Matrin 3 gene identified

Following on from our ’year of hope’ appeal last month an international team of researchers, including two funded by the MND Association, have identified mutations in the Matrin 3 (MATR3) gene as a cause of the rare inherited form of MND.

Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Clinical Research Fellow Dr Pietro Fratta was involved in the research, which was published on 30 March 2014 in the prestigious journal Nature Neuroscience.

Inherited MND is a rare form of MND (5-10% of total MND cases) and the MATR3 gene is the latest to be identified. This rare form of MND is characterised by a family history of MND.

New gene, new gene

When a new gene is first identified this creates a great deal of ‘buzz’ amongst the MND research community, often generating more questions than answers:

  • How common is this inherited MND gene?
  • How does this gene cause MND?

This is the starting point for MATR3. Unfortunately, we just don’t know the answers to these questions at the moment. Hopefully MND researchers will now use the discovery of MATR3 to find the answers to these questions and further our understanding of this gene.

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Celebrating posters

If you followed the reporting about the symposium last weekend, I’m willing to bet (but I haven’t checked!) that most it will have been about the talks that people attended or liked. When actually, a large proportion of the research presented at the International Symposium on ALS/MND is in the form of a poster.

Milan poster session discussion

Delegates discuss a poster presentation

A poster is a hard copy of a research study, it can be the latest results or developing a new methodology. It’s quite often a PhD student’s introduction into presenting their work face to face to their peers.

Following the day’s talks, on the first and second evening of the symposium, it was time for an opportunity for some informal networking around the posters. At allocated time slots presenters stand by their work and explain it to fellow delegates. (They also have time to visit other posters too).

For twenty of those presenting posters, there was an additional pressure. They were on the shortlist for the International Symposium Clinical and Scientific Poster Prizes respectively.

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The cell that never grew up

With Pantomime season kicking off back home in the UK, delegates in Milan were introduced to one of the newest cellular villains in the MND story – oligodendrocytes.

Although oligodendrocytes were first identified in the 1920s and are known to be affected in multiple sclerosis, they were generally considered as ‘bit part’ players in MND rather than ‘centre stage’.

All that has started to change in the past couple of years, with researchers in the USA and Belgium independently showing that, in both SOD1 mice and human post mortem MND brain tissue, the brain was making new oligodendrocytes to replace ones that appeared to be dying off.  The problem is that the new ones being formed appear to get stuck in an immature state and therefore do not perform their role of helping motor neurons to maintain appropriate energy levels and also send electrical signals down their long nerve fibres.

So, by getting stuck in a ‘Peter Pan’ scenario of never growing up, oligodendrocytes may be at best, unable to help protect the death of motor neurons or, at worst, they may actually contribute to the degeneration. Peter Pan rather than Captain Hook as the pantomime villain is a novel twist to the script!

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Tilting the scales

We know that in the 5-10% of cases where there is a strong family history of MND, there is likely to be a genetic cause at work, acting like a weight to push the scales in favour of the disease occurring.  These gene mutations are hidden somewhere within the 15 billion or so letters of DNA that make up our genome and, through collecting samples from extended families affected by the disease, coupled with huge advances in gene-hunting technology, researchers have managed to identify over two-thirds of the causes of hereditary MND in recent years and are hot on the heels of the other causes.

scales

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Clinical trials in a dish?

A packed room at the 24th International Symposium on ALS/MND was given a fascinating whistle stop tour covering stem cells, robots and cellular garbage clearing, by Dr Steve Finkbeiner of the University of California, as well as a glimpse into the future of developing ‘disease in a dish’ models of MND.

Dr Finkbeiner outlined how his lab is attempting to conduct “clinical trials in a dish” by generating huge numbers of cultured neurons cells for automated ‘high throughput analysis’ of their health and death. As he says, “we’re basically trying to develop a comprehensive physical examination for nerve cells”. Read the rest of this entry »

Researchers in Australia identify how blue-green algae may cause some cases of MND

A toxin known as β-N-methylamino-l-alanine (BMAA), which is found in blue-green algae, has been shown to cause proteins inside cells to clump together and cause cell death.

This finding suggests that BMAA may be a cause of neurodegenerative diseases like Alzheimer’s and MND and could lead to the development of new treatments.

What is BMAA?

BMAA is a non-protein amino acid. This means, that unlike the 20 amino acids that our bodies use to make proteins, it does not make a human protein.

BMAA is found in a type of bacteria called Cyanobacteria (more commonly known as blue-green algae), which are usually found in waterways as well as damp soil and on the roots of cycad plants.

Blue-green algae can occasionally cause algal blooms. This is when there is a rapid growth of organisms due to high levels of nutrients in the water. The resulting bloom can sometimes become so large that it can be toxic to wildlife.

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New MND Association Lectureship in Translational Neuroscience

Dr Richard Mead based at the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield has been awarded the Kenneth Snowman-MND Association Lectureship in Translational Neuroscience.

Dr Richard Mead, SITraN, UK

Dr Richard Mead, SITraN, UK

The five-year Kenneth Snowman-MND Association lectureship is aimed to embed preclinical expertise in motor neurone disease (MND) models within SITraN as a national resource.

Our Director of Research Development at the Association, Dr Brian Dickie, commented: “We are delighted to be able to help secure the position of an outstanding young scientist at one of the top European centres for MND research.

“Our understanding of the causes of MND and the reasons why motor neurons degenerate is increasing rapidly and we need more researchers like Dr Mead who are ideally placed to move this new understanding from the laboratory to the clinic.”

Read more about this story on our website: New MND Association Lectureship in Translational Neuroscience.

The 11th Annual ENCALS meeting highlights how TDP-43 spreads in MND

The European Network for a cure of ALS (ENCALS) held its 11th Annual meeting in Sheffield from 31 May to the 2 June. The weekend was full of glorious British sunshine and more than 200 international scientists and clinicians were also able to enjoy a range of incredibly interesting talks about the latest developments in MND research.

A particular talk caught my attention on the first day by Dr Johannes Brettschneider from the University of Ulm in Germany. Dr Brettschneider explained how his research had shown the stages and spread of the protein TDP-43 in ALS (the commonest form of MND).

Dr Brian Dickie, Director of Research Development, said: “The key to defeating MND lies in fostering strong collaborations between neurologists, healthcare professionals, research scientists, early career investigators and students in the field of MND and the 11th Annual ENCALS meeting in Sheffield provided that opportunity. The MND Association was proud to support this event.”

‘Special’ staining

At the end of an afternoon of talks on the MND- causing genes C9orf72, FUS and SOD1, Dr Brettschneider engrossed over 200 delegates with his talk on the TDP-43 protein and how it spreads in ALS.

Although TDP-43 genetic mistakes are a rare cause of MND, scientists are especially interested in the TDP-43 protein because in the vast majority of cases of MND (irrespective of whether it was caused by an inherited genetic mistake), TDP-43 protein forms pathological clumps inside motor neurons.

The study (which is a collaboration between Dr. John Trojanowski and Dr. Virginia Lee from the Penn University Center of Neurodegenerative Disease Research in Philadelphia, America and the group of Dr. Heiko Braak in Ulm) used a technique known as ‘immunohistochemistry’.  This technique involves taking tissue samples of the brain and spinal cord from people who have died from ALS. The researchers would then make extremely thin slices of the tissue, which could then be stained using a ‘special stain’ and viewed under a microscope.

The stain used by Dr Brettschneider only ‘stained’ the TDP-43 protein in the samples, meaning that he could see the amount of TDP-43 in different areas of the brain and spinal cord.

Using the clinical information and TDP-43 staining this would allow Dr Brettschneider to stage the disease.

Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.

Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.

Axonal ‘telephone wires’ do more than just talking

Dr Brettschneider showed that TDP-43 increased in different areas of the brain and spinal cord during different stages of the disease. Amazingly, he also showed how ALS (characterized by clumps of TDP-43) spreads from one are of the body to another.

A motor neurone consists of three parts; the cell body, axon and nerve ending. The cell body contains the nucleus, or the control centre of the cell. When a message travels from the brain the cell body sends the message down the axon. Like telephone wires, the axon carries the message to the muscle, where the nerve endings cause the muscle to move.

However, in ALS it seems that these ‘telephone wires’ do more than just carry a message. The protein TDP-43 forms ‘clumps’ in the motor neurones and it seems that these clumps use the axon to travel from one motor neurone to the next (possibly explaining why someone get’s weakness in their arm and then their hand).

Another key finding was that TDP-43 clumps develop in the front part of the brain (prefrontal cortex), which is responsible for personality and may explain the development of cognitive symptoms.

Dr Brettschneider explained the importance of this research While spreading of disease-related proteins has been described for other neurodegenerative diseases like Alzheimer’s disease or Parkinson’s disease, this had not been previously shown in ALS. Now, we can show evidence that supports a spreading of the major disease protein TDP-43 in ALS across specific regions of the brain and spinal cord with ongoing disease.

 If these findings can be confirmed (for example in cell culture or mouse model studies) then this could lead to the design of new treatments specifically aiming to impair the spread of TDP-43 protein clumps.

Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS

Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS

Furthermore, we believe that our findings offer a better understanding of disease progression in ALS.  Our data implies that TDP-43 spreads throughout the prefrontal cortex with ongoing disease, thereby lending support to the idea that all ALS patients could eventually develop “frontal type” cognitive deficits.”

The future

Dr Brettschneider commented why this research is important to people living with MND explaining that “If these stages can be reproduced in patients with ALS they could offer a new way to assess disease progression and response to new treatments. We hope that our study provides the essential groundwork for strategies designed to prevent pTDP-43 spread.”

This research is only the beginning and more work is needed, Dr Brettschneider also explained what he hoped to do next with these exciting results. “There were restrictions in time and availability of the tissue samples during this study, so we were unable to determine how and where exactly ALS begins in the very early stage of the disease. Therefore, an important next step in our work would be to analyze very early cases with ALS to look at TDP -43 spread as this offers the most promising window for therapeutic intervention.”

Reference

Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 May 20. doi: 10.1002/ana.23937. [Epub ahead of print]

Anne Rowling Regenerative Neurology Symposium

The sun was (uncharacteristically!) shining on Edinburgh last week for a symposium to celebrate the launch of the new Anne Rowling Regenerative Neurology Clinic. The clinic, which opened to patients earlier this year, was founded following a donation by the author JK Rowling, in memory of her mother, who died from complications related to multiple sclerosis (MS).  Run by Professors Siddarthan Chandran and Charles ffench-Constant, the clinic aims to translate laboratory research into clinical trials for neurodegenerative diseases such as MS and MND.

Anne rowling logo

The programme for the two-day meeting was packed with ‘big hitters’ from the world of neurology. In keeping with the regenerative neurology theme, the opening session was chaired by Sir John Gurdon, recent co-winner of the Nobel Prize for physiology and Medicine, whose pioneering work on cell cloning set the foundations for the more recent development of induced pluripotential stem cells, which are currently revolutionising medical research.

Different diseases, common challenges

The first day was given over to research areas such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease, as well as spinal injury and pain. What was also apparent is that different fields of neurology are wrestling with similar challenges: to diagnose disease earlier, ideally even before symptoms occur; to find biomarkers that tell us about the changes occurring in the Central Nervous System(CNS) at different stages of disease; to really understand the order in which these different aspects of pathology (the study and diagnosis of disease) occur and, given the theme of the conference, to sift the cellular changes caused by disease from the body’s attempts at cellular repair. All of these feed into the greatest challenge – how to take this accumulated knowledge from bench to bedside.

We can learn a lot from diseases that are further ahead in this process, such as the excellent overview by Prof Alastair Compston (Cambridge) on MS. It’s becoming clear that MS has distinct disease stages, starting off as an inflammatory disease, but progressing to a more ‘traditional’ neurodegenerative disease in more advanced stages. Whist there has been some considerable success in treating the former, the approaches to the latter have, as with MND, met with very limited success.

The use of imaging techniques to work out what is happening within the brain has been a vital factor in drug development for MS. As Prof David Miller (University College London) pointed out, magnetic resonance imaging (MRI) can pick up positive changes in small MS drug trials that are not large enough to show changes in disability. This sort of biomarker-based evidence gives drug companies the confidence to invest in the larger, much more expensive trials needed to show a clinical effect.

A presentation on the imaging of pain by Prof Irene Tracey (Oxford) provided a fascinating insight into the power of the placebo effect. She explained how neuroimaging has helped researchers to identify the brain regions associated with placebo effects and also gave examples of studies where the placebo effect has performed as well as (and even outperformed) commonly used painkillers! The power of placebo can be very strong indeed and it is important to always ensure that trials are rigorously performed to account for this.

Parkinson’s disease has always been viewed as a promising candidate for cell transplantation therapy, but clinical studies over the past 30 years have produced mixed results. Profs Roger Barker (Cambridge) and Anders Bjorklund (Lund University) discussed the various reasons for this ‘heterogeneity of response’ and how these are being addressed in the plans for a pan-European study.

In terms of cell transplantation, the approaches that will need to be taken for MND are very different from those for Parkinson’s disease. In Parkinson’s disease the strategy is to try and replace some of the key neurons that have died, but due to the immense length of human motor neurons, such a strategy of rewiring the nervous system is highly unlikely to work for MND. However, there are other approaches that can be taken, as Prof Clive Svendsen (Cedars-Sinai Medical Center) explained.

His approach involves a combination of gene therapy and stem cell therapy. By converting human stem cells into astrocytes, which are cells known to play an important role in keeping neurons healthy. By genetically modifying these cells to produce large quantities of a nerve protecting factor called glial-derived neurotrophic factor, and injecting them into the spinal cord of SOD1 rats, he has shown that the surviving motor neurons can be protected. He is in the process of gearing up for a phase 1 therapeutic trial in up to 18 carefully selected MND patients.neuron

Disease in the dish

Prof Svendsen also briefly spoke about the promising research arising from the use of induced pluripotential stem cells (iPSCs) to study MND – a topic taken up in much more detail by Prof Jeff Rothstein (Johns Hopkins University) who highlighted recent advances in understanding the C9orf72 form of the disease.

It may be possible to create specially tailored gene therapy approaches for some forms of familial (inherited) MND, as is currently being attempted in SOD1 MND. Prof Rothstein’s initial work using iPSC-derived motor neurons suggests that this approach is also worth considering for the more common C9orf72 from as well.

Prof Steve Finkbeiner (University of California) who is collaborating in the Association-funded international stem cell initiative elaborated on the use of iPSCs as a tool for drug discovery, demonstrating how fully-automated robot-based systems can be used to follow the fate of thousands of individual human motor neurons in the dish over a prolonged time period. The great thing about robots is that they don’t need sleep, so can analyse the cells at all times of day and night. They do, however, have Twitter accounts, so they can report in to the centre staff when they have completed their experiments!

One of the exiting prospects of using these automated systems is the potential to screen thousands of compounds. If human motor neurons can be protected in the dish, there are no guarantees, but it at least shortens the odds that the human motor neurons can be protected in the human as well. There are still many improvements that can be made to the process, but screening work is underway, with a particular focus on drugs that stimulate cellular process called autophagy (a process in which a cell breaks down damaged components), which is believed to be protective across a number of neurodegenerative diseases.

There were many take home messages from this meeting, but what was abundantly clear from all the work presented was the enthusiasm of each speaker for their field of research and an optimism that we are on the cusp of major advances in understanding neurological conditions. Sharing of new knowledge across the various diseases and disciplines can only bring those advances closer.

Jolly Good Fellows!

There’s a scene in the 1969 film Battle of Britain where Laurence Olivier, who plays the Air Chief Marshal, is in a meeting with his two Vice Marshals. One of them complains that they don’t have enough planes; the other is more concerned with keeping the airfields working. Olivier silences them both by telling them that the fight will be won or lost on one key factor – the number of trained pilots.

It’s a rather cheesy film, but I used that story earlier this month to illustrate the importance of investing in bringing through the next generation of researchers in our battle to defeat MND.  We organised a ‘get together’ of our Lady Edith Wolfson Clinical Fellows at the Sheffield Institute for Translational Neuroscience (SITraN) to share their research findings with the donor who has so generously supported the scheme. The ‘get together’ also provided a wonderful opportunity for them to exchange information and expertise with each other, as well as all the staff of SITraN, who over the course of the day were frequently shuttling between the lecture room and their labs.

The Fellowships are aimed at attracting and training the brightest and the best Clinician-Scientists (or ‘Doctor-Doctors’ as I sometimes call them – with both a medical degree and a science PhD). Even so, I couldn’t resist using this cartoon in my introduction, although the reality is very different for our Fellows – the bar is set very high and even applicants for the Junior Fellowships need to have considerable research experience and be fully ‘lab tested’.

image courtesy of www.vadlo.com

image courtesy of http://www.vadlo.com

Our host for the day was one of the world’s most respected MND ‘Doctor-Doctors’, SITraN Director Prof Pam Shaw, who welcomed everyone to the meeting and provided an overview of the multidisciplinary expertise and collaborative philosophy that underpins SITraN. Prof Shaw also has a great belief in the importance of nurturing the next generation of talent and it is no surprise that almost half of the Clinical Fellows in the programme are based at SITraN.

Are fit and active people more likely to develop MND?

Our first research presentation was from Dr Ceryl Harwood (Sheffield) who is carrying out research on the epidemiology of MND. Specifically, she is addressing the question of whether physical activity is a risk factor for MND. As she explained, this has been a long standing theory, showing us a quote from a medical journal written over 50 years ago which stated:

”Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases”

She outlined the plausibility that physical activity may contribute to a complex interplay between biological and genetic processes that may predispose an individual to develop the disease. Generating the evidence, however, is no easy matter, but she has developed and validated a novel questionnaire to measure physical history in adulthood, using data from a diabetes study in the 1990s where over 1,000 people had detailed measures taken of their actual energy expenditure.

A hundred of these participants have recently agreed to undergo rigorous face-to-face interviews and their responses were correlated with actual physical measures from over 15 years previously. In other words, she can now assess how accurately peoples’ recollection of their physical activity – both day to day work and vigorous exercise – links with their actual energy expenditure at the time. This questionnaire is now being used to compare the physical activity profiles in up to 350 people with MND and 700 control participants in Yorkshire and surrounding counties.

Should the results support the theory that physical activity is a predisposing factor in MND, she will be perfectly placed to delve into the genetic factors that underpin the selective vulnerability of motor neurons.

Repetition is bad….

Dr Pietro Fratta

Dr Pietro Fratta

Next up to the lectern was Dr Pietro Fratta, (University College London) who has been immersing himself in the mysteries of how the C9orf72 gene can cause neurodegeneration – especially MND and a related condition called Frontotemporal Dementia (FTD).

Like a needle on a vinyl record can sometimes stick and repeat the same fragment of music again and again, this gene sometimes carries a repeat in its genetic code – specifically with the letters GGGGCC occurring again and again.  Dr Fratta has examined many DNA samples from MND and FTD patients and finds that these ‘repeat expansions’ are very large indeed, occurring between 700 and 4000 times!

The process through which these repeat expansions cause nerves to die is still a mystery, but Dr Fratta showed results from his lab which suggests that rather than losing its normal function, the C9orf72 gene gains some additional activity, turning it into a ‘rogue’ gene. He and his colleagues have recently shown that the repeat expansions can lead to the formation of very stable chemical structures called G-quadruplexes that have been implicated in causing nerve damage in other disorders.

He is currently studying how these structures interact with other cellular components, interfering with normal neuronal function. He is also starting to look at possible therapeutic approaches in a collaboration with the UCL School of Pharmacy to develop compounds that will bind to and hopefully inactivate these structures.

Over lunch, we were given a guided tour of the superb SITraN labs by Prof Shaw. Although I strongly believe that research is only as good as the researchers doing the work, there’s no doubt that having a purpose built institute filled with state-of-the art technology certainly doesn’t do any harm!

Then it was back into the lecture room for our afternoon presenters.

A Sheffield double act

The post-lunch session was kicked off by Dr Robin Highley, a neuropathologist who has recently completed his Fellowship and now divides his time equally between pathology duties and MND research. Dr Highley’s area of expertise is in how neurons edit the genetic instructions into precise ‘blueprints’ to make proteins, the essential building blocks of every cell in our body.

He used an entertaining analogy of making dresses form a pattern to describe the process of how DNA is made into RNA copies which can be ‘tailored’ into slightly different protein designs (to find out more about how DNA makes RNA and subsequently proteins see our earlier blog post).

Dr Johnathan Cooper-Knock

Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Using a variety of approaches he has looked at gene expression (which genes are being switched on and off) and gene splicing (how the RNA copies are edited) patterns in both inherited and non-inherited MND, as well as in non-MND states. He finds changes occurring in thousands of genes, but by performing searches on databases of the ‘function’ of each gene he can then sort them into different groups (which are then involved in key cellular processes). This provides important clues as to which cellular pathways are altered in MND, which will help researchers around the world to focus their attention on the most common changes and hopefully start addressing the question of how these may be slowed or stopped.

Dr Highley focused his talk mainly on the TDP-43 and SOD1 forms of inherited MND, with his colleague and fellow ‘Fellow’(!) Dr Johnathan Cooper-Knock, concentrating on the C9orf72 form (the most common cause of inherited MND). Through the MND Association’s DNA Bank  he has been able to obtain a large number of cell lines from patients with C9orf72 MND, along with detailed clinical information, which will allow him to compare patterns between those with fast progressing and those with more slowly progressing disease.

Although at a much earlier stage in his research, having started only 6 months ago, Dr Cooper-Knock has already identified some specific gene expression effects that may be distinct to the C9orf72 form of the disease. For more details about Dr Cooper-Knock’s work see our earlier blog post about his fellowship.

BioMOx and beyond

It was fitting that Dr Martin Turner (Oxford) gave the closing presentation. Not only was Dr Turner the first recipient of a Lady Edith Wolfson Fellowship, but he has recently been awarded a new five-year Senior Clinical Fellowship through the programme – these are highly prestigious awards, with only one in seven applicants successful.

Dr Martin Turner

Dr Martin Turner, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Titling his talk ‘BioMOx and beyond’ Dr Turner outlined the challenge of identifying a specific signature of MND. He showed that whilst there is unlikely to be a single test for MND, a combination of tests (involving brain scanning and eye tracking techniques together with chemical analysis of blood, urine or cerebrospinal fluid) are showing some promise in aiding and speeding up the diagnosis, as well as predicting how the disease is likely to progress within an individual.

He highlighted the importance of international collaboration, such as the new formal link with Dr Mike Benatar in Miami, who for several years has been studying people at risk of developing inherited MND. Indeed, Dr Turner apologised for missing the morning speakers at Sheffield as he had been busy with one of Dr Benatar’s study participants in his MRI scanner at Oxford!

On the subject of international collaboration, our most recent Clinical Fellow, Dr Jemeen Sreedharan, was unfortunately unable to attend as the first two years of his Fellowship is based at the University of Massachusetts, returning to the University of Cambridge to complete his research. We look forward to having him at the next Fellows get-together!

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