cambridge where a kerb-side recycling scheme was implemented last year. If it’s good enough for California.

Stick with grubby bedsheets

My Dad is a retired civil engineer and unfortunately for him recently suffered a severe and itchy allergic rash on his legs caused by exposure to a biological washing powder.

After trying a topical antihistamine cream Dad went to his GP who prescribed antibiotics then, as a last resort, a steroid cream known as Betnovate-C.

According to the information leaflet accompanying the tube of cream it ‘may stain hair, skin, or fabric’. So, what’s it doing to your skin, my Dad wondered.

That aside, after a successful treatment, he was a bit puzzled as to how wash out a particularly stubborn mark on the bedsheets. His mind was put at rest by the instructions on the cream’s leaflet – ‘stains may be removed with a biological washing powder,’ it said.

Of course.

Elemental Discoveries

Elemental Discoveries was first published as a spread of chemistry news items written by David Bradley in the mid-1990s for the young chemists magazine New Elements (the name for which, incidentally, DB came up with). In 1996, he began hosting it on the web and by 1999 that proto-blog had morphed into the Sciencebase site, which ultimately became the Sciencebase Science Blog.

If you follow through the Sciencebase archives you may notice gaps, there are legacy pages that are not part of the main content management system (CMS), unfortunately, and so old, and perhaps out of date now, that it would be pointless to fold them into the CMS.

Issue 49

The visible way

The efficient conversion of sunlight to chemical energy has generally been the preserve of photosynthesising life. Until now.

Stellar system stifles landfill stench

Anyone living near a landfill will be familiar with the awful smell of decomposing waste. But, those nasty niffs could soon be history, thanks to British researchers who are tearing the odour molecules apart with a plasma.

A closed view of life

In the growing field of research into biospheres, scientists hope to improve their understanding of what sustains life and so improve our chances of colonising space and even saving the earth from environmental disaster.

Science news site Sciencebase

X-rays Make Smoother Chocolate

Chocolate

For manufacturers of drugs and chocolate bars, an understanding of how they crystallise can mean the difference between a best-selling product and a flop. X-ray diffraction could help them get a clearer picture at the atomic level.

The taste and feel of chocolate in the mouth depends a lot on the crystal form of the cocoa solids, while some medicines work more effectively in one polymorphic form than another. Until now a crystal clear understanding at the atomic level of how different polymorphs form in everything from chocolate to medicine has been little more than trial and error except in the laboratory setting of the vacuum. Now, Elias Vlieg of the Department of Solid State Chemistry, at the University of Nijmegen, describes how X-ray diffraction (XRD) techniques can be used to study crystals as they form and so provide clues as to how their growth can be better controlled. The chance of tastier chocolate and more efficacious drugs is on the horizon.

If the growth of crystals were clear-cut, there would be no need to study crystal growth, but many compounds can crystallise in different – polymorphic – forms. Even a material as seemingly simple as carbon has several polymorphs – graphite, diamond and fullerite. The differences between polymorphs of the same compound can be tiny, an atom shifted slightly to the left, or a tighter angle between two bonds. But, they can also be quite large differences that impact on the overall properties of the solid. For a drug in solid form this can have a real impact on how well it is absorbed by the body. One polymorph may take longer to be dissolved and absorbed while another might be faster acting. The result can also alter the drug’s side-effects. A slowly absorbed drug might sit in the stomach too long and cause irritation of the lining of the stomach for instance.

On the lighter side, the minute crystals of cocoa solids in a chocolate bar affect how the bar melts in the mouth. One crystal form may have a more pleasing texture on the tongue than another. According to Vlieg, XRD has been wholly successful in observing crystal growth in a vacuum. But for crystal growth from the more industrially realistic setting of a solution, melt or solid, it has until recently been little more than a dream tool.

Now, XRD is beginning to offer information on the structure of both sides of a growing interface. This, explains Vlieg, means that structural details like relaxation and reconstruction on the crystal surface and ordering in the solution can be included in the theoretical description of crystal growth.

Understanding crystal growth in vacuum and beyond, Surface Science, in press.

Carpet Consumers

Trust a scientist to take consumer rights to the extreme. Analytical chemist Gerry Clark bought a new carpet for his son’s bedroom. The carpet had that common ‘new carpet’ smell but after several weeks it still hadn’t dissipated and Clark began to worry about the fumes to which his child was being exposed.

He took a chunk of the carpet into his lab and recorded a gas chromatograph (GC) for the volatile emissions. Sure enough, there were spikes due to several organic compounds. Clark took the test sample back to the shop together with his GC results, complained, and insisted the sample be sent to the manufacturer.

A week later, the company was in touch offering a replacement because the original carpet had obviously not been left to dry long enough before dispatch to the outlet. Needless to say everything smells rosy now.

Such tales are all very well for lab chemists, but what about the rest of us fobbed off with fusty floor coverings, smelly sofas, and pungent pouffes? Maybe consumers should set up an action group with its own labs to help people make a scientific case for complaints. It could be called the Prevention of Odourous New Gear Society. Or STENCH, STINK, REEK…or whatever.

Sperm tap

Richard Evans, Catrin Pritchard and their colleagues at GlaxoWellcome discovered a way of blocking the path of sperm from the testes, which could produce semen that is virtually sperm free without the need for an irreversible vasectomy.

On the other hand, as it were, the control they have discovered could also be used to enhance the movement of sperm from the testes and so may have potential in male fertility treatment too.

I often wonder with these fertility researcher people whether they do their research manually…maybe not. For more on male fertility research check out the sperm tap article over on Reactive Reports.

Adverse Drug Reactions

A statue of Asclepius. The Glypotek, Copenhagen.The Wall Street Journal reports (Jan 2, 2009) that a new collaboration between pharmaceuticals giant Pfizer and two Boston hospitals will test whether computerized patient records can boost reporting of adverse drug reactions (ADRs) making it a routine part of filling out electronic patient charts.

Some time ago (Catalyst column, ChemWeb.com, June 1998), I discussed the implications of the more than 100,000 deaths in the US each year allegedly caused by patients’ reactions to their medication – three times the number killed in car accidents. So-called adverse drug reactions (ADRs) are, estimated to be the fourth biggest killer in the US after heart disease, cancer and stroke. Recently, there has been an upsurge of interest in ADRs and calls in the US for an independent body to be established to make control of drugs once they have passed though the regulatory process easier and save lives.

That 100,000 is just a statistic of course, except for those patients and their loved ones affected. Every drug has side-effects and although they do not exist through malicious design, one can perhaps see that the drug R&D process is not perfect.

A pharmaceutical company for reasons of economics and politics cannot possibly study the effects of every putative drug on every ‘type’ of individual in the different circumstances in which it might be used. This is where medication monitoring services come in handy. Pharmacogenomics and personalised medicine that focus on each patient’s single nucleotide polymorphisms (SNPs) may remedy this. But, despite the emergence of inexpensive genomics and predictions of the $1000 genome, this is still true when it comes to administering to the elderly and children as they can be more sensitive than the proverbial adult. Moreover, in the supposedly clinically correct environment of the hospital there are likely to be even more exacerbating factors at work for each individual patient than there might be for a patient with a straightforward bacterial infection, say.

An individual’s genome may be at the root of a particular type of adverse drug reaction. As Catalyst discussed early in 1998. Ten percent of Caucasians and about two percent of Chinese people cannot metabolise the analgesic (painkiller) codeine into its active form, morphine. The drug therefore simply does not ‘work’ for them. The problem boils down to those patients lacking the gene for the liver enzyme CYP2D6 responsible for the conversion. This particular effect was discovered by Alastair Wood a clinical pharmacologist at Vanderbilt University in Nashville, Tennessee. The drug having no apparent effect might lead the GP to prescribe a higher, perhaps intolerable dose. For a Chinese person lacking CYP2D6 the result can be severe nausea.

CYP2D6 metabolises a variety of drugs in addition to codeine, for instance, the antihypertensive propranolol (Inderal), propafenone (Rythmol), for heart arrhythmia, and many of the tricyclic antidepressants. In these cases though people lacking CYP2D6 actually experience an exaggerated effect as the active form stays in their system longer.

In the hospital environment, muscle relaxants used in anaesthesia can be a particular problem for some patients, because they have a faulty gene for the enzyme, butyrylcholinesterase, that would naturally metabolise that drug. For example, succinylcholine stops patients breathing during surgery, this is fine while mechanical ventilation is continued but for some patients the apnoea does not cease and they can die. Peculiar peak concentrations of the TB drug isoniazid have been seen with some patients and have been correlated with a faulty N-acetyltransferase.

In fact, there are many, many variations in drug response that have been recognised and the pharmaceutical companies are becoming well aware of the potential for profit these variations might bring if they can develop drugs tailored to an individual’s genome. The National Institutes of Health in the US has also recognised the potential for improving medicine and is in the process of establishing a Pharmacogenetic Polymorphic Variants Resource database for genes encoding proteins that determine variations in drug responses.

Pharmacogenomics ties in closely with the reporting of adverse drug reactions, although not all ADRs are due to genes. The anti-obesity drugs dexfenfluramine and fenfluramine which are often taken in combination with phentermine – as fen/phen – caused serious ADRs in the form of major heart valve problems in 31% of patients taking the combined medication. The eventual withdrawal of the drug once the problem was widely recognised and publicly known was swift but fenfluramine had been on the market 24 years.

However, while the voluntary reporting of ADRs is fairly common within the medical profession their existence is not well known. Indeed, aside from mentioning a few cursory side effects doctors are often unaware of potentially serious reactions to particular drugs and this is compounded by the fact that all this reporting of ADRs is purely voluntary with the onus on the pharmaceutical companies. As such, there are many people unfairly affected by these drugs and there are actions against pharmaceutical companies like the lawsuit against Levaquin, Actos, etc. It took twelve years before the antihistamine drug used by countless hayfever sufferers every summer was withdrawn in preference to its safer metabolite. The major ADR of terfenadine is potentially fatal heart arrhythmia especially in users taking certain antibiotics at the same time.

A group of medical scientists led by Alastair Wood, published a paper in the New England Journal of Medicine (1998, 339, 1851) calling for an independent drug safety board to be established to keep tabs on ADRs. This body would be there to help protect patients as well as ensuring that medical practitioners were made fully aware of the putative hazards of the countless drugs they prescribe.

According to Wood and his colleagues, ADRs are a serious cause of patient morbidity and mortality. They make the point that there have been independent bodies in place to investigate the likes of plane crashes, train and major traffic incidents, chemical and radiation accidents for many years. These bodies can make recommendations to prevent similar serious episodes happening again following an accident. But, there is no organisation with responsibility for monitoring ADRs and to ensure proposals put forward following an investigation are taken on board.

The ad hoc approach to reporting of ADRs and reactions to drug products seems at odds with the fact that we have Internet and information technology available. Wood and his colleagues say that for all this technology it is remarkable that little use is made of it for drug surveillance to help avoid the huge numbers of deaths that occur. The likes of terfenadine and phen-fen which do end up being withdrawn by the FDA are few and far between and the evidence on which the decision is based while strong is not often in the form of formal statistical analysis. One of the problems is that the US Food and Drug Administration (FDA) does not have the resources to carry this out nor is it in the interests of the pharmaceutical marketers to gather such data.

Wood and his colleagues believe that the solution to the problem is to make this surveillance obligatory through the creation of a body independent of the agency that carries out drug approvals – the FDA. A second, independent body would help avoid conflicts of interest, in that the FDA would not have to investigate problems with drugs it had approved! In their paper in the NEJM the authors state,

We must expect that predicted and unpredicted adverse events from drugs will continue to occur. If we accept that the true safety profile of a new drug is dependent on the experiment that necessarily follows the drug’s release into the marketplace, then we must fund and implement mechanisms to ensure that the experiment is properly monitored, the data appropriately analysed, and the conclusions disseminated rapidly.

Clinical trials can involve a few thousand people, once approved, millions may take it soon after especially now that TV marketing is available in the US to the companies.

Not all ADRs are lethal, just adverse, and some are simply unavoidable because of the individual circumstances in which a drug is administered. They may be unpredictable and unavoidable in some cases but once an ADR occurs the medical community should be made aware of the risks as soon as possible so that better judgements about prescribing a drug can be made and ADRs pushed right down that list of causes of death.

This original version of this article appeared in my Catalyst column in ChemWeb’s The Alchemist in March 1999 before Vioxx, pre TGN1412, and only the intro has been updated January 2009.

Automatic for the chemist

UPDATE: This work eventually led to the Synthia software from Merck.

For decades, chemists have toiled over reaction flasks searching for new ways to mix and match atoms to make new molecules with which to cure ills, boost crops and generally improve our standard of living. There are countless still who spend their working days scouring the scientific literature for shortcuts and using trial and error to find fast and efficient synthetic routes to that all-powerful catalyst or a wonder drug from an obscure soil fungus. Less than flask-happy chemists hope to use computer programs to design their reactions for them and ultimately control the robot arm to shake the test-tube for them.

German chemist Johann Gasteiger together with colleagues at the Institute for Organic Chemistry at the University of Erlangen-Nurnberg has spent fifteen years or so designing a neural network program that might be a first step on the way to hanging up the lab-coat.

cannabinoid comes easier?
Why spend weeks designing a synthesis?
His system uses the accrued information found in commercial databases containing hundreds of thousands of chemical reactions – each with its own reaction conditions: cooking time, pressure, catalysts, reagents and acidity, listed together with physical parameters about the molecules involved.

Today, a chemist might search such a database manually or use a search program to pick out reactions of interest. This, according to Gasteiger, can get embarrassing, “A single search can lead to a list of several hundred reactions from a database that can contain millions,” he explains, “so manual analysis is both laborious and time consuming.” One way to cut down on the effort involved is to classify the multitude of reactions.

Chemists have been classifying whole swathes of reactions for years by naming them after their inventors – the Wittig, the Beckman, the Diels-Alder, but, posits Gasteiger, this system does not help very much in indicating to the chemist exactly what takes place in a particular reaction brew. This is especially true because there are literally dozens of variants in each class. He felt that the solution would be a neural network could do the sorting for him. “There are two approaches to teaching a neural network chemistry”, explains Gasteiger, “supervised and unsupervised learning.” The former is labour intensive and involves presenting the network with input patterns for thousands of reactions and telling it which ones work in which circumstances. “We prefer the unsupervised approach,” says Gasteiger, “It cuts the workload considerably.”

How to teach a neural network chemistry? Gasteiger and his team have used a Kohonen network – a computer model of how our brains organise sensory information – sights, sounds, and tactile feelings in which inputs are mapped onto a two-dimensional network of neurones. By extending this mapping process to the properties of reactions in a database they could gain important information about many reactions at once.

Instead of sensory inputs for the network the researchers used each factor affecting a reaction – such as temperature and acidity – and these co-ordinates were fed into the neural network.

The team picked on a single broad class of reactions to test their networking ideas: reactions that involved adding a carbon-hydrogen group to an alkene. This type of reaction encompasses a variety of important schemes used to produce many industrially useful chemicals such as esters for artificial flavourings – so-called Michael additions, Friedel-Crafts alkylations by alkenes and free radical additions to alkenes.

They used a search program to narrow things down first – they obtained a set of 120 reactions from a 370 000 strong database. They then chose seven characteristic physical properties associated with the actual portion of the molecule that changes – the reaction centre – as the input for the neural network. For instance, the ability of the double bonds between carbon atoms to attract electrons, its electronegativity, the total charge, and the degree of possible distortion of the electron cloud in the bond, its polarisability.

The network they used is a grid of 12×12 neurones with a “weight” associated with the seven chosen variables. When a reaction is input the variables are mapped into the neurone whose weights are most similar to the input. Reactions are input sequentially and after each entry the weights on each neurone are adjusted to make them more similar to the input variables. The adjustment is highest the closer the hit on each neurone and tails off with distance.

The next input if it has similar variables will be mapped on to a neurone close to the first but if it is different a neurone it will locate on a distant neurone and the weights will be adjusted again. The result of these weight adjustments is that the network is trained to recognise patterns of parameters and to place a particular reaction accordingly. Eventually a 2D landscape of reactions is built up with similar reactions close to each other forming groups of reaction types. Logically, reactions far apart in the landscape are very different. Isolated peaks in the landscape point to unusual and uncommon reactions.

The most exciting aspect of the way Gasteiger’s neural network can classify reactions is not that it verifies the system already used by chemists every day, but that if they have a new compound they can look at the seven variables, feed them into the trained network and the network will assign it to a specific neurone. This allows the chemist to see the likely reaction a molecule will undergo in the lab. For instance, if a molecule finds itself at the centre of the area of the map covered by the so-called Michael addition then it is likely to undergo a standard Michael addition. If it is further afield it will probably undergo something more exotic.

It took less than 20 seconds for Gasteiger’s team to train the network with their sample of 120 reactions on a Sun workstation. So to train it on the full reaction database would take little more than a day or two allowing some time for checking. Gasteiger points out that computer time once the neural network is trained is very short (less than half a second) so making predictions about a particular molecule is very fast.

Classifying reactions is not the whole story though – once you know what type of reaction a molecule will undergo, the next step is to work out how it can be used to build up more complex molecules. Chemists usually picture a target molecule and cut it up into smaller jigsaw pieces that can then be re-assembled in the reaction flask. The difficulty lies not only in knowing where to make the breaks to simplify the reactions needed to put the puzzle back together, but in finding reactions that can make the lugs of each jigsaw piece fit together properly. This might be where Gasteiger’s neural network could help in predicting what would work.

Corey’s own program for automating the process, LHASA (Logic and Heuristics Applied to Synthetic Analysis), is marketed by LHASA UK, a company based at the University of Leeds). According to Nigel Greene of LHASA UK, “LHASA is a knowledge-based expert system not a reaction database.” It uses what he calls transforms to describe a generic chemical reaction class e.g. the Michael addition. These transforms are compiled manually from a study of the chemical literature. The program then searches the query compound for the correct stuctural requirements in order to apply the transforms, which is tantamount to picturing the break-up of the jigsaw.

According to James Hendrickson of Brandeis University, “there are literally millions of different routes possible, from different starting materials, to any substance of interest.” He and his team have devised a program (SYNGEN), which can find the shortest route to any molecule from available starting materials. First, SYNGEN looks for the best way to dismantle the target jigsaw. Then, for each dissection it generates the reactive chemical groups needed to carry out that reaction sequence to build the product. Results are displayed onscreen. “In a number of cases to date, the computer has generated the current industrial routes to several pharmaceuticals, such as estrone,” explains Hendrickson. SYNGEN has also proposed more efficient routes to numerous compounds such as lysergic acid, the precursor to ergot drugs and LSD. A new version of the program is in development ready for licensing to pharmaceutical companies this year.

William Jorgensen of Yale University in New Haven Connecticut is working on yet another program CAMEO (Computer Aided Mechanistic Evaluation of Organic reactions). The chemist feeds the starting materials – using a sketchpad – and the reaction conditions – via drop-down menus – into CAMEO, virtually speaking, and the program attempts to predict the course of the reaction. It assembles a reaction from underlying mechanistic steps because as Jorgensen points out a large fraction of organic reactions are just combinations of various fundamental steps.

Sometimes CAMEO (also marketed by LHASA UK) claims no reaction product will emerge, a chemical rule would be broken if it were. The chemist can then run the reaction again virtually in a different solvent or at a higher temperature and watch the result, cutting testing time in the lab.

The various programs apart may not seem to offer a chance for the chemist to boost their leisure time but together they may provide a way of classifying reaction types, working out what type of reaction might take to yield a new molecule using a neural network, feeding it into CAMEO to see whether reactions with other molecules could lead to it and then using SYNGEN to optimise the route.

Some chemists are not worried about losing their jobs just yet though. Al Meyers of Colorado State University at Fort Collins, says, “There is a delicate balance between reacting species, solvents concentrations, selective reaction behaviour, and most important, the human ability to observe what is happening, cannot be incorporated into a reaction software package.” Software will play its role though, “The synthesis programs can bring into focus the many options available to the seasoned chemist”, he adds.

We will have to wait and see who or what is shaking the reaction flasks in ten years time.