Communication, communication, communication.

It's been 5 months since I sat my last exam at university, and I can tell you, I miss my studies terribly. So now I've had a good long break, moved house, spent lots of quality time with my children, and applied for vast numbers of jobs, I think it's time to get back on the proverbial horse and do some writing!

In my opinion, the communication of science and other STEM (Science, Technology, Engineering, Mathematics) subjects is vastly important, for several reasons. We need to engage young minds, because they are the future of STEM subjects - the next generation of scientists, technologists, engineers and mathematicians. We need to show them how utterly cool our fields are. We need to inspire and delight. It is also vital that we engage the general public. This is important for several reasons, not least the promotion of rational thought and the suppression of misinformation and popular myths, but also to promote charities that fund vital research. And again, our fields are really cool, and I for one want to enthuse! Citizen science projects are hugely valuable in the promotion of science (and other fields), and the understanding of complex research. But it also takes good old fashioned word of mouth to spread the love for STEM subjects.

In that spirit, I write this blog. But why stop there? Following on from the success of social network pages that are intended to promote science (my particular STEM subject), many of which I follow, I have opened my own social network page! It occurred to me that there are few opportunities available to the lay person to ask scientists questions, so why not provide that opportunity myself? My page was started 6 months ago, and it is still small, with just 30 followers, but already I have had some great questions. There have been questions on a range of subjects, from the epigentics of mid line defects such as ankyloglossia (tongue tie) and the benefits of folate consumption, 'does water float?' (a favourite of mine!) and a complex quantum physics question about the change in quark flavour in collisions involving hydrogen atoms. Fortunately, I have recruited a physicist to answer such questions, because try as I might, I could not get to the bottom of the matter! I'll stick with medical and molecular biology I think.

So. If anyone who reads this blog would like to join me and my fellow science nerds in enthusing about science, or would like to ask questions, please come to Facebook and search for Ask a Scientist a Question, or use this link: https://www.facebook.com/AskAScientistAQuestion. We (or rather, mostly I) do our best to provide accurate information, and as much as possible, reliable academic references and/or further reading is included. Please feel free to contribute anything you find interesting, and make corrections where you see fit. Science is, after all, all about the quest for knowledge, and we find success in our failures. In science, it is good to be proved wrong!

Now, what do you have to look forward to here on Serious Mad Science? Well, news of interesting and inspiring science comes thick and fast, and there is a wealth of topics to cover. I'm going to start with a series of posts on stem cells. In discussing a module I undertook on this subject with friends, it became apparent that it is unclear to many lay people what exactly a stem cell is or how they work, the difference between the different types of stem cell, the concept of potency and how this applies to research, and the application of stem cell therapies in medicine, the reporting of which is often vague in the popular press. This was my inspiration for this series. So watch this space!

What Can the Humble Fruit Fly Teach Us About Alzheimer's Disease?

What Can the Humble Fruit Fly Teach Us About Alzheimer’s Disease?
Seminar presented by Amrit Mudher
Southampton University School of Biological Sciences
In association with The Alzheimer’s Society

Abstract

Alzheimer’s disease, modelled here in Drosophila, is characterised by to types of lesion, identifiable post-mortem in AD patients. These lesions are neuritic plaques, caused by β amyloid oligomer aggregation, and neurofibrillary tangles caused by oligomers of tau protein. Hyperphosphorylation of tau results in microtubule instability, loss of neuronal cytoskeletal integrity and impaired axonal transport. GSK inhibitors are shown to rescue this phenotype by inhibiting phosphorylation of tau, decreasing its solubility. It is possible that some small, insoluble species of tau confer protection against tauopathies. A new therapy, a microtubule stabilising agent known as NAP, is currently in phase 3 clinical trials. This therapy has yet to show ant toxicity.

Introduction

Alois Alzheimer, the namesake of the disease, was first to state that Alzheimer’s disease (AD) has a distinct and recognisable neuropathological substrate (Mudher. 2012). There are two primary lesion types associated with the disease: neurofibrillary tangles (fig. 1a) and neuritic, or senile plaques (fig. 1b) (Mudher. 2012) (Perl. 2010). The result of these lesions is neuronal loss and a visible reduction in brain tissue.

Figure 1a: (Mudher.2012): Neurofibrillary tangles, caused by accumulations of abnormally phosphorylated tau protein within the perikaryal cytoplasm of neurons. Tissue obtained post mortem from an AD patient (Perl. 2010).

Figure 1b: (Mudher. 2012): A neuritic/senile plaque in tissue obtained post-mortem from an AD patient. The plaque is made up of β-amyloid deposits surrounded by abnormal neurites (Perl. 2010).

Definitive diagnosis of AD can only be made at autopsy, because there are no definitive biomarkers to test for the disease. Distinguishing between normal ageing and AD, particularly in early stages of the disease, is also very difficult (Perl. 2010). Studies using autopsy-derived tissue, and animal models, are therefore vital for scientific progress in the understanding of AD, and the search for therapies.
Drosophila melanogaster is a model well suited to such research. Drosophila has a long history as a powerful genetic model; indeed, it has been used as a model organism for some 100 years. Its genome has been sequenced and highly annotated. It has thus provided researchers with an array of powerful and effective genetic tools, which have been used to study the underlying cellular and molecular bases of many key physiological processes and disease pathologies. A summary of factors which make Drosophila an ideal model organism:

• It’s small size

• Inexpensive to maintain (it costs approximately £2000 for a six month study using flies, which would take an equivalent of 3 years in rodents at a cost of approximately £250 000)

• Rapid propagation

• Short life span

• Genetic tractability

• 75% of genes implicated in human disease have Drosophila orthologues.

(Mudher. 2012) (Cowan et al. 2010).

Introduction

The focus of this research is how tau affects neuronal homeostasis.
The normal function of tau is microtubule binding in neuron axons. It conveys stability to the cytoskeleton of these structures. Microtubules are cylindrical in shape. They provide a network, like ‘roads’, via which transport vesicles move within the cells (fig. 2). Hyperphosphorylation of tau (p-tau) results in reduced binding with microtubules, loss of cytoskeletal integrity, and reduced axonal transport (Cowan et al. 2010). This can be viewed in vivo, using live fly larvae. The larval cuticle is
clear wih greatly innervated musculature beneath. This is a well characterised network of motor and sensory neurons, therefore, it is possible to visualise physiological and/or pathological processes that occur within them. This is done by tagging a protein that participates in these processes with a fluorescent marker. Visualisation occurs in real time. An example of this type of experiment was carried out by Cowan et al (2010, Modelling Tauopathies in Drosophila: Insights from the Fruit Fly). UAS/GAL4 was used to drive expression of GFP (green fluorescent protein) tagged neuropeptide Y and a wild-type isoform of human tau (0N3R-, which is constitutively hyperphosphorylated) within motor neurons (see results) (Cowan et al. 2010).
So the question must be, is neuronal dysfunction caused by the hyperphosphorylation of tau alone, or the later formation of tangles?

Figure 2: Microtubules in neuron axons are cylindrical in shape. They are composed of tubulin. Kinesin plays a role in vesicle transport along the microtubule network, which act like ‘roads’ (Stebbings. 2005).

Results

True to the prediction made by the tau microtubule hypothesis, expression of p-tau, which causes dissociation and solubility, leads to loss of microtubule integrity. As a result axonal transport is disrupted, there is dysfunction within synapses, and locomotor impairment (Cowan et al. 2010). This is seen as ‘traffic jams on the roads’; vesicles passage along axons (via microtubules) is blocked. Ultimately, p-tau toxicity results in neuronal death by apoptosis. Together, these problems result in the behavioural phenotype of AD, even prior to the presence of p-tau aggregations or neuronal death (Mudher. 2012). Loss of microtubule integrity can be seen in figure 3a and 3b.
It is possible to rescue the behavioural phenotype, restoring microtubule number and integrity, using GSK-3β inhibitors (Glycogen Synthase Kinase-3β). GSK inhibitors therefore must increase levels of h-tau (human tau). Figure 4 depicts this. However, a side effect of GSK inhibitors is the appearance of electron-dense granular structures within the cytoplasm of neurons. These are aggregations of granular tau oligomers.

Figure 3a: (Top) Healthy tissue. Borders of cells are well-defined by plasma membranes, and the
microtubules are clearly visible as small circular structures (Mudher. 2012.) (Mudher
et al. 2004).

Figure 3b: (Bottom) Tissue affected by hyperphosphorylated tau protein. Cells have lost their well defined shape and cell contact is poor – gaps are present. Microtubules are deformed (see black arrows) (Mudher. 2012) (Mudher et al. 2004).

Figure 4: Levels of human tau are increased with GSK inhibition (Mudher. 2012).

Discussion

The physiological and pathological nature of AD means cognitive function in patients is progressively impaired. Glycogen synthase kinase is responsible for phosphorylation of serine and threonine residues on target substrates, in this case tau. It is this that prompts dissociation of tau from microtubules, creating the instability. It is this (together with formation of neuritic plaques) which results in cognitive impairment. It is possible to reverse damage (prior to tangle formation) and restore phenotype with GSK inhibitors. This therapy increases tau by decreasing its solubility. In its insoluble state, tau binds to microtubules, restoring integrity and normal function of neurons.
Further work is underway to investigate AD therapies which increase microtubule stability, and the possibility that they could prevent and rescue tau-mediated phenotypes. One such agent is NAP (full name NAPVSIPQ) is able to preferentially bind with tubulin in neurons and glial cells. It promotes microtubule assembly and reduces p-tau in vitro. Peripheral administration (intravenous) of NAP shows significant efficacy in various in vivo models (Matsuouka et al. 2008), and is now in phase 3 clinical trials as a therapy for AD (Mudher. 2012).

Conclusion

Certain species of small insoluble Tau proteins are non-toxic and are thought to confer protection against tauopathies such as AD. Hope for future tauopathy therapies lies with microtubule stabilising agents, such as NAP, which unlike current therapies, shows no toxicity at this stage of clinical trials (Mudher. 2012).

Bibliography

Cowan, C.M.; Sealey, M.A.; Quraishe, S.; Targett, M.T.; Marcellus, K.; Allan, D.; Mudher, A. (2011). Modelling Tauopathies in Drosophila: Insights from the Fruit Fly. International Journal of Alzheimer's Disease. 2011 (598157), 1 - 16.
Matsuouin, Y.; Jouroukhin, Y.; Li, H.F.; Feng, Li.; Lecanu, L.; Walker, B.R.; Plantel, E.; Aracanio, O.; Gozes, I.; Aisen, P. (2008). A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Conitive Function in a Mouse Model Of Alzheimer's Disease. Journal of Pharmacology and Experimental Therapeutics. 325 (1), 146 - 153.
Mudher, A. (2012). Seminar Powerpoint presentation. 2/11/2012.
Mudher, A.; Shepherd, D.; Newman, T.A.; Mildren, P.; Jukes, J.P.; Squire, A. Mears, A.; Drummond, J.A.; Berg, S.; Mackay, D.; Assuni, A.A.; Bhat, R.; Lovestone, B. (2004). GSK-3beta Inhibition Reverses Axonal Transport Defects and Behavioural Phenotype in Drosophila. Molecular Psychology. 9 (5), 522 – 30.
Perl, D.P. (2010). Neuropathology of Alzheimer's Disease. Mt. Sinai J Med. 77 (1), 32 - 42.
Stebbings, H (2005). Cell Motility. Online: eLS. 1.

My first blog entry!!!

Ok folks, this is it. My blog. I'm going to start with the first assignment I did at uni, which was a mock article for a local newspaper. The response from my tutor, Dr Thomas Caspari, was that it is a well written piece, although preachy at the end. And I agree, it is. I just couldn't think how to end. Oh well. But here's the thing. I love factual writing. I love the research that goes into it. So when Dr Caspari went on to suggest that I consider writing as a career, I... was rather pleased. I had to tame my usual use of language there. I do get excited. Anyway, that conversation was the inspiration for this blog. I hope someone reads it, and if you do, I hope you at least learn a little something from it. Oh, and thank you.

Bsuc42 Tasha Stubbs-Davies

                                         

                          North Wales Coast Pioneer                          

                           Science Special                                   

 

     Money makes the world go round… but the future of medical research is in your hands…    

The case of Henrietta Lacks and the issue of ‘ownership’ of tissue removed during surgery, has been the subject of debate amongst human rights groups, patient advocates and medical researchers this week  following the UK release of the book The Immortal Life of Henrietta Lacks’, by science author Rebecca Stott. So what does happen to our tissue post-surgery? Is it our right to deny consent for the use of our tissues for research on the grounds of a lack of remuneration, or is it in fact our responsibility to provide such consent, for the advancement of medical science which benefits us all? Tasha Stubbs-Davies investigates…

Henrietta Lacks of Baltimore, Maryland, USA was 31 when she died from cervical cancer. However this was not the end of this young woman’s tale. Henrietta was immortalised when Dr George Gey, a researcher at John Hopkins Hospital, pioneered a technique to grow human cells in the laboratory. Since then, the cells, which became known as HeLa cells, have been used in research internationally, for genetic studies and gene mapping, AIDS research, the effects of radiation and toxins,  polio and flu vaccine formulation, manufacture of drugs, in vitro fertilization techniques and many, many cancer studies, with new studies commencing daily. In fact Rebecca Stott states that HeLa cells have been named in more than 60,000 journal articles, and upwards of 50 million tonnes of Henrietta’s cells have been grown since her death (see Box 1, The Science).

This plentiful supply of cells capable of aggressive growth gave rise to a whole new branch of medical science and biotechnology and has provided pharmaceutical companies with massive profits, while the Lack family suffer financial hardship, and Henrietta’s son was quoted: “If our mother is so important to science, why can’t we afford medical insurance?” The case of Henrietta Lacks was used in court proceedings when John Moore tried to gain a share in profits when his own cell line was developed and commercialized following his treatment at UCLA Medical Centre in California for hairy cell leukaemia. In the case of Moore v Regents of the University of California, the Supreme Court made the landmark judgement that Moore was “not entitled to a share in any profits realized from the commercialization of anything developed from his discarded body parts.”  

Box 1. The Science How did HeLa cells (the original tumour made up of them) come about? Tumours of the kind that killed Henrietta Lacks are caused by Human Papillomavirus 18 (HPV18). The virus is passed, during intercourse into the cervix of the host, where it transfers its own genetic material into cells lining the cervix. This known as horizontal genetic transfer. When the genes of the virus were incorporated into Henrietta’s own genes, the HeLa genome was created. This genome is different from the genome of either parent genome (that of Henrietta or the virus) in several ways, most notably because it has 82 chromosomes (the discreet arrangement of DNA within cells); humans have a total set of 46 chromosomes. Based on the ability of HeLa cells to replicate indefinitely and the vast differences between it and the human genome, a scientist, Leigh Van Valen has written a paper describing them as “an example of contempary creation of a new species, Helacyton Gartleri. His conclusion relies on three main points: ·         The incompatibility of HeLa chromosomes and that of humans or the papillomavirus. ·         The “ecological niche” of HeLa cells. ·         Their ability to proliferate well beyond the desire or intention of cultivators. Van Valen proposes that they belong to a new family, Helacytindae, and the genus Helacyton. This is known as a paraphyletic group, where the cells are no longer Homo Sapien (human) nor the papillomavirus and so they cannot be classified as either, but these are its closest ancestors.

You may think that this is a shocking truth about greedy pharmaceutical companies.  But consider this: is it morally right to essentially buy and sell human tissue? The black market trade in organs has been highlighted in the media many times, and to be paid for our tissues blatantly encourages this trade and puts vulnerable people in society at risk. Would Henrietta Lack deny Dr Gey permission to use her cells because there was no ready cash in it for her? It’s doubtful. Her children should be proud that their mother has changed the face of medical science and that her cells have helped to save millions of lives, all be it posthumously, instead of feeling resentful that they can’t share a profit from it. The truth is that research is a necessity for advancement in the diagnosis and treatment of diseases; individual governments have to rely on funding from the private sector to fund research in order to provide us with the best possible standard of healthcare and it is the private sector that develops products for our treatments and diagnoses. 

Having said all of this, it is an irrefutable fact that legislation should be in place to protect our rights as patients; we have a right to know what will happen to our tissues and organs after surgical procedures, and to deny permission for any such uses. Here in the UK, The Human Tissue Act 2004 specifies what the requirements for tissue harvest are. It came about following the Alder Hey organ scandal, in which the organs of deceased children were retained without consent. The act states that “appropriate consent must be given for the retention of any relevant material which has come from the body of a deceased person.” This includes the use of tissues and organs for research, which is clearly defined in the act. It requires licenses for any organisation intending to publicly display human remains (for example BODIES-The Exhibition, which showcased preserved dissected human bodies). The act also allows for anonymous organ donation, and that the wishes of the deceased with regard to organ donation, takes precedence over that of relatives (although this is not an enforced regulation; a government report in 2006 concluded that doctors would not be willing to confront families in these circumstances).

So, we are safe from the body snatchers. Henrietta Lack was an ordinary lady with an incredible legacy and her contribution to modern medicine has been invaluable. The take home message here is that research holds the key to our collective future health, we can all contribute, even after death and perhaps we all should. For more information go to: http://www.organdonation.nhs.uk/ukt/default.jsp

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