BBC Documentary - Pain, Pus and Poison - Part 2

Following Part 1 of this BBC trilogy of medical documentaries, presenter Michael Mosely focuses on our ability as humans in tackling some of the most serious, and fatal bacterial, fungal, and viral infections. One of the biggest feats of human medical intervention ever has been the eradiction of the smallpox virus, the culprit responsible for millions of deaths in that dark period of the epidemic. Featuring this, and other major infectious diseases, Dr Mosley narrates a scientific journey through which numerous scientists, doctors and corporations worked together to find the elusive cure.


It starts with an account, describing the last moments of the life of George Washington, the first president of the United States. Mosley comments that he probably died from a simple infection - the fate of million of people around the globe at that time, a time which medicine as we know it was very primitive. Even the 'best physicians' in the country could not find a successful solution for President Washington. This is an alarming contrast to today's world, where a small scratch proves nothing significant at all, but back then, it could lead to something life-threatning. Even in World War 1, more soldiers died of wound infections, than from 'direct hit'.

To appreciate just how dangerous bacterial and viral infectious agents are, and how easily they can spread, Dr Mosley visits the Centres for Disease and Prevention (CDC) in Atlanta. It is one of two centres in the world that currently contain repositories of the deadly smallpox virus, with virtually unbreathable security. Even the BBC had extremely limited access. If the virus were to get into the wrong hands, the consequences could be disastrous - many precautionary measures are in place to minimise this possibility indefinitely. The CDC holds some of the worlds 'worst serial killers' to put it simply.

In the 1790's America especially, microbes weren't remotely considered to be the cause of such sudden deaths such as Washington's. Only after the Germ Theory was discovered, that people's perceptions began to change regarding infection and disease. Through subsequent wars in history, medicines advancements have been accelerated - medical science has professed to a point where we may be considered 'ahead of our time'.

Even further progress came when Methylene blue dye was dissevered by Paul Ehrlich to be remarkably effective in 'illuminating' the hidden world of bacteria. Staining is still used enormously today, so that we may appreciate how complex the small world really is. With the right stain for a particular bacteria, scientists were able to make discoveries into how a certain bacteria strain causes a particular disease.

From here, the next step was to find substances that can destroy these bacteria - we have been seeking 'magic bullets' ever since.

English Surgeons to Publish Death Rates in New Proposals

In the news this week there's been some controversy over the proposals set by NHS England regarding the publishing of data on surgeons. More notably, the publishing of death rates by surgeon. Sir Bruce Keogh, Medical Director of NHS England has said "surgeons must publish the death rates for their patients or face penalties". This raises concerns over whether current surgeons will continue to practice under further statistical scrutiny. Indeed this has been a 'move to increase transparency', perhaps in a way too drastic in the view of many surgeons across the country. With over a decade of medical training, we should trust surgeons to have the best of intentions for every patient, no matter the condition, no matter the person. Perhaps this new movement will question every single surgeon in the country of their competency, and the techniques they utilise in the operations they carry out.

Sir Keogh also added that "we will lose some surgeons...as a consequence of this endeavour". In addition, he made the point that as those surgeons doing few operations may avoid attempting more under this new regulation, more procedures will be 'passed' between colleagues. The potential advantage is that surgeons will have their work load slightly reduced, enforcing the importance of quality, not quantity when performing surgeries. A heart surgeon himself, even though he is involved heavily in this field, he is adamant that 'this is not going to go away'.

Above: Surgeons performing operation (Wikipedia)

Let us consider the implications of this. The statistics shown for death rates may be physically true, but in the wrong context, they may be misleading. If so, this would provide doctors and governing bodies to make invalid conclusions. It will be important for surgeons to publish all deaths to make the results valid. For example, one particular heart surgeon may have a 'significantly high death rate', however it may be overlooked that he is considered the best in his department, having most extremely difficult operations passed onto him by his colleagues. Currently, most surgeons do publish death rates, and the patient has control on whether they would want an operation from a particular surgeon 'based on their figures'. I believe that there is a danger that patient could make poor decisions from these statistics alone, for reasons above, and that they may overlook the expertise and experience of a surgeon. Therefore it is important other factors are considered and presented to the patient for them to make a fully informed decision.


Credit to Ben Tufft for his article 'NHS Medical Director: Surgeons must publish death rates', published in The Independent, 16th November 2014. The full article can be seen here

Are You Getting the Right Match?

In the UK, there has been a big increase in the number of patients requiring transplants over the last decade or so. In fact, this pattern can be reflected worldwide. In order to understand why we need more donors to accommodate the continual increase in patients requiring transplantation of solid organs, its useful to know how we determine matches between donors and patients. "Solid" organs as you could infer, relate to organs that are in a solid state. Examples of these include the kidneys, pancreas, heart and lungs. It is widely accepted that it isn't easy to find compatibility between donor and recipient straight away - there must be biological compatibility of two types. The first is the well-known ABO blood group system. There are four different groups that an individual can fall into: A, B, AB, and O. Each group signifies the types of antigen present on the surface an erythrocyte, or red blood cell. Antigens are proteins on the plasma membrane of a cell, giving it its own 'identity'. This is essential in the multiple processes of the immune response, for example. A person identified with an 'A' type blood group has only 'A' type antigens on the cell surface membranes of red blood cells. However they will also have 'Anti-B' antibodies circulating in their blood plasma. The converse is true for those with a 'B' blood group. If someone were to have AB however, they would have both types of antigen on the cell surface membranes of red blood cells. Therefore no antibodies acting against these antigens would be circulating in their blood plasma. Now, those with type 'O' blood group are seen to be rarer than those with other blood groups, but it means as a donor you would be 'compatible' with any recipient of any blood type. For this blood type, no ABO antigens are present on the membranes of red blood cells, but the serum of these individuals will contain the 'Anti-A' and 'Anti-B' antibodies.

Chart showing the differences in cell type, antibodies and antigens present in individuals with different blood groups (Source: Wikipedia )

To illustrate this, let us consider a potential liver transplant between a donor with blood group O and recipient with blood group B. The donor has red blood cells with no ABO antigens, so when mixed with blood (and plasma) containing red blood cells with the B antigen and therefore 'Anti-A' antibodies, there will be no immune response. After all, the antibodies are not able to form an antigen-antibody complex.

Most people will be aware of the ABO blood group system; however there is another factor that always needs to be considered by doctors before carrying out any surgeries involving organ transplantation. This is what is known as the human leucocyte antigen (HLA) system. All cells known to contain nuclei in the body possess these protein complexes on their cell surface membranes. Therefore it is useful to know that red blood cells do not have these antigens as they have no nuclei, no genetic material encased. HLA types are inherited from both parents, and 'research has shown that the fewer the number of mismatches between donor and recipient HLA, the less likely it is that the organ will be rejected post-transplantation'. This is why it has become increasingly imperative for doctors to screen individuals for this type of antigen so that matches between patients and potential donors can be confirmed. A patients HLA type can be confirmed by a series of tests. The polymerase chain reaction (to create multiple copies of DNA) followed by gel electrophoresis (allows the scientist to visualise the result) being one of the more notable methods.

After the HLA type has been confirmed, the patient's serum is analysed to 'screen for the antibody profile'. Firstly, the serum is 'mixed with microbeads that have multiple HLAs on their surface'. This essentially serves to identify antibodies that are targeted at particular donor HLAs, using a fluorescent marker. This is needed as there is always a possibility that the recipient could have developed antibodies against a particular HLA in the past, whether it be pregnancy, previous transplants, or blood transfusions. These are known as 'sensitisation events'.

In addition to this, another test is carried out, involving mixing of recipient serum with donor cells. This is primarily to see if there is any immunological reaction to the donor cells, thus proving whether a donor is in fact compatible with the patient. The donor cells are those with nuclei, so scientists can test whether the HLAs of the donor form an antigen-antibody complex with antigens present in the patient's serum. 'Complement' molecules are also added which help to destroy cells (by lysis) that have their HLA antigens bound to patient antibodies. To see whether a reaction has occurred or not, a visualisation stain is applied, dead cells staining red, and live cells staining green.

Not only is it important to choose the right donor, but selecting viable organs for surgical use is also vital. Donors can either be living or deceased, but living donors 'are generally family members or close friends of the patient'. That isn't to say all are, of course, as altruistic donors are on the rise - these people are willing to donate an organ without knowing who will receive it in due course. Kidney donation is by far the most common transplantation from live donors. In fact, 'in the UK, 2732 out of 3740 transplants performed in 2011 were kidney transplants'. Donations from the deceased however can be divided into two sub-groups: those who are pronounced brain dead (DBD), or those with circulatory death (DCD). DCD is when the heart has completely stopped beating and thus there is no circulation flow throughout the body. DBD donors have organs 'kept alive' by a ventilator, with a constant blood supply in place.

A patient can be found to have their donated organs rejected by their own immune system at several possible stages after surgery:

Hyperacute: Rejection occurs immediately, even within a few minutes of transplantation. Surgeons would need to work quickly to remove the donor organ completely from the body. Nowadays, hyperacute rejection is very rare.

Accelerated acute: Rejection could happen within a few days to a week after surgery. The rejection may be due to the fact the patient has experienced a sensitisation event in the past, which produced the relevant antibodies.

Acute: Rejection occurs within the first 6 months of surgery, and is mainly due to a few mismatches in HLAs between the donor and the patient. This sort of rejection can be brought under control with certain immunosuppresant drugs that are specific to the recipient.

Chronic: Rejection could even occur after 6 months from the point of surgery and mainly due to repeated episodes of acute rejection. This is the main problem facing patients with transplants - some patients will be required to take immunosuppresive drugs for the vast duration of their life.


With a population as ethnically diverse as the UK, it has become increasingly difficult for those of minor ethnic origins to receive the right matches for organ donation, although overall there is a big gap between the numbers requiring transplants and willing donors.Those of Black and Asian origin have been known to have 'uncommon HLA types'. Many countries, such as Spain, Belgium, France and the USA have implemented an 'opt-out' scheme nationwide. This means it is presumed you give consent for your organs to be donated, unless you state otherwise. In the UK, the public's view may be changing on whether we should carry on with our current system in order to meet the piling demand for organs across all ages, all backgrounds, and all ethnicities.


Credit to Steven Jervis, clinical scientist at the Manchester Transplantation Laboratory who wrote for the Biological Sciences Review (Volume 24, Number 1)

"Dead Heart" Transplant - World First in Cardiac Surgery

In Australia this month, surgeons have managed to resuscitate a heart from circulatory death and use it for transplant in patients with 'end-stage heart failure'. Prior to this, hearts used for transplant were only sourced from brain-dead patients but whose hearts were still beating. Some have heralded this as a 'paradigm shift' in organ transplantation. The heart was able to be revived using what has been  dubbed as the 'heart-in-a-box' machine (the OCS - Organ Care System). Now the machine is commercially available to hospitals in Europe and Australia for clinical use. Usually, a beating heart is kept iced for a long period of time, however this machine is claimed to be a 'portable, warm perfusion, monitoring machine'. As of now, St. Vincent's Hospital Heart Lung Transplant Unit in Australia has transplanted two patients using this technique. However it is important to note that the OCS has already been used and approved for other types of transplantation such as the liver, kidneys and lungs. Up until now, it has proved difficult to repeat the same technique on 'dead' hearts.

The benefits of this new technique prove essential - the maximum possible number of donor hearts available will inevitably increase. In fact, it is estimated that 30% more lives could be saved with the introduction of this technique. Professor Peter MacDonald, Medical Director of the St Vincent's Heart Transplant Unit has said "this is a timely breakthrough. In all our years, our biggest hinderance has been the limited availability of donor organs". With regards to the OCS machine, portability is useful if it is needed in various departments in a hospital. It would also mean ease of transportation nationwide, or even worldwide.

 

Top: OCS "Heart-in-a-box" machine (TransMedics)

Above: OCS machine maintaining liver for transplant (BBC)

Interestingly however, this isn't the first time that this idea of using a dead heart donor has been experimented. Professor Kumud Dhital perfumed both of the operations in Austrailia says that "It is interesting to note that DCD hearts were utilised for the first wave of human heart transplants in the 1960's with the donor and recipient in adjacent operating theatres. This co-location of donor and recipient is extremely rare in the current era leading us to rely solely on brain dead donors -- until now".

The recovery of patients is even more astounding. Michelle Gribilas, 57, was the first patient to be treated with the surgery. Before the operation she was suffering from congenital [end-stage] heart failure. Two months after the procedure, she told the BBC: "Now I'm a different person altogether. I feel like I'm 40 years old - I'm very lucky". Senior cardiac nurse at the British Heart Foundation, Maureen Talbot, added "without this development, [patients] may still be waiting for a donor heart".


Credit to the BBC for their article 'Surgeons transplant heart that had stopped beating', published 24th October 2014. More on the subject can be found here.

Credit to St Vincent's Health Australia, whose story was published in ScienceDaily on October 24th 2014. The original article can be found here.

BBC Documentary: Pain, Pus and Poison - Part 1

Over the last 150 years or so, the story of the advancements of drugs, treatment, and techniques in medicine has developed at a great pace. Dr Michael Mosley recently presented a trilogy of documentaries for the BBC, telling tales of the beginnings of anaesthesia and the birth of the antibiotic era. In part one of the series, he focused on man's pursuit to free pain. It begins where you may not expect - the poppy. From this rather innocent-looking plant, a resin was extracted and given the name opium. Dissolved in alcohol, the medicine was called laudanum. Morphine, the drug we are familiar today with unprecedented properties in alleviating excruciating pain, was formerly discovered by 19th century pharmacist Friedrich Sertürner. Morphine works by blocking nerve endings associated with pain at the site of pain and in the brain. The direct blockage of these signals proves morphine very effective. Eventually isolating the active ingredients in raw opium, he had managed to obtain a substance that could now be quantified and measured for ease of administration. This fact is often underestimated about drugs - simply by being able to measure out a quantity of a substance offers a huge element of control and indeed safety. It was considered back then that medicines which originated from plant sources were alkaloids, containing the suffix -ine in their name. Hence we are familiar with morphine, whose former name was morphium. According to Dr Moseley, these alkaloids were considered 'our first real medicines'. Dr Walter Sneader, Former Head of Pharmacy at the University of Strathcylde says that the discovery of morphine was 'the single most important event that has ever occurred in drug discovery - far more important than the introduction of penicillin, in terms of advancing the science'. Sertürner then went on to isolate many more alkaloid chemicals, some of which include caffeine, nicotine and quinine. Another well known alkaloid that was discovered was cocaine. Ironically enough, at the point of introduction in industry this compound dissolved in alcohol was approved by the Pope himself. The famous neurologist Sigmund Freud went on to investigate more into the properties of cocaine.



Although these alkaloids were a start, these weren't considered potent enough to be effective in the operating theatre. Sir Humphrey Davy saw nitrous oxide as a potential drug for use in surgery, however surgeons still went on to attempt operations on people who were unfortunately, fully awake. It was only until William Morton and the introduction of ether as a gaseous anaesthetic agent, that anaesthesia started to advance rapidly. To read more on the subject of William Morton's discovery, visit my post, 'The History of Anaesthesia'.

After this remarkable discovery, chemists from all around the world began to experiment with various substances, coal tar notably being one of the 'more unlikely places'. Chemist and presenter Andrea Sella, mentions that using coal tar was able to open 'a whole new library of starting materials'. Some of the most iconic drugs in today's world were a product of this seemingly unpromising raw material, aspirin and heroin just to name a couple. In the 20th century, many more drugs with anaesthetic properties were developed. However it wasn't just anaesthetics; the world's first sleeping pill was discovered, chloral hydrate which became very popular. The barbiturates were another group of drugs that had the ability to put people to sleep. Sodium thiopental was one of the more notable ones, the 'truth drug' so given the name for it's use in interrogation, is featured in the documentary.

Now in the 21st century, we have made great strides in the development of even more effective and safer drugs for use in surgery, prescription, and treatment of diseases. It has come to a point where we can, with suitable starting materials such as simple molecules, develop any molecule we want to. This means we can develop any drug we want to. A surge in technological advances in the last few decades has supplemented our understanding of anaesthesia and how pain is managed.


Credit to the BBC for their medical documentary trilogy, 'Pain, Pus and Poison', broadcasted in September 2014.

Repairing Damaged Heart Tissue With Embryonic Stem Cells

Heart disease is now considered the most common cause of death in the UK, according to the BBC. This pressing issue has initiated research projects to find the best treatments, long-lasting treatments that involve the regeneration of heart tissue. Experiments back in 2005 involved deliberately inducing heart attacks in 18 sheep in order to test the potential of embryonic stem cells from mice. Research prior to this revealed that attempting to use stem cells from the patient would prove futile as adult stem cells do not have the capacity to differentiate into heart (cardiac) tissue. If this was possible, this would undoubtedly be a desirable solution as the patient's own cells are being used, reducing the risk of rejection.

Therefore embryonic stem cells have been labelled the next hope in the regeneration of damaged heart tissue. The experiment back in 2005 involved separating the sheep into two groups, one the control, the other being given 'multiple injections' of the embryonic stem cells [from mice] after a rest period of two weeks. These cells had been given growth factors to trigger them into developing into cardiac cells. Five sheep from this group were also given immunosuppressants in case there is an issue of rejection. Tagging the stem cells with 'fluorescent proteins' helped scientists to track their progress of colonisation, which was successful after one month. As anticipated, the cells were effective in regenerating the heart tissue in the non-control group, replacing the scarred tissue. In fact, the scientists were able to measure the heart's effectiveness to pump blood from the left ventricle. In the control group, blood ejection rate decreased by an average of 6.6%, whilst it was raised by 10% in the group given stem cell treatment.

By this data, the treatment seems very effective, however only 18 sheep were used in this set of experiments and embryonic stem cells of mice were used. Nevertheless the fact that this technique works in principle gives hope of new treatments involving stem cells. What was more encouraging for the scientists, is that there was no evidence of an attempt of rejection by the immune systems of sheep that were administered immunosuppressant drugs. However geneticist Robin Lovell-Badge, researcher at the National Institute for Medical Research, London, says that there is a "need to be cautious. Other tissues might reject the stem cells". He also pointed out that the sheep were only monitored for one month after the investigation. Side effects to the treatment or rejection could well occur further down the line - this is another implication for human trials.

Since these experiments, another study at the University of Washington Institute for Stem Cell and Regenerative Medicine also found success in the use of embryonic stem cells to regenerate tissue, this time in monkeys. The study summary stated that the stem cells "assembled muscle fibres and began to beat in synchrony with macaque (monkey) heart cells". What was interesting is that this time, human embryonic stem cells were used. The findings were published 30th April 2014 in Nature. 

Above: Green areas depict newly transplanted stem cells forming a graft with the primates original cardiac muscle cells (red). Full credit to the University of Washington

Credit is given to Anna Gosline, writer for New Scientist. Article can be found here. Original study findings can be found in The Lancet (Volume 336, pg 1005). 

University of Washington findings report can be found at ScieneDaily here.

World First In Organ Transplantation

Recently in September, it has been revealed that a woman in Sweden gave birth to a baby boy, only possible with a womb transplantation. This pivotal event in medical science has given hope to thousands of women around the globe who are unable to conceive. Some cancer treatments and birth defects are a couple pf the reasons why women have this problem. The donor of the uterus was a friend of the 36-year old, who was in her 60's at the time of transplantation. The birth was successful, however premature at 36 weeks, the baby weighing in at 1.8kg (3.9lb). Prior to the birth, the unidentified couple underwent IVF treatment in order to produce 11 embryos. These were frozen until the point of transplantation at the University of Gothenburg. As with the vast majority of organ transplants of today, the woman was given immunosuppressant drugs before the transplant, in order to reduce the risk of rejection by her own immune system.

After the transplant, doctors were then able to select an embryo from the ones frozen to implant into the new uterus. However this was only after a period of a year. In the short period before the birth, the baby was said to have developed an abnormal heart beat, hence the premature birth, however now the baby's condition is said to be 'normal'. However complications with this sort of transplant don't just stop there. If the couple were to have a second child, they would need to consider the fact that the immunosuppressant drugs can be 'damaging in the long term'. It would be considered that if they decide not to have a second child, then removing the transplanted womb would be a necessary precaution.

There have been several fails attempts at womb transplants, whether it be due to the organ becoming diseased, or birth resulting in miscarriages. Now, Professor Mats Brannstrom, who led the surgical team expressed relief and happiness in response to the success. In fact it has emerged that two more women will be receiving womb tranplants by the end of this year; suregons in the UK will be choosing 5 patients out of 60 who will undergo this potenially life changing opeation, according to the Sunday Times.

"Our success is based on more than 10 years of intensive animal research and surgical training". Despite the success however there are still concerns about the 'safety and effectiveness of the invasive procure', according to the BBC. This breakthrough is somewhat comparable to the leap in medical science that IVF allowed over 30 years ago. The Chairman of the British Fertility Society, Dr Allan Pacey said the operation "feels like a step change", however he is aware that it will need to be proved repeatable, reliable, and safe in the future for many more patients.


Credit to Oliver Moody, for his article 'More womb transplant babies on the way' which can be found here.
Additional credit to James Gallagher, Health Correspondent for the BBC, for his article 'First womb transplant baby born', which can be accessed here