Formulation Science: Continued

 

In a recent blog post, I discussed the essentials of the Formulation Science discipline, using a long explanation involving cake. I am not a Formulation Chemist, but I quite liked writing this post. For my own enjoyment, and to be more technical, here’s a follow up!

The Role of Formulation Science

So, Formulation is an essential discipline, but specifically why? As a synthetic chemist, I deal with chemicals in their purest forms. And the majority of organic chemicals manifest themselves as unassuming white powders. These are not acceptable as consumer products for several reasons. Namely:

  • Regulation
  • Marketing
  • Storage
  • Consumption
  • Delivery

I’d like to explore all these functions in more detail below.

Regulation

Before a product can go to market, it is regulated by its relevant industry agency – be it the FDA, MHRA or EC. These agencies exist such that consumers know what they are buying is what it says it is, and that it is safe. It’s as simple as that.

Pure chemicals are not good consumer products because they are unlikely to be efficacious. Therefore formulations are necessary to dilute them down to consumable levels. These formulations must be uniform so that the consumer knows exactly what they are getting.

Marketing

If you know of or remember the Herbal Essences marketing campaigns, you will be aware that scent is an attractive attribute for a shampoo formulation to have. You can mount your entire marketing strategy based on it, it seems.

Marketing can also use appearance or texture to sell their food products. Though whether either is actually central to the marketing in my examples is disputable, what is indisputable is that these are desirable qualities.

Storage

Substances, whether they be shampoo, food or medicine, must be storable until they are consumed. The product can smell delicious and have the perfect gooey texture of the perfect shampoo, but if it smells of mould and separates into a liquid and solid after a week it is not acceptable.

hair-care-3-1507938

You also want the formulation to afford the stability to maintain those desirable qualities that have been instilled in the property. Loss of flavour or texture is not something we want in foodstuffs. Ice cream, for example, contains anti-freeze molecules to ensure it does not turn into a solid block of ice: instead it maintains a soft, scoop-able texture.

Desiccants are substances that absorb moisture. These are often included in packets to avoid the product absorbing the moisture in transit to the consumer, but they are also included in formulations to ensure, for example, that a laundry powder doesn’t clump up. In solid formulations, products are often spheronised (to form sphere) and coated to aid longer storage and slower release.

Finally, medicines. Indisputably, we want these to maintain their medicinal properties even after we have opened the container. Essential reactive ingredients need to be formulated such that they don’t break down when exposed to heat or moisture. Otherwise, medicines would be far more expensive and equally far less useful.

Consumption

This ties into the marketing section somewhat, as many of the formulated products we buy are for consumption. It is important to instil pleasant scents, textures and flavours into foods and soaps, but also into medicines to enhance patient compliance.

However, it is important that products must be safe to consume as well. Reactive ingredients are included in products simply because they react with the body in some way. But it is undesirable to expose the body to too high a concentration, as they can be irritant or even toxic. Formulations both dilute these chemicals and structure the mixture so that they are released more slowly.

Delivery

This section I have included predominantly to discuss medicine formulations. And this is the area in which drug companies expend most of their research, so I am unlikely to do more than touch upon it here.

drugs-1328529

Drugs cannot contain chemicals that are toxic to the body. Unless they need to, for therapeutic purposes.

This is the paradox that drug companies encounter with their products. Any effective drug will alter the activity of a cell, protein or receptor within the body. And therefore we want the drug to do this only where it will help us.

Drug molecules must therefore be formulated to be released only where we need them, and to release at the correct rate so as to be effective. Many tablets are broken down by the acid in the stomach, thereby releasing their drug loads. These drugs are therefore formulated such that they will have a high enough dose to hopefully reach the area of interest even when delivered to everywhere else in the body simultaneously. But equally, they must be formulated such that they will not cause damage when they are non-specifically delivered to areas outside that of interest.

For this, drugs must not have toxic break-down products that will damage the body when they encounter the rest of the gastro-intestinal system or are broken down in the liver. Chemists that know their drug will be broken down in a particular organ can alter them chemically such that only their breakdown product will be reactive (enhancing the slower release profile).

Much of the specificity drug delivery process is covered by the actual structure of the drug lead compound – this is why we have hybrid protein or polymer conjugates on the market. But the role of the Formulation Scientist must not be underestimated.

 

 

References:

(1) An excellent online resource on cosmetic chemistry, which is a form of formulation science.

(2) The RSC subgroups pages on formulation.

“What are all these chemicals for?” – aka, a very basic primer on Formulation Chemistry

Formulation Science?

I’m currently studying for a PhD in Chemistry, and yet never during my Chemistry Undergraduate or Postgraduate career have I come across any modules or even seminars touching on formulation science. This is largely because formulation science is seen as an industry staple, something that doesn’t have a place in more blue-sky, academic research such as university is geared towards. Formulation, outside of industry, is considered more something that a good chemist will be able to pick up on the job.

And yet, it is an absolutely crucial discipline. Formulation scientists do exactly what you might expect from the name: formulate the complex mix of chemicals that makes up a tablet, powder, aerosol, gel, cream (etc.). Without them we wouldn’t have shampoos, deodrants, paints, medicines and even some foods.

But why all the chemicals?

Funny how you might ask that, reader, but everything is made up of chemicals. Foods found in nature actually have a colossal number of different chemicals in them. This is because a very delicate balance is required to maintain a stable, pallatable formulation.

19cththprtrp4png

Having a mix of chemicals means you can more finely tune the properties of a particular substance. Think of it like a carrot cake.

Formulating a Carrot Cake

In all cakes, you need butter, margarine or oil to lubricate the mixture and enhance the texture of the finished product. For a carrot cake, you also need self-raising flour and baking powder. Proteins within the flour form a network of gluten when mixed with moisture, which allows the cake to rise. Baking powder creates bubbles of air in the mixture which enhances this rise.

To enhance the flavour of our carrot cake, we also add in some cinnamon, nutmeg and ginger. Sugar also enhances the sweet flavour of the cake – but in addition it absorbs moisture from the mix and thus avoids the cake from getting too hard.

Carrots and orange zest are also needed to tune the flavour of the cake (the former giving the cake its name, after all). However, these ingredients also add moisture to the mix that it would not have otherwise. The quantities of the other ingredients must thus be altered to allow for the inclusion of the wet fruit and vegetables to stop the final product being too dense.

Last but certainly not least: eggs. Eggs are an emulsifier, meaning they can help in the combining of oily and watery mixtures. In cake, they help to combine the liquid and solid ingredients into an even mix. And this is even without thinking about the icing!

carrot-cake-1562464

So you see, it is essential to consider the exact properties you need for your final product, and to tailor the ingredients to ensure you achieve this. I’ve found that chemists are well-suited to baking for precisely this reason: they appreciate the complexity and intricacy of a good formulation.

 

References:

(1) An excellent online resource on cosmetic chemistry, which is a form of formulation science.

(2) The RSC subgroups pages on formulation.

(3) Article showing three naturally occurring foods’ chemical “ingredients list”.

Problems in Pharmacology: The Unexpecting Guinea Pigs

 

Clinical trials are the bane of doctors and researchers alike. They are expensive, they rarely pay off, and they take a long time. But of course no one wants a situation where we simply don’t test drugs before we give them to vulnerable patients. The consequences of under-testing are dire, and it still happens that drugs get withdrawn (as a case study, have a look at Benfluorex’s staggered withdrawal in the EU).

Much as it is clear that drug trials are essential before their widespread introduction to a hospital drugs chart, it is also clear that there are risks involved.

On Clinical Trials

The clinical trial process goes something like this:

  • Several months testing in up to 100 healthy volunteers to assess its safety and appropriate dosage (though the latter will vary depending on the patients’ condition).
  • Up to 2 years testing in a few hundred patients with the disease of interest to assess efficacy against the disease and side-effects.
  • Several years’ testing in up to 3000 individuals with the disease of interest to further assess efficacy and side-effects.
  • There may then be a 4th phase of testing to further assess the safety and side-effects if not enough is known.

There are several reasons why clinical trials are expensive, why they fail, why they take so long – these are things I could easily spend a whole post discussing. What we are talking about here is just SAFETY.

waiting-room-1631142So why is it that, after a whole clinical trial, things can still go wrong?

My favourite word to describe patients is “idiosyncratic”. And it fits perfectly here. Patients are idiosyncratic, different, individuals. They have different bodies, different organs, different cells, different DNA, and therefore their reaction to a chemical being ingested or injected is going to differ from another person.

Sure, we can look at measurable variables such as age, height and weight and predict how these affect a patient’s response to a drug. We can even sequence someone’s DNA and look for heritable characteristics that predict a response as well. But there’s an infinite number of non-heritable characteristics, and non-nuclear DNA to account for as well.

So why do we use drug trials, if they’re so very useless? Simply put, it’s the best thing we have. With novel gene-sequencing technology available to us, we may be able to streamline the process quite a lot in the future, but it’s likely to still be imperfect. Especially as so many life-threatening disorders and diseases only manifest themselves beyond the point of no return.

 

Who are the guinea pigs?

At the beginning of the year, the Independent published an article about the three most recent drug trials that led to devastating consequences for the volunteers. I’ll link it here as a summary of what can go wrong for the guinea pigs choosing to participate in drug trials.

Other than these participants, there are two other groups that effectively are treated as guinea pigs: children and pregnant women.

baby-hand-1-1316351It is precisely due to the risks outlined above that we do not include the “at risk” groups of children and pregnant women in clinical trials. Side-effects that could be a minor inconvenience in a healthy individual are exacerbated drastically in unborn children and young people as they could effect their development.

This means that a paediatrician must rely on their expertise and experience alone to prescribe adult-tested medicines on children: tailoring the dosage to the child’s height and weight. As explained above, this isn’t enough. As adult patients’ bodies are idiosyncratic, a child’s body is an entirely different matter. There are countless chemicals running around that we don’t see in an adult, that may interact with the ingested drug in an adverse way.

In addition to the difficulty in predicting side-effects, adherence to a medicine regime is also more tricky. Children don’t want to take in nasty-tasting drugs (I personally would only take sweet-tasting cough syrups), and they don’t want to have to take several at once (which may be necessary in combination therapy).

 

Teratogens

Pregnant women are also guinea pigs. This means that a gynaecologist must make the same judgement calls as a paediatrician must with children, and these choices affect not only the pregnant woman but their unborn child as well.

As stated many times in this post, it is difficult to predict the activity of a drug in an individual. It is especially difficult to predict the activity of a drug in an individual who has not yet been born. In particular, it would be useful to know just how much of the drug is sequestered by the fetus. The mother and child have a semi-permeable barrier maintaining the separation of their blood systems. As with the testing of a drug’s ability to cross the blood-brain barrier, we need to know how much of the drug crosses this membrane in the placenta to know how much will be taken in by the unborn child.

a-baby-s-coming-1442252

This lack of knowledge leads to doctors estimating the appropriate usage of a drug. In fact, it is not unheard of for doctors to prescribe a drug to a pregnant woman for off-label purposes (ie. for purposes other than it has been tested for).

Thalidomide is a terrifying word in chemistry. It has come up in my education separately at least half a dozen times, and with good reason. If you need to brush up, have a look at this Wikipedia article or this article by the Science Museum. Notably, this is a case in which a drug used for morning sickness led to teratogenic effects in unborn children (ie. birth defects).

Inside their mother’s body, the fetus grows from a single cell to form a full baby. This process follows a delicate series of chemical signals within the developing child to ensure that the baby is born fully formed. It therefore follows that anything affecting the chemical environment the developing child is subjected to will have an effect on its development.

The Bottom Line

We need to somehow safeguard child or pregnant patients against preventable adverse effects. There are indeed clinical trials involving children in existence.

We know that clinical testing has an inherent risk, but we do it anyway because the risk in a clinical trial is far lower than going without. That is why it makes sense to test (with due care) in these vulnerable patient groups.

So why are we still lacking data? Unfortunately the issue comes down largely to funding. As with infectious disease drug trials lacking momentum due to less chance for profit from poorer countries, trials that have smaller target patient populations are less common because the final drug brings in less money. There’s less financial incentive to offer trials just for these select patient groups.

The cynic’s bottom line: we need to encourage funding in trials in these essential patient groups!

 

 

References:

  1. European Medicines Agency document recommending Benfluorex withdrawal.
  2. Chemistry world article on Benfluorex.
  3. The FDA’s site on the Drug Development Process: Clinical Rsesearch.
  4. The Independent’s article “The troubled history of clinical drug trials”.
  5. Page on placental transport.
  6. Thalidomide articles: 1, 2.
  7. WHO page on Clinical trials in children.
  8. NIH page on Clinical trials in children.

Images used: 12, 3

Five shorter (political) stories: 2

 

The UK is a worrying place to live at the moment, with soothsayers preaching about economic, social and environmental collapse at every street corner (or posting about it on Facebook, at least). This makes it a perfect time to post a few stories about factors leading to political persuasion! In science we trust.

Research by various political scientists has suggested that around half of the variation in political preference is heritable (that is, determined by our genetic makeup). In this post, I’ll be talking about non-heritable (that is, social and lifestyle) factors that affect political persuasion.

Birth order

It may well affect political persuasion. There have been various studies suggesting the impact of birth order, including one in which parents’ social persuasion was not linked. Though it is difficult to ascertain why, it has been suggested that this is due to the “dominance hierarchy in the sibling relationship”. It is suggested that being the first born fosters a sense of privilege that leads the offspring to swing towards favouring the “political status quo”.

Siblings and stereotypes

Men raised with sisters tended to be more conservative according to a recent study. This has been proposed to be related to the attitudes related to gender roles instilled from a young age. Boys with sisters will see their sisters encouraged to engage in household chores and more “girly” pastimes (toys are still very gender segregated to this present day, though attitudes seem to be changing gradually). This early gender stereotyping may translate into more stereotyped roles, again maintaining the status quo, in later life.

Conversely, growing up with a sister had no effect on young girls. In addition, the study has suggested that the effect decreases as the young men grow up. Unfortunately (though not related to this story), the data did show the persistence of gender stereotypes for longer.

Personality profiling

A study has suggested that political persuasion can be predicted as a function of 5 personality traits: Openness, Conscientiousness, Emotional Stability, Extraversion and Agreeableness.

Openness and Conscientiousness were found to be the best predictors, with more of the former correlating to conservatism and more of the latter correlating with more liberal attitudes. The other traits varied more, though Emotional Stability and Extraversion had moderate links to social conservatism but more effect on economic persuasion. Agreeableness, conversely, was related to social conservatism by economic liberalism.

These data in particular suggested that politicians with certain values could have predictable views on an array of policy domains, which is supported by the relative cohesion within a political party relative to beyond.

Oxytocin: the “moral molecule”?

Oxytocin plays a role in social interaction, particularly during sexual reproduction and during and after childbirth. It has been shown to be related to the formation of monogamous pair bonds in humans and other species.

Research undertaken in the Center for Neuroeconomics Studies (CNS) in the US investigated the role of oxytocin in political persuasion. Synthetic oxytocin (or placebo) was administered to volunteers (not females due to its affect on the menstrual cycle) and they were asked about their feelings towards various political figures.

Those of a Democratic persuasion showed more warmth towards their opponents with than without oxytocin, whilst it had no effect on Republicans. This data suggested that those who lean more to the left are less fixed in their views and are more affected by their emotional response.

Voting participation and stress

Though not related to political persuasion, another hormone may have an affect on voter turnout.

A small study explored how cortisol (often dubbed “the stress hormone”) may have an effect on voting activity. Lower cortisol levels in the afternoon were associated with increased voting frequency, but not with non-voting political activity (such as campaining). Baseline cortisol levels predicted behaviour that was not affected by demographics.

Cortisol is a hormone that can also predict participating in social interactions. The paper’s authors note that, as political activity is a stressful undertaking, it makes sense that those with lower stress thresholds might avoid engaging.

The other factor most highly affecting voting turnout was age, with older people voting more often. This study suggested that hormone levels, as well as demographics, should be taken into consideration, however.

 

One thing to note is that much of this research is that it is based primarily on surveys conducted where participants self-report. Although participants have no reason to lie in such studies, there is always the chance. But data on these larger scales is likely to be fairly indicative, and statistics do not lie (most of the time).

 

A note from the author: As I sometimes write on emotive subjects, comments are disabled after 14 days. This is because ongoing discussions tend to stagnate.

Microbiomes and Moods

Our Friendly Gut Bacteria

The recent discovery of the importance of our Microbiome (our “friendly” gut bacteria) has served as a critical reminder to medical researchers that the body does not exist as a series of disconnected notes or phrases, but as a wondrous song with many interconnected melodies and harmonies that each play an essential part. Of course, this is what makes the human body so interesting and wonderful, but it’s incredibly difficult to take into account as a researcher. In fact, a lot of good research comes out of being able to tease out the causal relationship between individual factors and their response.

There are few areas where this is more evident than in mental health research. Various studies have linked depression to inheritance, social factors, general health, drugs, alcohol, hormone levels and the list goes on… But unfortunately a physician cannot counter all these different issues. They require complex intervention that amends all aspects of a person’s life, in many cases.

 

Using the Microbiome in Medicine

Sometimes this can be all too overwhelming. How can we treat something that is no more under our personal control than government legislation? And this is before we take into account the diagnosis. Mental health practitioners cluster certain behaviours under the umbrella of a certain disease type so as to be able to try certain treatments that have worked for people with those conditions in the past.

carrot-kale-walnuts-tomatoes

The recent research into the Microbiome has suggested that it may serve as a valuable fingerprint, as another way in which we can identify specific areas in which a person’s body deviates from the “healthy norm”. Using this data we could look for critical changes in bacteria levels that may account for nutritional deficiencies or changes in hormone/chemical levels. And this can all be altered by simply altering what we consume.

This gut-fingerprint would simply mean taking a sample of stool from a patient and analysing the different bacteria levels, and then treating their abnormalities with probiotics or even just bacteria. This has been proven to work by several landmark studies into “faecal transplants” wherein unhealthy mice were given healthy stool to successfully fix various disorders.1

What About Mental Health?

So let’s get back to the original premise. Depression in particular is a challenging disorder to treat because patients are idiosyncratic. Unlike in many disorders, it is hard to tell which treatments would be successful. So what if we could find a potential cause of depression by looking at someone’s poop?(1)

black-and-white-person-woman-girl

That’s just what has been done by several research groups.(2) Many neurotransmitters (used by our brain to talk to itself and other tissues in the body) are produced by bacteria. In particular, serotonin is produced almost exclusively by our Microbiome in adults (80-90% of the body’s serotonin can be found in the intestines). This means that changes in the levels of the serotonin-producing bacteria of an adult can seriously alter the levels of serotonin in their brain. This link is key because serotonin is a key mood regulator in our brain. Specifically, low levels of serotonin or less receptors for serotonin has been implicated in depression, as well as anxiety, panic and anger disorders.

Other work has implicated the Microbiome in GABA-signalling. GABA action is related to calming nerves and treating anxiety. Mice that are stressed during their pregnancy pass on less of a GABA-secreting bacteria to their pups: and these pups thus have lower levels of GABA.

It’s hard to measure depression in mice, as unfortunately they do not respond particularly well to counselling and certainly will not tell you in detail how they have been feeling since you last saw them. But there are certainly some factors we can look at, such as behaviour. Researchers can clearly see if mice are acting less sociable with their peers. They can also do experiments to see if mice give up on impossible tasks earlier, such as in a test where they are unable to escape a tank of water. Those who give up earlier display a higher level of “behavioural despair”.

Mice that are not exposed to the normal levels of serotonin- or GABA-producing bacteria show adverse effects in these behavioural tests, which are reversed upon application of probiotics. Other research undertaken elsewhere has shown the effects of the gut bacteria Bacteroides fragilis in autism, and how mice with “autistic traits” such as repetitive behaviour acted more normally with probiotics. These results have implications in the treatment of autism.

Research has thus shown that the gut Microbiota are affected by stress, development and diet. In turn (in just this look at mental health) the Microbiota can have an affect on our hormone and chemical levels, which has widespread effects on signalling in the brain. This research has massive implications in the types of therapies we could use in these disorders in the future. Much of what is currently used affects receptors in the brain – whereas these therapies could, in theory, target chemical level imbalances at the source.

Our little bacterial friends, in only the short time in which we have been focusing our research on them, have already proven to have massive effects. I’m sure we can look forward to even more advances in the future!

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 4 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

 

Postscript: Going Forward with Mental Health Research

The evidence for trying probiotic treatments for mental disorders in humans looks good! It could be argued that the evidence for this has existed for a long time, and it has. A lot of the chemicals we use in our bodies originate in our gut, and from food we eat. Approximately 50% of patients with Irritable Bowel Syndrome (a condition that requires sufferers to restrict their diet) have anxiety and depression, and this makes sense.

So why have we not considered this before now? Really, interest in research into mapping the human Microbiome only fully began since the Human Microbiome Project plans began in 2007. Why did we not consider before looking into something that weighs about as much as our brain? It’s hard to imagine, but we have only very recently (within the last century) begun to understand a lot about our bodies, particularly the brain. Medical research has come on leaps and bounds since the 19th century, and it is accelerating.

The problem with mental health research is that, in some ways, it has lost its way. In many disorders we have psychopharmaceuticals and psychiatric therapy, and these two unrelated things are combined. The value of both of these two avenues is indisputable, but they are diverging. Alas, the nature of cross-discipline research does not necessarily end itself to cross-discipline therapy. Practitioners trained in one or the other find it difficult to cross over, or may not even want to. It’s the same as asking a heart surgeon to treat an infectious disease, effectively. But it shouldn’t be. Modern medicine is moving ever onwards towards personalised therapy, where every aspect of a patient should be considered in every aspect of their treatment.

In this way, I see this probiotic research as being a bridge that reminds us of what we already know: that considering the patient as a whole rather than a sum of parts is essential to medical practice.

As a special note for this postscript, I would like to point out that I am a chemistry lab researcher with some experience working in clinical science laboratories and with medics. This article is written from my own knowledge, my own experience, and therefore any alternative views are very welcome!

 

 

References:

Independent Article

NY Times Article

(1) Michaelides, M., and Hurd, Y. L. (2015) More than a Gut Feeling : the Microbiota Regulates Neurodevelopment and Behavior The realization of the importance of the. Neuropsychopharmacology 40, 241–242.

(2) Kelly, J. R., Clarke, G., Cryan, J. F., and Dinan, T. G. (2016) Brain-gut-microbiota axis : challenges for translation in psychiatry. Ann. Epidemiol. 26, 366–372.

If you’re interested in more information, please have a look at the work of the researchers at University College Cork and McMaster University, there is some fantastic stuff :D.

 

Ars Medendi reads: Do No Harm

The Book

Do No Harm – Stories of Life, Death and Brain Surgery

Henry Marsh

Weidenfeld & Nicolson, 2014

What it’s about: A Summary

I don’t want to spoil the book by giving too much away in this summary. I would simply say that, if you are looking into a career in the medical profession, this book is an excellent resource.

Simply, Do No Harm is the memoirs of a senior neurosurgeon, from the beginning to near the end of his career. It encompasses the good, the bad and the ugly of his field and medicine as a whole.

I would not say that Henry Marsh is a good role model for budding doctors. I would instead say that he acts as a reminder to all that doctors are as human as the rest of us.

On the Author:

Henry Marsh is one of the UK’s foremost neurosurgeons. It should be noted that, although I felt that only a cursory amount of attention is paid to his work in Ukraine in the book, the film The English Surgeon details this in far more detail. If you find this book to your tastes, it is worth giving the film a watch.

 

The Review:

“It is not surprising that we invest doctors with superhuman qualities as a way of overcoming our fears. If the operation succeeds the surgeon is a hero, but if it fails he is a villain.”

Henry Marsh is only human. In his memoirs he publishes truly honest, sometimes disturbingly honest, stories of his daily life and work. In it, he challenges the basis of the age-old Hippocratic oath “Do No Harm”, by reminding us that, in their humanity, doctors and even surgeons make mistakes more often than we care to admit. Even truly excellent ones! In fact, all fields of medicine and all treatments come with risks that cannot always be accounted for. Walking along the corridors of a nursing home, he recognises “at least five” of the residents as his own failures. And these failures are what populate the book from page 1. “The idea that neurosurgery is some kind of calm and rational appliance of science… is utter crap.”

In fact, Marsh provides a window into his world in a very honest sense. Neurosurgeons must, on a daily basis, make life-changing, or life-saving, decisions that could lead to immense success or utter failure. It is with this dilemma that Marsh presents us.

In the course of the book, we also can see the sacrifices made in the pursuit of becoming an excellent neurosurgeon. The career served to shape Marsh’s character, such that he feels a certain entitlement as a result of his importance at work. One particularly memorable example of this is the moment in the book where, after performing a protracted operation, he expresses frustration at the menial world outside the hospital by imagining asking the person in front of him in a supermarket queue “What did you do today?” It is this frank self-awareness of how pompous he sounds that makes Marsh somehow so relatable.

Marsh, conversely, approaches the subject of being treated as a patient by his colleagues, and seeing his close family treated as well. It is through this intense vulnerability that he understands the plight of his patients. Through the connection Marsh makes to his patients, we can see the powerful exhilaration in performing a successful procedure to save a life. It is the wonder that Marsh feels that we also feel, even starting as a trainee first working on the brain, “a mystery… as great as the stars at night and the universe around us.”

And yet, the book still feels like a cautionary tale of the old ways of medicine: strict hierarchies where the senior doctor’s word was law. The world Marsh trained in, whose values are so ingrained in his practice, is gradually fading away, turning him into an “impotent and angry victim of government targets”. And it is being replaced with fresh bureaucracy, new management structures, corporate training programmes and regulation of junior doctors’ working hours. We can all certainly relate to the bizarre frustration he feels at current juniors being free of the excessively-long hours he endured as a trainee, but he also describes with understandable anguish administrative staff brought in purely to police government policies and agency staff that do not know the whereabouts of their patients.

It is with these thoughts that the book ends. It is an appropriate finish to a book that encompasses the daily thoughts, successes and failures of a human being who is also a surgeon. And really that, in itself is poignant in this new era of personalised medicine: in the same way that doctors must view patients as human beings, we must acknowledge that doctors, too, are people with their own hopes, desires and full lives.

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 14 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

Ars Medendi reads: The Man Who Mistook His Wife for a Hat

The Book

The Man Who Mistook His Wife for a Hat

Oliver Sacks

Picador, 1986

What it’s about: A Summary

Welcome to the world of a neurologist. Oliver Sacks compiles many case studies he has published in medical case journals. These serve both as incredibly insightful looks at particular neurological disorders.

This is the only one of Sacks’ books I have read, but it is the most iconic. And it is worth a read for anyone interested in the subject area. In fact, I would recommend it as a window into the personal nature medicine takes on especially in matters of the brain, our most misunderstood organ.

The Review:

“Constantly my patients drive me to question, and constantly my questions drive me to patients – thus in the stories or studies which follow there is a continual movement from one to the other.”

Throughout the book, Sacks refers to Luria’s neurological case work, and he uses his extensive knowledge to craft the cases, peppering them with appropriate quotations and scientific context. And yet throughout, the patients are depicted as profoundly human and deeply sympathetic. It is these patients that lie at the centre of the book, and at the centre of Sacks’ life.

Oliver Sacks’ book is varied by the different tales in it. Therefore it stands to reason that a review should look into each section separately.

Losses

This section of the book encompasses the deficits, or the “A”s – Aphasia, Ataxia, Agnosia etc. It is this section which includes the iconic “The Man Who Mistook His Wife for a Hat” – the true story of a man unable to visually process shapes and assign them with identify. It is for this reason that, during his interview with Sacks, he “took hold of his wife’s head and tried to put it on”. This section of the book explores the impact of memory disorders. Another story “The Lost Mariner” describes a man trapped in his past, unable to form new memories or understand his present.

Excesses

This section is perhaps the opposite to Losses, comprising of manias and hyper-activities of the brain such as Tourette’s. Striking is the story of one man plagued with the latter (“Witty, Ticcy Ray”), wherein the patient decides that he will only undergo treatment by Haldol for his condition on certain days of the week. It is in this way that we can understand how intrinsic the workings of the brain are to a person’s personality and creative ability; such that, perhaps, we cannot treat the former without affecting the latter to a degree.

Transports

This section is exactly as it sounds. Stories of patients transported elsewhere by their brains. “A Passage to India” is a story of an Indian girl with a malignant tumour that expanded to compress areas of her brain. It is at once a melancholic and beautiful tale. In a way, her visions of India were her salvation from an impossible prognosis, as understood fully only by her: “I like these dreams – they take me back home.”

The World of the Simple

It is this section that explores the world of the “autistic savant”: those dismissed due to their placement on the autistic spectrum, but who have intense creative or mathematical talents. “A Walking Grove” is the story of a man with severe developmental deficiencies able to ”retain an opera or an oratorio on a single hearing”. Is it through these abilities that he develops with relationship with his musical father, despite being unable to express himself through other means.

Bottom line: if any of these cases sounds interesting to you, I highly recommend picking up this book. It is truly extraordinary.

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 14 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

Ars Medendi reads: The Noonday Demon

The Book

The Noonday Demon – An Atlas of Depression

Andrew Solomon

Scribner, 2003

What it’s about: A Summary

First of all, I have to say: the book is LONG. Very long. It took me maybe two months to read, but then I don’t have much time to read in the evenings after work. Despite it’s length, I highly recommend it.

As suggested in the title the book is an entire atlas of the disorder: providing insight into all relevant areas of context from a personal to a society-wide level. What the title doesn’t tell is how beautifully written it is.: “In depression, the meaninglessness of life itself, becomes self-evident. The only feeling left in this loveless state is insignificant”.

I would recommend a read for anyone suffering from depression, or interested in the disorder.

On the author

Andrew Solomon is a journalist, and this is evident from the sheer volume of research and detail going into the book. In the book, he often brings in his own experience into the writing, laying bear his vulnerabilities and the devastation depression has wrought to his life.

The Review:

“My depression has grown on me as that vine had conquered the oak; it had been a sucking thing that has wrapped around me, ugly and more alive than I. It had had a life of its own that bit by bit asphyxiated all of my life out of me.”

The strength and power of The Noonday Demon lies with the dozens of stories that feed into it. Each is the story of an individual, but they together give valuable insight into the understanding of one of the world’s most prevalent diseases.

Although the author admits he is not a scientific expert of any kind, his dedication to studying depression is shown through his detailed exploration of the disorder from its historical, cultural and political roots, to its chemical pathways and various treatments. And, as I mentioned before, the writing is at once compelling and stunning. The story of the author is interwoven with an exploration of all the aspects of our modern day (and historical context) that cause so many to suffer from depression.

In Breakdowns, the author explains the debilitating acute condition, and it is a powerful read. The author then goes on to describe talking therapies (those which come out of traditional psychoanalysis and are subscribed to by psychiatrists) and the physical interventions (from psychopharmacological therapies to harsher therapies such as electroshock therapy).

Both types rely on restoring a “normal” balance to the patient, both in encouraging positive thought and constructive action, and in restoring chemical balance. And both are personalised to the idiosyncratic patient’s needs, and must work together. In particular, antidepressants are chosen primarily based on their side-effects, something which is at once paradoxical and essential as many are incredibly unpleasant even now: “you take antidepressants like you take radiation for cancer.” Solomon also does not avoid discussing alternative medicines. This is particularly important due to the tendency to hail Prozac or nothing, despite the availability of alternative therapies of all types.

The next sections describe the various aspects of a person’s life experience that can lead to the depressive condition. It is in these sections that the stories of depressives truly shine and make the reader understand the importance of different cultural prejudices, addictions and poverty. He does not overdramatize or sweep these issues under the Prozac blanket as is so often tempting in the media. And yet he depicts the cycle of depression experienced by all too many people in our society.

Overall this is an honest, stark text depicting the often under-represented truths about depression as well as those we have heard often. Aptly, the final chapter is simply title Hope.

“Some people suffer mild depression and are totally disabled by it’ others suffer severe depression and make something of their lives anyway.” It is hope that makes the difference.

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 14 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

Ars Medendi reads: The Man Who Couldn’t Stop

I have absolutely no illusions about this blog, and I am fully aware that the majority of the time I’m talking to myself. So I thought it would be worthwhile starting a new feature where I review books I have read. If you are reading this and have yourself read the book I am reviewing, I’d love to hear your thoughts!

 

The Book

The Man Who Couldn’t Stop

David Adam

Picador, 2014

 

What it’s about: A Summary

Broadly speaking, the book is the personal story of our author’s struggle with Obsessive Compulsive Disorder (OCD), interspersed with vital information on the historical, political and medical context of the disease. I adored this book.

It gives a slice of life into the struggles of an OCD sufferer, whilst educating you in an fascinating way that shows you it is more than just a “behavioural quirk”. The straightforward way in which the author reveals his deepest, darkest obsessions is both compelling and incredibly insightful for someone who has never truly understood the disorder before.

It is separated into different sections, each providing a different context for the development of the modern disease model and treatment. The writing style is also of note for its scientific and yet personal nature.

 

On the author

David Adam is a writer and editor of the journal Nature. That he was a correspondent for The Guardian whilst in the thralls of his disorder speaks volumes for his bravery.

 

The Review:

“An Ethiopian schoolgirl names Bira once ate a wall of her house… By the time she was 17 years old she had eaten eight square metres of the wall – more than half a tonne of mud bricks.”

It is hard to explain a mental disorder to one who has not studied medicine, and yet, from this book, I feel as though I have seen through the eyes of a person with OCD. At times hard to read and at others impossible to put down, I found that the take home message was simply that of enlightenment. Enlightening readers that no one is “a little bit OCD”; but that OCD is a serious condition that is frustratingly, and painfully, hard to treat (consider the famous “white bear” experiment referenced throughout this book).

In terms of historical context, the existence of OCD in the religious community, the animal world, and the difficulty of its treatment even up to the current day are explored. The grisly chapter on lobotomies is particularly striking, with almost unbelievable tales of “brains irreversibly damaged by cavalier surgeons armed with nothing more precise than knitting needles”.

These contextual sections at times descend into an Oliver Sacks-like description of patient cases, which is incredibly compelling (amongst the more well-known being Phineas Gage and the Collyer brothers). Also of note is the amusing use of paradoxical Freudian psychoanalyses, encouraging OCD sufferers to obsess more deeply into their intrusive thought, as a more “successful” early treatment.

The book also chronicles evolutions of diagnosis, and how it is essential that we consider such psychiatric disorders on a sliding scale rather than as black-or-white diagnoses. Also key to consider is the importance of personalised medicine, and further research into the use of behavioural therapies as well as drugs to treat patients where it is not possible to pinpoint something “physically” wrong.

I recommend this book to anyone curious about OCD or any psychiatric disorder.

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 14 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

Let’s have a talk about homeopathy

A note from the author: As this is an emotive subject, comments are disabled after 4 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

 

As my first post in a very, very long while, I thought I’d post an extended discussion about some aspects of homeopathy.

Homeopathy is an alternative medicine (as stated in Tim Minchin’s famous song), based on the theory that “like cures like”.(1) This means that “a substance taken in small amounts will cure the same symptoms it causes if it were taken in large amounts”.(2-5)

As I work as a research Chemist, I have to state that I am biased when it comes to alternative medicine. To me, science must be evidence-based to have value; and thus medical practice, which is based on the science, should also be inherently evidence-based. By “evidence-based, I mean there is insufficient scientific research to justify the inclusion of homeopathic method in the standard library of standard medical treatments.(4)

However, in order to fully examine the potential of this theory, I believe it is worth discussing some instances where the homeopathic approach might actually be successful. In doing so, perhaps we can find a reason for the use of alternative medicine by so many people.

 

Successes: X-rays

 

In the modern age, cancer treatment is either through the use of chemicals (chemotherapy) or radiation (radiotherapy). X-rays were discovered in 1895, soon after which scientists unlocked their use in therapeutic applications. In 1986, Emil Grubbé (a physician with training in homeopathy) assembled an x-ray machine and used it to treat a recurrent breast carcinoma.(6)

Though unsuccessful at first, Grubbé’s treatments were potentially more successful than others due to his use of lower exposures for less time, and throughout the rest of his life he taught many others his techniques. X-ray radiation therapy today actually uses a “fractionated” process where low doses are administered over a longer course of time to minimise side-effects.(7)

Homeopathic theory in the case of X-rays works because they kill cells. Therefore it stands to reason that a low dose is best to avoid killing the desired cells. Our intrepid homeopathic physician, Grubbé, unfortunately, fell foul of the damage that X-rays can do at higher exposures, and himself had to undergo many surgeries to treat recurrent cancers.

 

Successes: Hay Fever

 

As another example of homeopathic “success”, let’s look at hay fever.(8-11) The majority of people with hay fever can simply avoid the pollen that triggers it in various ways, or take anti-histamines. Those with more sever allergies may be referred to immunotherapy. Immunotherapy is a treatment where the body’s immune system is exposed gradually to increasing levels of the allergen (pollen), such that their immune cells become tolerant.

The reason to only gradually increase the dose is to minimise side-effects, but this does mean that it takes a long time to reach the point at which the patient is “cured”. At this point, they must take maintenance doses to sustain tolerance. It stands to reason, then, that exposure to allergens (at a homeopathic dose) would potentially reduce the symptoms for some hay fever-sufferers as a form of immunotherapy for those with less severe symptoms.

 

Why successful?

 

So what do these two “successes” have in common? Both are situations where the homeopathic approach happens to coincide with what we currently use in medical practice anyway. They work because exposure to X-rays kills cells, and we want that to happen in cancer treatment. Lower doses result in less peripheral cell deaths and thus less side-effects. They work because pollen induces immune cell responses. Lower doses result in less immune cell responses and thus less side-effects (and thus immune cell tolerance). These are both therapies where evidence exists for their success.

 

As Tim Minchin says, “Do you know what they call alternative medicine that’s been proved to work? Medicine.”(1) But that’s not the appeal of homeopathy.

Stripping down the theory, people like homeopathy because it is “natural”, using the same “natural” cause of a disorder to fix it. And they like it because it has few side-effects. Let’s explore these things.

 

The Unfortunate truth

 

Alas, this is where I look less optimistically into homeopathic method. This is because, as a Research Chemist, I am used to spending my days purifying chemicals and diluting them down to acceptable concentrations for use on cells or proteins. Side-effects tend to occur where the given dose of a drug has effects beyond the desirable local effects. The reason that homeopathic remedies have little to no side effects is because the doses are so low as to have no effects in the body.

Dosage

The homeopathic dilution method uses a logarithmic scale, with C being a dilution by 100 and X being a dilution by 10.(12) A 2C dilution is 1 part in 100, repeated twice (so 1 in 1002 final concentration), 6C is 1 part in 100 repeated 6 times (1 in 1006 final concentration). A 10C dilution is 1 part in 10 repeated 10 times (so 1 in 1010 final concentration) etc etc…

As I have never taken a homeopathic remedy, I had a cursory glance at some online shops to see if anything interesting popped up. I found Mercurious Chloride (Calomel, Hg2Cl2 – I will refer to it as Mercurous Chloride, it’s proper chemical name).(14) This is acutely toxic, causes respiratory sensitization and is hazardous to the aquatic environment according to Sigma-Aldrich, but that is not mentioned on homeopathy suppliers’ websites.(13-14) Not to spoil the surprise, but this is likely because of the very small quantities of active ingredients.

Let’s do some Maths. One supplier offers a pack of 160 g of tablets at 6X potency (for £22.35). 6X potency is 1 in 106 – so 0.00016 g of Calomel is in this 160g. From the shop I looked at, each tablet was approximately 0.11 g.

So, per tablet, we are looking at 0.00000011 g of the chemical. This is a tiny, tiny amount.

The amount of mercury in the water supply (determined to be a entirely safe amount that has no effect) is around 1 microgram per litre.(15) So 1 l contains 0.000001 g of the chemical: or, around ten times as much as in a homeopathic tablet. Frankly, this makes it obvious why people claim that homeopathic remedies are placebos (medicines with no therapeutic benefit).

The cost for this 0.00016 g of Mercurous Chloride is also extortionate: considering that 5 g of the pure chemical would cost less than £30, the mark up is therefore more than 2,300,000%. The numbers speak for themselves.

Natural Remedies

I’d also like to briefly step on the issue of “natural sources”. Some Mercury is purified from mined cinnabar (HgS), and this source gives the most “natural” method (the least steps) of Mercurous Chloride production:

Step 1) Cinnabar ore is heated in air and the resulting Mercury vapour is condensed and collected.

Step 2) Mercuric Chloride is formed by adding Hydrochloric acid to this elemental Mercury.

Step 3) This Mercuric Chloride is then reacted with elemental Mercury to form our Mercurous Chloride.

In the modern age, there is an increasing trend to consume “natural” food and to “detox” your body. It therefore stands to reason that people are concerned about putting potentially harmful substances in their body. I completely understand this and I subscribe to keeping a healthy diet. However, it does not apply when it comes to medicine.

Pure chemicals do not occur in nature, and thus natural remedies are not inherently more safe than those prepared in a lab. Chemical intervention is needed in every case to obtain pure substances, whether for purification or (in this case) to actually make the chemical in which we are interested. Regulated homeopathic remedies are always subject to some form of purification before they are sold on. I would be far more concerned about anything unregulated, as you cannot know whether you are consuming something harmful. If the mood calls for it, I’ll be happy to discuss the natural vs. natural debate at another time, but I have no time for it here.

 

But what’s the harm?

 

What is the harm indeed? If people are willing to spend lots of money on something that has no effect, then it is their choice.

This has been discussed before, and I don’t want to retread very well-trodden ground, so I’ll just summarise here. Individuals using homeopathic treatments instead of conventional medicine are spending more money for treatments that, more often than not, do not work.

A good book to read on this issue is “Trick of Treatment?: Alternative Medicine on Trial” by Simon Singh and Edzard Ernst. There are also other articles on the same subject such as here.

 

What can we learn from homeopathy?

 

So here’s where I go back to my original thoughts. What is the potential in homeopathy?

The inherent value of alternative therapy is that people are different. Not all people like to be told that there is one, and only one, way of curing your disease or disorder. Being treated by alternative medicine is like being part of an exclusive club, like being a medical hipster – and there are huge online communities dedicated to discussing it. These communities have their own “experts” – people who have tried homeopathic treatments and recommend them to others. Obviously people like to feel like they understand what’s going on in their own life, and health is potentially the most important aspect. And subscribing to alternative therapy is one way of regaining control.

Is it really worth it though? Homeopathy becomes most attractive where patients are at their most vulnerable. Where patients are scared to take a nasty treatment with known side-effects, or when they have no other available treatment. Homeopathy cuts through the jargon of complex medical treatment and uses simplistic theories that anyone can “understand”. But, in doing so, the industry takes advantage of a patient’s vulnerability.

It’s easy to blame your condition on toxic chemicals and unnatural sources. It’s hard to admit that sometimes your body needs outside “unnatural” help in the battle against a disease, especially if it’s a battle you’re losing. But if you broke your leg, you would get it fixed. Internal “breakages” also need medical intervention.

 

Conclusions

 

What is my conclusion? Listen to your doctor. They are trained in treating human diseases and disorders; in fact, they have dedicated their lives to it. Talk to them about your concerns. If they dismiss them, then speak with them more: it’s their job to listen to you. Nowadays medicine is more patient-focussed and doctors should be willing to work with their patients. Doctors will be able to determine where a homeopathic treatment may be appropriate for you, as in the above cases.

If your condition is beyond help with conventional methods, by all means homeopathy may help you. If your conviction is strong enough that a placebo is sufficient, try homeopathy. But really nowadays homeopathic treatment is best alongside conventional medicine: there’s a reason it’s sometimes called complementary medicine.

If you want to try homeopathic treatment, just make sure it’s from a reputable source, and that it’s safe.

 

 

Postscript:

This blog is my opinion only, and it is largely my personal exploration of homeopathy as a treatment. In the case of X-rays, I have compacted an extremely large amount of information into a short space, so please do have a further look at the literature if you are interested! In particular, I would recommend the book “Strange Glow: The Story of Radiation” by Timothy Jorgensen.

Also, I am aware that I did only one calculation for the homeopathic remedies. So here is another, for fun:

 

Homepathic remedy:

Alium cepa (red onion)

160 g, 3X potency, £22.35

3X potency is 1 in 103

This is 0.16 g onion in the 160 g

Each tablet is 0.11 g; so, per tablet, we are looking at 0.00011 g of onion

 

Tesco medium red onion:

1 onion (according to tesco.com) is £0.16, about 220 g

The amount in one tablet is therefore one two millionth of an onion.

The mark up for this remedy is therefore 19,000,000%.

And another, as requested:

Homepathic remedy: Weleda Sulphur 30c 125 Tablets

125 tablets, at £0.05 per 100 mg tablet
30C potency is 1 in 100 to the power of 30
This is 1 x 10^-61 g of sulphur in each tablet

– Please note that the mass of a proton (the smallest chemical element) is 1 x 10^-23 g. This is less than that. This means that, in one tablet of this stuff, there is not even one atom of sulphur present.

Sulphur from Sigma-Aldrich (chemical company):

This is £26.50 for 1 kg.
The mark up for this remedy is 2.65 x 10^64 %. Which is 265 with 62 zeroes after it %.

References:

  1. Tim Minchin’s song, Storm: https://www.youtube.com/watch?v=KtYkyB35zkk
  2. British Homeopathic Association Website, accessed 19/06/16: http://www.britishhomeopathic.org/
  3. The Society of Homeopaths’ Website, accessed 19/06/16: http://www.homeopathy-soh.org/
  4. Science and Technology Committee evidence check on homeopathy, 8th February 2010: http://www.publications.parliament.uk/pa/cm200910/cmselect/cmsctech/45/4502.htm
  5. Homeopathy on NHS choices, accessed 19/06/16: http://www.nhs.uk/conditions/homeopathy/pages/introduction.aspx
  6. Nice article on the use of X-rays in radiation treatment: http://www.pbs.org/newshour/updates/emil-grubbe-first-use-radiation-treat-breast-cancer/
  7. The evolution of cancer treatments: Radiation, accessed 19/06/16: http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/the-history-of-cancer-cancer-treatment-radiation
  8. Hay fever on NHS choices, accessed 19/06/16: http://www.nhs.uk/Conditions/Hay-fever/Pages/Introduction.aspx
  9. Hay Fever on Allergy UK, accessed 19/06/16: https://www.allergyuk.org/hayfever-and-allergic-rhinitis/hay-fever-and-allergic-rhinitis
  10. Kim LS, Riedlinger JE, Baldwin CM, Hilli L, Khalsa SV, Messer SA, Waters RF (2005). Treatment of seasonal allergic rhinitis using homeopathic preparation of common allergens in the southwest region of the US: a randomized, controlled clinical trial. Annals of Pharmacotherapy; 39:617–624.
  11. Reilly DT, Taylor MA, McSharry C, Aitchison T (1986). Is homeopathy a placebo response? Controlled trial of homeopathic potency, with pollen in hayfever as model. Lancet; ii: 881–885.
  12. Homeopathic preparations, Wikipedia, accessed 19/06/16: https://en.wikipedia.org/wiki/Homeopathy#Preparations_and_treatment
  13. Mercury(I) chloride on Sigma-Aldrich: http://www.sigmaaldrich.com/catalog/product/sial/230405?lang=en&region=GB
  14. Helios homeopathy shop, accessed 19/06/16: https://www.helios.co.uk/shop/mercurius-dulcis
  15. Water purification standards, accessed 19/06/16: http://www.anglianwater.co.uk/_assets/media/Standards_Current.pdf or  http://dwi.defra.gov.uk/consumers/advice-leaflets/standards.pdf