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Entries in Medicine (16)


A time-line for diabetes research

6th century BCE – The first known diagnosis of diabetes was made in India. Doctors called the condition medhumeha, meaning "sweet urine disease", and tested for it by seeing whether ants were attracted to the sweetness of the urine.

1st century CE – Diabetes was diagnosed by the ancient Greeks. Aretaeus of Cappadocia named the condition διαβήτης (diabētēs), meaning "one that straddles", referring to the copious production of urine. It was later called diabetes mellitus, "copious production of honey urine", again referring to the sweetness of the urine. Unlike the Indian doctors, Greek doctors tested this directly by drinking a urine sample. At the time a diagnosis of diabetes was a death sentence: "life (with diabetes) is short, disgusting and painful" (Aretaeus of Cappadocia).

It is probably that the ancient Egyptians and early Chinese cultures also independently discovered diabetes.

10th century CE - Avicenna of Persia provided the first detailed description of diabetes (diagnosed through "abnormal appetite and the collapse of sexual functions" as well as the "sweet taste of diabetic urine"). He also provided the first (partially) effective treatment, using a mixture of lupine, trigonella and zedoary seed.

1889 – Joseph von Mering and Oskar Minkowski in Germany developed the first animal model of diabetes using dogs, discovering the role of the pancreas.

1921 - Federick Banting and Charles Best in Canada first cured canine diabetes by purification and injection of canine insulin.

1922 - For the first time diabetes stopped being a death sentence. In 1922 Federick Banting and Charles Best treated the first human patient with bovine insulin. Notably they decided to make their patent available globally without charge.

1922-1980 - Treatment of patients with animal insulin or human insulin extracted from cadavers. Substantial life extension but also significant side-effects.

1955 - Determination of the protein sequence of insulin by Federick Sanger in the United Kingdom.

1980 - First commercial production of recombinant human insulin, by Genentech.

Today there is no cure for diabetes, but when treated it only results in an average loss of 10 years (the same as smoking).


The ethics of biobanking

The University of Leuven hosted two lectures on biobanking today, one by Hainaut from the International Agency for Research on Cancer and the other by Juhl from the biobanking company Indivumed.

Biobanking is a tricky ethical area, with little consensus and vague law. Who owns the material taken from a patient? The patient? The hospital? The surgeon? If someone wants to use the material, what is the default position? Should the patient have to provide consent or is consent assumed unless the patient opts out? Does the patient even have the right to opt out at a latter time point? Hainaut made the case that there is a moral duty on every person to allow access to their biological samples for the good of humanity. His example was that a excised breast cancer not only belongs to that woman, but also to all other women who may develop breast cancer in the future.

This is an attractive argument but has flaws. If the information generated goes into the public sphere, such that new treatments can be developed and accessed, it may be reasonable to use the moral argument, in the same way that organ donation as the default option can be argued on moral grounds. However, to me this argument is flawed if the information generated does not go into the public sphere. If the information is not published (a secretive researcher or company keeping back information for potential future uses) or if it is published with restrictions on use (ie, patented) that information is not open to all of humanity. Isn't it unethical for a biobank to appeal to the moral duty to all of humanity unless legal restrictions are placed on the biobank to ensure that the proceeds of the bank are available to all of humanity? Doesn't informed consent require donors to be told the status of information generated from their samples?

Unfortunately, Hainaut was not able to answer this question when asked, as Juhl (CEO of a biobanking company that only publishes a fraction of the data it generates) jumped in with a rant about for-profit vs not-for-profit. His contention was that every person acts through the personal profit motive, so that whether the biobank made a profit or not didn't matter. His position is that only private companies have the money to put forward to do the research, and they deserve a profit for the research they do. Perhaps, but irrelevant to the ethical question. If the research outcomes are utilitarian then the utilitarian argument should be put to prospective donors - such as DeCode offering all future drugs free of charge to Icelandic people in exchange for access to the medical records and genome of the Icelandic people. Material can be collected for a utilitarian motive using utilitarian appeals, or for a moral motive using moral appeals. What is unethical is to use a moral appeal to collect material destined for a utilitarian purpose.

Hopefully we will see future legislation reflect the ethical considerations of biobanking in more a more thoughtful manner than was presented today. Donations made by the public for the public good should be legally bound to this use. It is illegal for a charity to accept a monetary donation, keep 90% of the money for personal use and spend 10% on charitable works. Likewise it should be illegal for a biobank that accepts material presented as a public donation to only release 10% of the data produced by the donation, and keep 90% to itself.


Infectious cancer

It has long been known that the several causes of cancer are infectious. Typically a virus contains a number of oncogenes to enhance its own proliferation, and in an infection gone wrong (for both virus and host) a viral oncogene is incorporated into the host DNA, creating an uncontrollable tumour cell. One of the best examples of this is human papillomavirus (HPV), a virus which infects most sexually active adults and is responsible for nearly every case of cervical cancer worldwide (which is why all girls should be vaccinated before they become sexually active).

However these cases are not "infectious cancers", they are infectious diseases which are capable of causing cancer. True infectious cancers, where a cancer cell from one individual takes up residency in a second individual and grows into a new cancer, were unknown until recently. With the publication of a new study in PNAS we now have three examples of truly infectious cancers.

1. In the most recent study, researchers in Japan documented the tragic case of a 28 year old Japanese woman who gave birth to a healthy baby but within two months had been diagnosed with acute lymphoblastic leukemia and died. At 11 months of age the child also become ill and was diagnosed with acute lymphoblastic leukemia. Genetic analysis of the tumour cells in the baby demonstrated that the tumour cells were not from the child herself, but rather maternal leukemia cells that had crossed the placenta during pregnancy or childbirth and had taken up residency in their new host. With this information, retrospective analysis indicates that this is probably not a one-off event, and at least 17 other cases of mother-to-child transmission of cancer have probably occurred.

2. In addition to mother-to-child transmission of cancer, cancer can spread from one identical twin to another. Identical (mono-zygotic) twins have identical immune systems, preventing rejection of "transplanted" cells, unlike non-identical (di-zygotic) twins. Thus a tumour which develops before birth in one identical twin can be transferred in utero to the other identical twin, where it can grow without being rejected. In one improbable but highly informative case, a set of triplets were born where two babies were identical and the third was non-identical. A tumour had arisen in one of the identical twins in utero and had passed to both other foetuses, but had been rejected by the non-identical foetus and accepted by the identical foetus. Of course, with the advent of medical transplantation, transmission of infectious cancers is now no longer limited to the uterus. Transplantation of an organ containing a cancer into a new host can allow the original cancer to grow and spread, as transplantation patients are immunosuppressed to prevent rejection. There is also a single case of a cancer being transmitted from a surgeon who cut his hand during surgery to a patient who was not immunosuppressed.

3. In a medical mystery well known to Australians, the population of Tasmanian Devils has been crashing as a fatal facial tumour has been spreading across the population. The way the fatal tumours have spread steadily across Tasmania and sparing Devils on smaller islands first suggested a new infectious disease that causes cancer, similar to HPV in humans. However a suprising study demonstrated that the cancer was directly spreading from one Devil to the next after having spontaneously developed in a single individual. These scrappy little monsters attack each other on first sight, biting each other's faces. The cancer resides in the salivary glands and gets transmitted by facial bites to the new Devil. Unfortunately for Tasmanian Devils, a genetic bottleneck left all Devils so genetically similar that they are, for immunological purposes, all identical twins. This means that the cancer cells transmitted from one Devil to another through biting are able to grow and kill Devil after Devil. The cancer from a single individual has already killed 50% of all Devils, and it is possible that we will have to wait until the cancer burns out by killing all potential hosts before reintroducing the Devil from the protected island populations. As unlikely as this seems, another similar spread occurs in dogs, where a cancer that arose in a single individual wolf is being spread through sexual transmission from dog to dog around the world. This example also illustrates the point made about cancers being "immortal" - the original cancer event may have occured up to 2500 years ago, with the tumour moving from host to host for thousands of years without dying out.


When you eat matters

A very interesting study has just been published in the journal Obesity. The work, by Arble and colleagues in the Turek laboratory, fed mice high-fat food either during the day or at night. The surprising result was that mice fed during the day put on 20% more weight than mice fed at night. In both cases the mice had unlimited access to food yet both groups of mice ate the same amount, so there was no difference in net calories. Instead, what this result suggests is that the body deals with calories differently at different points of the diurnal cycle. During the active phase (night for mice) calories are shifted into burn mode, while during the resting phase (daytime for mice) calories are stored with greater efficiency.

If this result can be translated into humans it would suggest that large meals should be concentrated in the active phase of the day, breakfasts and lunches, and that evening or night meals should be restricted. An interesting proposal is that the American evening-biased eating rhythm compared to the European lunch-biased eating rhythm is partly responsible for the obesity problem in America. Of course it could only ever be a fraction of the problem, as many other correlates with obesity are well recognised. For example, a study by Pickett and colleages has demonstrated that countries with higher income inequality have higher calorific intake and obesity, and another study by Bassett and colleagues points out that Belgians burn 62 extra Calories per day by walking and cycling, compared to a poor 20 Calories per day by Americans.

The other important aspect of this study is that it contributes to the growing body of evidence dispelling the simplistic "obesity = too many calories and not enough exercise" formula. As published by the Segal laboratory, the majority of difference in body mass index (BMI) is due to genetics (64%). Being overweight does not mean that an individual is making worse eating or exercising decisions than a healthy range individual - the majority of the difference in weight just comes down to the fact that different genetics leads to different metabolisms.


The Placebo Effect

What is the "placebo effect"? The words are bandied around constantly but tend to be poorly understood. Put simply, the "placebo effect" is the medical response of your body to the idea that you are taking drugs, in the absence of actual drugs. How can this occur? There is nothing mystical about this, the effect of mood on brain chemistry is well documented, and the physiological effects of brain chemistry on our body are surprisingly strong. What is more unusual is a question posed by a recent article in Wired - why does the placebo effect appear to be getting stronger in drug trials?

Is this true? Is the placebo effect actually getting stronger? Actually we have no idea. Drug companies never test the strength of the placebo effect. To actually test the placebo effect you need to have three groups: no treatment, placebo treatment and drug treatment. The "no treatment" group measures the spontaneous remission rate (is, the background of how many people would get better over the treated period of time without treatment). The "placebo treatment" group can then measure any additional effects of the patients thinking they are taking drugs, while the "drug treatment" group measures the biomedical effect of the drug. Since drug companies almost never include a "no treatment" group, the increasing effect in the "placebo treatment" group could either be due to increasing spontaneous remission rates or due to an increasing effect of placebos. Changes in spontaneous remission rate are just as feasible as changes in the placebo effect, as the health of the population is generally increasing over time, and a generally healthy person has a higher spontaneous remission rate.

If we assume, however, that it is the placebo effect that is increasing over time, do we have reasonable explanation for this? The answer is probably a lot more simple than drug companies are making it out to be. Changes in the scale of the placebo effect are regionally localised and concentrated in conditions such as depression, epilepsy and pain. The simplest explanation (and hence, according to Occam's razor, the one we turn to first) is that the patient composition of these groups has been changing over time, especially in certain regions. In particular, we have observed large improvements in medical diagnosis, such that more subtle cases are being detected. We have also experienced a "medicalisation" of non-medical conditions, strong moods or emotions being labelled as medical conditions and lumped together with cases caused by biomedical disruptions (ironically driven largely by drug companies seeking to expand their markets). It would be predicted that less severe cases of medical conditions, and emotional/behavioural conditions misdiagnosed as medical conditions, would be more amenable to the effects of placebos on brain chemistry. A simple test for this hypothesis exists - take an existing drug and recruit a patient cohort using identical criteria as the original drug trial. If the "altered patient cohort" hypothesis is correct a new drug trial using past inclusion criteria should show the same level of placebo effect as the original trial.

Of course the real issue for the drug companies is that the drugs being developed and tested are less and less efficacious. The placebo effect is only an issue when drugs have borderline effects. If a drug company invented a new quinine or penicillin there would be no concerns about skating around the edges of statistical significance.


Through the Valley of Death with the Light Brigade

Our main focus today was on Sevastopol. Sevastopol is considered the third best natural harbour in the world (with 39 harbours), after Hong Kong and Sydney. The city was built as a naval city, with Odessa being the merchant port. When Catherine the Great visited it on her first tour of the Crimea, Potemkin (who wanted to impress her) gave her an escort of 10 000 carriages. He also brought with him many Russian serfs and dressed them in satins and gave them bread and salt, setting up props of a village. Then each night he moved the fake village forward so Catherine the Great could see how prosperous he had made her new region (leading to sayings about “Potemkin villages”)

Sevastopol has been the main naval base for the Russian Black Sea Fleet since its development. As an aside, there are three theories for why the Black Sea is called the 'Black' Sea. The first is due to the ancient Greek name, the 'Inhospitable Sea', Pontos Axeinos, which may have later been converted to the Iranian axšaina or Dark Sea. The second is due to the ancient Greek habit of labelling compass directions by colour (and north was black). The third is because of the darker colour of the sea, due to increased algae levels in the top brackish 200m (below that the sea is dead and heavily saline due to low input of freshwater and slow mixture through the Bosphorus to dilute out the evaporated salts, with a layer of hydrogen sulfide separating the two). Anyway, now that Sevastopol is part of the Ukraine, Russia leases the port for $97million/year. The lease is through to 2017, and there is tension as the President of the Ukraine does not want to release it, while Russia of course does (Sevastopol itself is the most pro-Russian of all the Ukrainian cities, due to the large investments from Russia in the city).

Sevastopol was also central stage for the Crimean War. The origin of the Crimean war was an argument over who had the duty to protect the “Holy Land”, with both Russia and England/France claiming the duty to protect it from Islam. After Russia asserted its right by invading Romania (under Ottoman control), England and France (worried about the growing power of Russia) joined forces with the Ottoman Empire (and Sardinia) to push back Russia. They invaded Romania in 1853 and pushed Russia out quite quickly, then moved into the Russian Crimea in September of 1854 in a war which lasted until 1856 and became known for poor generalship, incompetence and stupidity.

The main push was to stop the Black Sea Fleet, which meant taking Sevastopol. The Admiral of the Black Sea Fleet (Admiral P. Nakhimov) scuttled his fleet at the entrance to the Sevastopol harbour, to prevent the British from conquering it by sea. Instead, the British landed at Balaclava (which rapidly became known as “Little Liverpool”, just outside Sevastopol, and pushed towards the city. The first battle on the 20th of September was a British slaughter due to poor coordination with the French (although they eventually won), setting the scene for Lord Raglan’s disregard for human life. The British expected it to be a very short war, and so their troops were not prepared for winter (the French, on the other hand, remembering Napoleon’s route from Moscow, were prepared well). After the first terrible winter, with more troops dying from malnutrition, cold and disease than from military action, better equipment was sent over. It was due to the English families knitting woolen cover-all hats for their Crimean troops and sending them to Balaclava that the name acquired its current English meaning.

The most famous battle was on the 25th of October, 1854, the Charge of the Light Brigade. On this day 18 000 Russians marched from Sevastopol to take Balaclava, a movement which could have pushed the British out of Crimea. They rapidly crushed four of the six Turkish redoubts, and were only stopped from reaching Balaclava by the 550 men of the 93rd Highlander division. These men, lead by Sir Colin Campbell, formed “a thin red line, tipped with steel” two men deep across the valley, withstood the fire and waited until the last minute to retort, causing horrible damage to the Russians. They managed to hold the line until Raglan got the Heavy Brigade to charge in and break the Russians. Lord Raglan then sent the Light Brigade to stop the remaining Russians from carting off the Turkish guns from the redoubts as trophies (a standard policy after Waterloo). He was very vague (negligently incompetent) as to his directions, however, so the glory-hungry Lord Cardigan, leader of the Light Brigade, lead his men to capture the Russian guns still in Russian hands. He charged his men into the “valley of death” with “canons to the left of them and canons to the right of them”, rushing light horse straight into volleys of canon shot. In a twenty minute span, of the 663 who charged 118 were killed, 127 were badly wounded and 500 horses were killed. The French general watching said “this is magnificent, but it is not war”. Despite the odds, the Light Calvary succeeded in its mission and so it was technically a victory, but at horrific cost. Despite this loss, Sevastopol eventually fell, after 149 days resistance. There were 500 000 causalities during the war, with 180 000 Russians, 60 000 British, 35 000 Turks, 35 000 French and 200 Sardinians killed. At the Peace of Paris, the borders remained unchanged, with the only outcome a binding of the Russians to lose their right to a Black Sea fleet for 17 years.

There were a few bright spots of the Crimean War too. One was the heroic doctors and nurses. The best known is Florence Nightingale, the head of the unit of 34 nurses at the British hospital in Balaclava. Perhaps even more deserving of recognition is Mary Seacole. She tried to enlist with Florence Nightingale, but was refused as she was from Jamaica and was black. She made her own way to the Crimea anyway, and served on the battlefield itself, helping all soldiers of either side, becoming known as the “Crimean angle”. On the Russian side, Danya Mihailova (known as “Dasha Sevastopolskaya”) also served on the battlefield as a nurse, while the doctor Nikoli Pirogov became known as the “father of the field hospital” as he utilized a systemic approach to battlefield anaesthesia, plaster castes and a five level triage system. The Crimean War was also the birthplace of military journalism, with a corespondent publishing his letters in the London Times. They directly lead to the 1864 Geneva Convention of the protection of the sick and wounded on the front line and the founding of the Red Cross (which, despite popular misconception, is not a religious institution but was founded as a secular one - the Red Cross was selected as the inverse of the flag of neutral Switzerland).

On our visit to Sevastopol we saw the Valley of Death, Lord Raglan’s look-out, the Monument to the Scuttled Ships and the Defence of Sevastopol Panorama (a beautiful building displaying the magnificent panoramic painting of the Crimean War). We also walked along Grafskaya Pier, full of Russian military hardware. There are few old buildings in Sevastopol, as the city was heavily damaged by WWII (only 8 houses were left intact, but the city was rebuilt within seven years by Stalin’s order), but lots of monuments to war.

Following Sevastopol we visited Chersonesus. Chersonesus is an ancient Black Sea Greek city, founded in the 5th century BCE. You can see the old walls (10m high, 3m thick with two layers and a “corridor of death” in between, built as protection from the Scythians), the mint (casts for coin making were found inside), the agora and what little remains of the theatre (built to house 1500, it doubled in size during Roman times but was destroyed under Christian rule as theatre was considered promoting sin). The city survived for nearly 2000 years, but gradually died due to the decline in trade and was abandoned in the 12th century CE. On the same site is St Vladmir’s Cathedral, built 1861-1891.

We have now left Sevastopol and are on an overnight train to Kiev. Lydia, John, Martin, Julia and myself played geography quiz games until it became too hard.

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