Wednesday, 20 May 2015

Big Data: Could It Ever Cure Alzheimer's Disease?


I was struck by this article by Masud Husain http://www.medscape.com/viewarticle/833784 (closed access in BRAIN so you cannot read the original) which is reprinted on medcsape.

The article nudged me to write a post because it reflects the challenge and opportunities created by two behemoths which like galaxies, are slowly colliding. Its addressing an area of growing interest because organisations are waking up to the value of having information that comes from existing datasets, generating targeted data, and looking within it to drive insight, rather than establishing an hypothesis and finding data to support or refute it.


"From business to government, many have been seduced by the possibilities that Big Data seems to offer for a whole range of problems."
Alzheimer's (AD) has been accreting datasets and large scale studies. Projects such as Alzheimer's Disease Neuroimaging Initiative (ADNI) ($200M invested so far) is sequencing several hundred full human genome sequences of patients with AD. At the same time, supported by the Cure Alzheimer's foundation, our group at Harvard, at Massachusetts General Hospital and here in UK at the Sheffield Institute for Translational Neuroscience (SITraN) is analysing a set of 1500 whole genome sequences of AD sufferers. Our group is amongst the first laboratories world wide to have undertaken a study of this magnitude, and that we have done so outside of the domains of the current academic sequencing centres is difficult for funding agencies and patients alike to comprehend. Given this relatively pioneering approach, it has taken a lot of time to develop the infrastructure and analytical capacity to address the magnitude of the study we have undertaken. We are learning the hard way that datasets of this size are at best unwieldy. The computer resources alone have taken a year to master and apply, yielding the variations in each genome that seem to be more frequent in patients that have the disease. 

In parallel, Schizophrenia studies, like the Psychiatric Genomics Consortium (PGC) boast 123,000 samples from people with a diagnosis of schizophrenia, bipolar disorder, ADHD, or autism and 80,000 controls collected by over 300 scientists from 80 institutions in 20 countries. Given the magnitude and complexity of these projects, it fast becomes clear that collaboration, data sharing and internal communication are powerful components i.e.: drivers of success in contrast to traditional innovation, insight and raw scientific discovery.

Other diseases are by no means on the sidelines. Although relatively rare, the debilitating and lethal neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS) is also on the "galactic plane". Combining resources at a global scale, Project Mine has generated over 5000 full genome sequences with a goal of completing another 10 000 within a year. Whole countries are sequencing their populations. Here in the UK the plan is to complete 100 000 genomes by 2017. In Qatar they will sequence 300 000, in USA the plan is to complete 1 million people's whole genomes. The tiniest nations are also on the plane - even the Faero Islands plan to complete 50 000 subjects and Iceland has just published the first 2000 whole genome sequences in their population. Although this sounds like a great deal, the means to adequately process and analyse these, and other large scale datasets is in its infancy. How can we analyse all this data? One way is the obvious route of training and education. We are part of a new National programme to establish graduate training in genome medicine. Offered here at Sheffield, the MSc makes a solid step towards beginning to understand the use of genome data for health.


"The critical intersection of Genomics Big Data Medicine, delving into 'bleeding edge' technology & approaches that will deeply shape the future."
Also here in UK we have been building groups across institutions so that we can collaborate to analyse and handle big health data. Working with representatives across Sheffield Institutions that will become part of a "Health North’ initiative, we are looking to combine de-identified, consented, health and environmental data across cities so that we can ultimately engage in actioning new forms of health data analysis.
 
In my view, Eric Shcadt currently leads the new field at the intersection between big data and genomics and medicine - at least in terms of vision. He has driven the development of multi-scale biological research projects that have captured thousands of genomes, clinical records, related datasets and drug profiles to launch a new form of highly networked big data medicine. The first really broadly accessible application of this is will be the launch of a new app together with Apple's health ecosystem Apple ResearchKit that will help doctors interpret medical data on an iPhone. What data is that? Simply put it's your lifestyle - how many steps you take, how many stairs you climb, your blood pressure, blood oxygen, when and where. Ultimately combining that with genomics and other health data means that apps in the future could have the potential to truly and effectively predict when you and you alone are most likely to die. Schadt calls his adventure the 'death app' - not a name that is likely to live long.



By Professor Winston Hide, Chair of Computational Biology and Bioinformatics




Monday, 18 May 2015

Astrocytes - “Stars of the brain”


Astrocytes, the most prevalent cell type in the brain, are increasingly recognised as playing a role in neurodegenerative diseases including Alzheimer’s disease. 


When you think of the brain and the cells that comprise it what do you think of? I’m guessing it’s neurons? Although it is true that there are billions of neurons in the brain and that they are responsible for executing everything we say and do there are another population of cells in the brain which for a long time have been overlooked – the glial cells.

Glia – sticky cells?

The word glia literally translates as ‘glue’ and these cells were first officially described back in 1846, when a German Anatomist called Rudolf Virchow described a connective substance that forms a ‘cement’ in the central nervous system (the brain and spinal cord) in which the neurons were embedded. For a long time after (and despite the work carried out by these early physiologists showing that these cells were not simply ‘glue’) most studies of the brain have focused on neurons with little regard to the potential role of glia in brain function or their contribution to disease. However in recent years there has been an increasing recognition that glia are crucial for healthy brain function and these cells are now stepping into the limelight and being given the recognition they deserve.

There are several different types of glia in the brain; 

oligodendrocytes which ensheath neurons enabling the fast transmission of neuronal signals; microglia are the defence cells of the brain, they scavenge for pathogens, damaged neurons and plaques; finally there are the astrocytes and these cells are the focus of this blog.

The stars of the brain

Astrocytes are typically star shaped, hence their name (Greek astron = star, and kytos = cell, hence a star-shaped cell). They were first officially described by Santiago Ramón y Cajal in 1909 (although the concept of glia and their morphology had already been around for about 60 years). Cajal won the Nobel Prize in Physiology in 1906 for his work on neurons but he also had a very keen interest in glia. The drawing below is one of Cajal’s early depictions of human astrocytes surrounding a blood vessel in the cerebral cortex of human brain.





Cajal’s drawing of fibrous astrocytes in human cerebral cortex
(Garcia-Lopez et al, 2010).
 In human brain it is estimated that there are 1.4 astrocytes for each neuron, and one single astrocyte can contact up to 1 million neuronal processes – amazing (and quite hard to imagine)! It is thought a lot of the complexity of human brain can be attributed to the evolution of astrocytes since human astrocytes are larger and more complex than those of other mammals. There are also distinct populations of astrocytes in human brain that are not found in the brains of other mammals. You can get an idea of the complexity of these cells in the image below from a researcher called Nancy Oberheim who also has a huge interest in these cells. The astrocytes can be seen in white, with neurons in red, you can see how complex (and pretty) the astrocytes are with long projections which will be extending to numerous (thousands and thousands) of neurons. 



Human astrocytes are shown in white, with neurons in red, from Oberheim et al., 2009.
Notice how the blood vessels are also white, this is because astrocytes
ensheath blood vessels so that they can regulate blood flow to the brain and
regulate the passage of substances in and out of the brain

Astrocytes are the workhorses of the brain

Astrocytes have numerous functions, a few of which are outlined below to highlight just how important these cells are for brain functioning! They are responsible for maintaining the barrier between the brain and the rest of the body (called the blood-brain barrier), which prevents the unregulated passage of substances into the brain. They are crucial in the formation and maintenance of synapses (the junctions between neurons), without these synapses neurons would not be able to signal to one another and they also regulate blood flow to the brain, increasing blood flow when there is a lot of brain activity and reducing it when brain activity decreases. In addition they are also crucial in repairing damage which occurs due to injury or disease.

Why all the fuss about these cells?

My specific interest in these cells relates to their emerging role in Alzheimer’s disease. In fact astrocytes are the focus of a number of researchers here at SITraN since there is evidence for astrocyte involvement in Motor Neurone Disease and Parkinson’s disease
as well as other diseases of the brain. My interest in astrocytes was sparked during my PhD at the Institute of Psychiatry where I discovered that astrocytes actually seemed to enhance the effect of toxic amyloid proteins.



Images from my PhD showing how astrocytes (in green) change in the presence of
toxic amyloid peptides which are present in Alzheimer’s brain.  Garwood et al., 2011

From London I moved here to SITraN as Prof. Stephen Wharton’s research group focused on astrocytes in ageing brain and Alzheimer’s disease – a perfect match! I have recently been awarded a research fellowship from the Alzheimer’s Society to continue investigating the role of astrocytes in Alzheimer’s disease, this will focus on how astrocytes respond to insulin and the role this plays in Alzheimer’s disease. This is interesting because there is a strong link between diabetes and Alzheimer’s disease and because evidence suggests the brain becomes resistant to insulin at the earliest stages of Alzheimer’s disease. In addition I am developing a system to grow astrocytes and neurons in a three-dimensional environment so it more closely mimics human brain.

I hope I have convinced you that astrocytes are very important cells that are deserving of our research time and do not simply function as ‘glue’. Below is one of my favourite cartoons from cartoon neuroscience which highlights just one of the roles of astrocytes! 


 Follow the Star!
Reproduced with permission from Immy Smith http://www.redbubble.com/people/immy


 By Dr Claire Garwood



I am an Alzheimer Society Research Fellow and my research focuses on understanding the role of astrocytes in the disease process.  You can follow me on my twitter account (@geekyclaire) or find me on Researchgate for a full list of up to date publications and research (www.researchgate.net).






Image references:
1. Garcia-Lopez P, Garcia-Marin V, Freire M (2010).
The histological slides and drawings of Cajal. Front. NeuroAnat. 4:9. 

2. Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA, Nedergaard M (2010).
Uniquely hominid features of adult human astrocytes. J Neurosci. 29(10):3276-87.

3. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011).
Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2;2:e167.
 
4. Cartoon reproduced with permission from Immy Smith http://www.redbubble.com/people/immy