Discovery at the Discovery Museum

Aside

 

Great Hall

Great Hall

Ready to replicate the success of last year’s Away Day, it was en masse outing time for ICaMB again! Time to find out who all the new faces are, and to find out exactly what that person you have a ‘hello and a nod in the corridor’ relationship with actually does at the bench all day. This year we headed to the Great Hall of the Discovery Museum. Despite the leaking roof caused by the downpour outside and the sometimes dodgy acoustics the day was still a success.

Serious faces, this is science

Serious faces, this is science

ICaMB is a fast paced, constantly evolving institute. Everybody is busy with their own research, making a break and a get-together once in a while a vital part of reminding ourselves of the vast range of expertise and diverse set of interests beavering away in our labs and offices. The answer to that tricky problem or that elusive technique is quite possibly just a few yards away.

But also fun!

But also fun!

With that in mind, this year’s Away Day felt particularly important as we welcomed 8 new academic groups to ICaMB from CAV (Campus for Aging and Vitality) as well new IRES fellows and a list of other recent recruits. Drs Victor Korolchuk and Gabi Saretzki from the CAV both spoke at the away day about their interests in neurodegenerative diseases and the role of oxidative stress in the ageing process.

As ever the day was kicked off by the Institute director, Bob (Professor Robert Lightowlers), who gave us a taster of ICaMB’s growth and success stories over the past year. Without breaking into the tune of that well known Christmas song; 7 Vacation Studentships, 6 BBSRC awards, 5 MRC awards, 2 Wolfson awards, 2 Senior Investigator awards and 1 Henry Dale ………. Not to mention all the promotions, outstanding research papers and commercial contracts = 1 happy Bob.

ICaMBAwayDay1(2)

ICaMBAwayDay3

 

 

 

 

 

 

 

 

A cell-tastic morning then ensued: the completely dispensable nature of bacterial cell walls (Professor Jeff Errington); the role of NF-kB in the pathogenesis of lymphoma (Dr Jill Hunter); and the cell death independent functions of inhibitors of apoptosis (new IRES recruit Dr Niall Kenneth). The session was wrapped up by Dr Paula Salgado summarising 3.5 years of structural C. difficile research in 15min. Some feat Paula!

Of course just as last year, an absolute highlight of the day were the six, animated, three minute thesis presentations by our brave PhD students ……..  Soon to be followed by the look of horror on several Professorial faces when it was suggested by PAN!C that at next year’s Away Day we have a session of 3 minute PI pitches! We can’t ignore the demands of our PhD students now can we? And congratulations to Mandeep Atwal from the Cowell/Austin lab who against steep competition was awarded the prize for best three minute thesis.

The possibilities of alginate bread?

The possibilities of alginate bread?

A spot of oxidative stress and the evolution of peroxidases by Dr Alison Day, and some lunch completed the morning’s discovery. Though half an hour later and Dr Peter Chater had us all wishing we’d had an alginate packed lunch (and a go with the model gut!). Perhaps the Pearson lab can cater next year’s event? If it’s good enough for the One Show it’s good enough for the ICaMB Away Day.

A major focus of the Away Day is not just to learn about the breadth of exciting research carried out in our institute, but also to learn all about the very latest techniques and expertise ripe for exploitation. This year the focal point of new techniques came from Dr Alex Laude and the Bio-Imaging facility, with some beautiful images and super resolution microscopy techniques, which again left a number of the audience wanting a turn!

P1000375An afternoon transcribing and translating with Dr Danny Castro-Roa; learning about how the crucial nature of cell polarity means we really don’t mix up our arse from our elbow (thank you new IRES recruit Dr Josana Rodriguez); and last but by no means least, how on earth all that DNA manages to faithfully copy and repackage itself time after time from yet another new recruit, Professor Jonathan Higgins.

This completes our diverse and entertaining line-up, just leaving enough time for complementary wine, and the amusement as speakers and audience alike embarrass themselves at the ICaMB quiz (and I hear also in the pub afterwards).

Antisense Science: A Science Blog by Students

 

Blogs are now a widespread science communication tool, with many researchers taking to the blogosphere to discuss the latest scientific discoveries, explain the basic concepts in their research field to a wide audience or just talk about science and scientists. Our 3rd year bioscience students have done just that, and this week we have a guest post prepared by them.

 

by Antisense Science

Antisense Science is a science blog founded by a group of 3rd year bio-scientists from Newcastle University. As a team, we recognise that science is not as accessible to the general public as it should be.  We therefore make it our primary aim to translate complex scientific principles and research articles that interest us personally, into topical, thought provoking blogs accessible to everyone.

Our project is small but our ambition is big! Since our founding in October 2013 we have published 58 articles covering psychoactive baths salts, human evolution and the neurobiology of love, to name a few, and with a growing following (we’ve had over 6000 hits since inception) we were thrilled to be given the opportunity to guest post on ICaMBlog. As Newcastle University students, our interest in research was stirred by the professors at Newcastle University, including those who founded this blog. With planned guest posts focusing on research by Prof Rick Lewis among others, maybe YOU will feature on Antisense Science in the near future! We foresee (we hope!) that our blog can form a bridge between researchers here at Newcastle and the student body, raising awareness of what is actually being discovered right under our noses. By forming mutually beneficial collaborations, we hope to diversify and grow our following and expose our current readers to a continual stream of stimulating articles which never fail to pique the interest of the curious.

Meet the Antisense Science team

Meet the Antisense Science team

Currently, we have a total of 7 writers, all of whom enjoy sharing the intrigue of the latest developments in science, from biochemistry to microbiology (and even physics) and we have no plans of stopping. Although many of us will be moving on from our BScs to ever greater things, Antisense Science will remain and we are even in the process of recruiting further up and coming bio-scientists as writers (keep your eyes peeled for blogs from first year students Bethany Lumborg and Lucy Gee, as well as our fellow third year Emily Lawson and a multitude of guest posters from across the student body). The future looks bright and we’re very glad with the progress we have made thus far!

For an example of what we do, here is an article on depression written by our very own Joe Sheppard. We hope you enjoy it!  If you ever want to be involved in any of our projects feel free to drop us a message.  We also have Facebook (www.facebook.com/antisensescience) and Twitter (@AntisenseSci) so there are plenty of ways to keep in the loop.

 

The Confounding Contradictions of Depression

If you currently have or have had depression then you may already be able to tell your MAOIs from your SSRIs, but if you haven’t then what you read here might actually help. Knowledge is power and I believe learning a little something about depression could contribute a bit of control to an otherwise daunting and often underestimated medical condition.

Depression is perhaps the ultimate “common complex disorder”. Unlike pathogens or mutations that affect physical body tissue, depression is a condition that alters the very consciousness and emotional state of an individual making it a truly unique affliction. Throughout the course of our lives 1 in 5 of us will experience depression or anxiety of some kind, yet the majority of people conceive depression  simply as a disease of “sadness” when the truth is much more complex. “Anhedonia“, an inability to feel joy in anything and “congruent memory bias”, the inability to remember or altered recall of specific memories, are extremely common cognitive behaviours in depression that we often inflict upon ourselves on a day to day basis.

It may surprise you to know that modern science can say with little certainty what neuro-physiological changes initiate depression, and linking those that we do think are involved to the broad psychiatric manifestations seen in cases of depression is even harder as human experience and consciousness is beyond the understanding of molecular neuroscience (and by extension, definitely me). But from the murky depths of our own minds patterns do emerge, and as such there are a few good theories out there.

Rather confusingly the best fitting theory of depression is actually based on the drugs WE ALREADY USE to treat it, not a common theme in medicine, I might add. “The monoamine theory of depression” states that depressed brains have reduced signalling between neurons via a group of specific chemical neurotransmitters called monoamines. Two in particular called 5-hydroxytryptophan (hereafter referred to as serotonin) and dopamine are released into a synapse to induce electrical signals between neurons in the midbrain. These two neurotransmitters and the resulting electrical signals are most notably perceived as feelings of joy, euphoria, reward and attention. And there is some evidence to back this up: depletion of tryptophan, an amino acid essential for serotonin synthesis in the brain, caused mood congruent memory bias, and altered reward-related behaviours. Biochemical evidence exists too, abnormalities of the protein that binds serotonin in the brain called the 1A receptor have been noted in multiple brain areas of major depressive disorder (MDD) patients. Why does serotonin decline in patients with depression? Well, search my pockets, you will find no answers.

Rather reassuringly this hasn’t stopped treatment of depression at all, and several drugs for which the theory is named are all targeted at increasing serotonin, and so good feelings, within the brain. The so named selective serotonin re-uptake inhibitors (those “SSRIs” I snuck in earlier, such as fluoxetine and sertraline) are the most prescribed group of antidepressants and work in a way best aided pictographically:

Neuron

Schematic representation of neuron activity

Serotonin is synthesised in the presynaptic neuron from tryptophan, from here it is packaged into vesicles and upon nerve impulse firing (see previous article “ shedding light on neural networks”) is released in the synaptic cleft (the space between neurons).  Serotonin then binds to receptors on the postsynaptic neuron, stimulating a similar nerve impulse. However, serotonin is also able to control its own release: By binding to the 1A receptor on the presynaptic neuron it prevents continued release of serotonin, allowing the proposed channel protein SCL6A4 to re-absorb serotonin in the presynaptic neuron to be destroyed.

This is where SSRIs come in. Believed to bind to SCL6A4 and prevent the re-absorption of serotonin, it allows serotonin to remain in the synaptic cleft for longer and therefore stimulate nerve impulses in the post synaptic neuron for longer, and so increase the degree of monoamine signalling.

Let’s not forget our friend dopamine:

Dopamine too is a monoamine consistently found reduced in the blood of patients with depression, as a result of decreased synthesis and degradation in the brains of these patients. Neurons that signal using dopamine (as opposed to serotonin) are found in a region of the brain called the substantia nigra that degenerates during Parkinson’s disease. Interestingly the motor impairment (shaking) in this disease is often preceeded by major depressive disorder in 50% of Parkinson’s cases!

This brings me quite nicely to my final point. Since so little is known about the basis of psychiatric disorders their treatment has been almost purely symptomatic for the last 60 years. Thomas Insel, director of the US National Institute for Mental Health was quoted in 2013 as saying “In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain, or the quality of fever.” This was following the release of the 5th edition of the diagnostic and statistical manual of mental disorders (DSM-5), that diagnoses psychiatric conditions based on common symptoms presented by each condition. Despite the strong agreement with Insel by many psychiatrists that this method is outdated, the shift to a more objective and molecular diagnostic is years away given the outstanding complexity of these diseases. But keep the hope, recent booms in neuroscience research are a sure step towards a less archaic means of treating depression and other mental disorders.

A new approach spearheaded by the same Thomas Insel called “Research Domain Criteria” or RDoC is already doing just that by utilizing genomic sequencing technology, fMRI imaging techniques and cognitive science to develop an entirely new platform for diagnosis based on new data being attained all the time, rather than the laboured DSM-5 classification. While still in its infancy this new approach aims to start looking at broader groups for diagnosis rather than classification of different disorders by the symptoms they present. For instance, by looking at a group of patients with different disorders but all experiencing anhedonia will not only allow a greater insight into a unifying cause for these symptoms, but also speed up treatments in the future.

Of course, there are always two sides to each argument and depression does in some sense stand alone from other psychiatric disorders such as schizophrenia in that it imparts a greater emotional influence on the sufferer – if “precision medicine” were able to prescribe a pill for the treatment of emotional conditions, would you want it to? Of course this is a quandary we won’t face for some time, but worth a thought.

J.

Some interesting but by no means comprehensive reviews on depression, its far too huge for 3 articles!

Hasler G (2010). Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World psychiatry : official journal of the World Psychiatric Association (WPA), 9 (3), 155-61 PMID: 20975857

Martinowich K, Manji H, & Lu B (2007). New insights into BDNF function in depression and anxiety. Nature neuroscience, 10 (9), 1089-93 PMID: 17726474

Frances, A. (2013) One manual shouldn’t dictate US mental health research
(Accessed: 07/01/14).

Deep Impact

Alginate bread on a pedestal under show-biz lights

Alginate bread on a pedestal under show-biz lights.

 

Another excellent post by ICaMB’s Dr Matthew Wilcox as the fame of alginate spreads and seaweed bread goes on tour!

Well, I was kindly invited along to the BBSRC Fostering Impact awards ceremony in London a couple of weeks ago and although I wasn’t up for anything, Newcastle University were.

Fostering impact is a scheme run by the BBSRC to capture the economic and social impact of research funded by them.  There are three competitions that fit the fostering impact scheme; ‘innovator of the year’, ‘activating impact’ and ‘excellence with impact’.  The first is for an individual researcher, the second is for the knowledge exchange teams and the final award is for research organisations (runs from 2013 – 2015).

Outside eventInside eventThe knowledge exchange and commercialisation team at Newcastle University has changed substantially over the past couple of years.  What was once a centralised Business Development Directorate has now become the Research Enterprise Service, comprised of three teams, each embedded in one of the Faculties.  Each Institute or School now has their own dedicated business development manager (BDM), with ICAMB’s BDM being Laura Rush (who is very nice).  They are now much easier to contact, whether it’s just a quick question or the drafting of patents.

Home baking

Home baking practice.

Newcastle’s application for the Activating Impact award was submitted back in October 2013 and used the wonderful research done by the beautiful people of ICAMB as its basis.  In January the RES team found out that they had successfully made it to the final five (from 18) and through to the grand final in London.  Newcastle was up against the knowledge exchange and commercialisation teams from King’s college London, Queen Mary University of London, University College London and University of Aberdeen. One of the requirements of the competition was to bring along someone to the final who had worked with RES, a ‘user’ (according to the BBSRC).  They also wanted an iconic object?!  Alginate bread it was then.  Back in the kitchen I went. How many loaves would I need to feed the people there? Two should do it, right?

Martin and Laura on the train gearing up for competition.

Martin and Laura on the train gearing up for competition.

In London Martin Cox presented the case for Newcastle in front of a panel of scientists, business types and other technology transferers, assembled by the BBSRC. Demonstrating what Newcastle does well, how BDM’s have been embedded into each institute and also what they would do with the money if we won (£100k).  He also described the additional internal funds that are available to help activate impact.  FMS has two funds available; the first is to help with data collection for translational grant applications, the second is to support further claims in patent applications.  The two internal grants can both potentially support a post doc salary for three months, plus consumables.

Dengue fever carrying mosquito

Dengue fever carrying mosquito.

The awards ceremony combined the ‘innovator of the year’ and ‘activating impact’.  I got a glitzy stand for my bread and also had the chance to look around the other pretty amazing stuff that was on display, like Dr Luke Alphey’s work. Luke ended up being named both social innovator and overall innovator of the year for his work on the genetic control of pests, including the dengue fever carrying mosquito.

I even got to meet the new (ish) CEO of the BBSRC, Professor Jackie Hunter, who was definitely not snapped stuffing free stuff into her bag!

BBSRC's CEO Jackie Hunter enjoying the exhibition

On the right BBSRC’s CEO Professor Jackie Hunter enjoying the exhibition.

Unfortunately Newcastle did not win, but being down to the last five of the competition is brilliant and should give confidence to ICAMB scientists that when help is required in achieving impact (social or economic), we have a great team to help.

Queen Mary University of London, whose entry was also being supported by a previous BBSRC Enterprise Fellow and King’s College London, ended up being joint winners each scooping £100k.

Perhaps if a few more of the world leading researchers in ICaMB engaged with the Enterprise team, they might not have to only take some eejit and his bread to the competition next year and increase NU’s chance of winning!

Pruning the Tree of Life

Dr Tom WIlliams

Anyone who has studied biology has seen an image of the tree of life in the text books.  Most of us think of this as being set in stone, one of the rock solid foundations on which evolutionary biology is built.  However, all is not quite as settled as it seems.  Recently, a Nature article from the laboratory of ICaMB’s Professor Martin Embley challenges the traditional three domain structure of the root of life.  Here, first author on the paper, Dr Tom Williams, tells us the story.

By Dr Tom Williams

Our modern understanding of the tree of life began in 1977 when Carl Woese and his colleagues discovered the Archaea, a group of prokaryotes originally isolated from extremely hot or salty environments. Although Archaea looked indistinguishable from Bacteria under the microscope, their gene sequences were at least as different to those of Bacteria as from the eukaryotes – the group of organisms, including fungi, animals and plants, whose cells contain a mitochondrion and a nucleus. According to these analyses, living cells should be classified into three main groups: Bacteria, Archaea and eukaryotes – rather than the two (prokaryotes and eukaryotes) that had previously been established based on cell structure. In 1990, Woese and his colleagues published another seminal paper in which they argued for this “three domains” classification. This three-domains tree has become an iconic image in biology, and is often found in the popular science literature, as well as many textbooks – you’ve probably seen it before. Here it is from a 1997 review by Norman Pace:

The traditional 3 domain Tree of Life. From: A molecular view of diversity and the biosphere. Pace NR Science (1997) 276: 734-740

 

Professor Martin Embley

This was certainly the tree of life that I was familiar with, first as an undergrad and later as a Ph.D. student at Trinity College Dublin. So I was surprised and very intrigued when a certain Martin Embley came to talk at an Irish bioinformatics meeting, claiming that support for the three-domains tree was not as strong as you might expect. New work from his lab instead favoured the “eocyte tree”, in which the eukaryotes (or, at least, some of their genes) actually evolved from within the Archaea. If true, this tree would imply that there were originally only two types of cells – Bacteria and Archaea – and that the eukaryotes (i.e., us!) originated later in a partnership between the two primary domains.

The new model of the Tree of Life proposed by the Embley lab

Fast-forward a couple of years, and I was thinking about where I wanted to do my postdoc. I remembered Martin not only from that talk, but also from some interesting work (2nd link) he had done on a group of parasitic fungi called Microsporidia. I joined his group and began working on microsporidians, but I was still very interested in the tree of life and the origin of eukaryotes. In the meantime, DNA sequencing technology had been improving, and microbial ecologists were beginning to publish genomes from new groups of Archaea that could not be grown in the lab, and so had never been studied before. One of the really exciting findings from these studies was that some Archaea contained genes that looked very similar to fundamental components of our own cells, such as actin and tubulin – two proteins that help to define the microscopic “skeleton” of eukaryotic cells. When we added these new genomes to our analyses, we found even stronger support for the eocyte tree; those findings were reported last year in Proceedings B. At about the same time, a number of other researchers were reporting something similar: as our view of archaeal biodiversity increased, support for the three-domains tree was on the wane. Given the prominent position of the three-domains tree in the literature, and the importance of this question for understanding early life on Earth, we decided to write a review summarizing these recent developments in the field – it came out in Nature this week, and it’s the reason for this blog post!

As we delved back into the 30 years of literature on the molecular tree of life, one of the most interesting discoveries for me was a seam of eocyte literature that I hadn’t been aware of previously. Although many analyses over the past three decades have recovered the three-domains tree, and it appears in all the textbooks, the literature has actually never been unanimous in its support. Nonetheless, it is only in the last five years or so that support for the eocyte hypothesis has reached critical mass, perhaps due to improvements in our statistical methods and, more recently, sampling of archaeal biodiversity.

The Embley lab: Back row, left-to-right: Kacper Sendra, Martin Embley, Tom Williams, Robert Hirt. Front row: Shaojun Long, Ekaterina Kozhevnikova, Andrew Watson, Paul Dean, Maxine Geggie,Alina Goldberg-Cavalleri, Sirintra Nakjang.

Of course, our latest work is almost certainly not going to be the last word on the relationship between eukaryotes and other cells. Our methods are getting better – in part thanks to the statisticians we are collaborating with here in Newcastle – but there is much room for improvement, and so much about the microbial world that we still have to discover. Still, if the eocyte tree is correct – and it appears to be the best-supported tree on the current evidence – then that has important implications for how we understand early life on Earth and the origin of our own cells. For one thing, it rules out the eukaryotes as a primordial cellular lineage, as old as the Bacteria and Archaea. Instead, it suggests that the Bacteria and Archaea were established and diversifying on Earth before the origin of eukaryotes, resurrecting the concept of an “Age of Prokaryotes” on the early Earth. Of course, when you think about the phenomenal number of Bacteria and Archaea that live in your own body, never mind the wider environment, you might well argue that it never ended…

This work was supported by a Marie Curie postdoctoral fellowship to Tom Williams. Martin Embley acknowledges support from the European Research Council Advanced Investigator Programme and the Wellcome Trust.

Links

The Nature Article: http://www.nature.com/nature/journal/v504/n7479/full/nature12779.html?WT.ec_id=NATURE-20131212

The Proceedings B paper: http://rspb.royalsocietypublishing.org/content/279/1749/4870

The Embley lab website: http://research.ncl.ac.uk/microbial_eukaryotes/

Microsporidia papers: http://www.nature.com/nature/journal/v452/n7187/full/nature06606.html

http://www.nature.com/nature/journal/v453/n7194/full/nature06903.html

Leading the Way… in Protein Structure

 

By Kevin Waldron

This week, ICaMB welcomed the Leading the Way winners into our labs for an exciting day of science. As you may remember from our previous post a couple of weeks ago, Leading the Way was ICaMB and Leading Edge’s collaborative pilot scheme to take some of ICaMB’s great science (and early career scientists) into a local school, George Stephenson High School in Killingworth. That week was a great success, inspiring all of its participants: students, teachers and ICaMB members alike.

The overall winners during the week in GSHS were the AU team, made up of Lucy Hainsworth, Libby Macpherson, Rebecca Brown, Lauren Rhodes, Abbey Wrightson, Kimberley Stoker, Sophie Anson, Connor Little, Nathan Clapperton. AU designed an outstanding poster to illustrate how the prion protein represents a biomarker of mad cow disease (or, more scientifically, variant Creutzfeld-Jakob disease, vCJD), how the structure of this protein changes from the ‘normal’ form to the ‘abnormal’, disease-causing form, and how knowing the structure of the prion protein can enable us to design a diagnostic test.

AU’s prize was to spend a day in an ICaMB laboratory, learning about how we determine the structure of a protein, with the members of the judging panel, Dave Bolam, Paula Salgado and myself.

After a brief welcome and introduction, we kitted our guests out in fetching lab coats, supplied them with ‘Leading the Way’ lab books and got started.

Showing the kids how to plate cells on a petri dish

 

First, the kids tried their hands at microbiology with the Waldron lab, streaking E. coli cells onto agar plates and then picking colonies to inoculate cultures for recombinant protein production.

 

 

Practising to become a PhD student, staring at a pouring column…

Next, Dave Bolam and his team demonstrated how a His-tagged protein can be purified using affinity chromatography, and then the kids loaded each of their protein samples on SDS-PAGE gels. Remarkably, all of the students successfully purified their target protein, though it’s worth noting that this was not actually the prion protein, PrPC (Imagine the risk assessment!).

 

“Here, let me help you” says Dave.

 

It was great fun spending time with enthusiastic kids and giving them a flavour of what we do. It reminds you why you do science in the first place“, says Dave after taking part in this type of activity for the first time.

“We’re doing science now, Miss!” – shouted one of the students

 

 

The day finished with a demonstration of protein crystallisation with Paula Salgado and Will Stanley of the Structural Biology Laboratory. The students attempted to crystallise lysozyme (with mixed success), and then observed protein crystals under the microscope.

It’s always great to share our love for science with young minds and see them get really excited about carrying out the experiments we do routinely. It’s a breath of fresh air in the lab. Hopefully we’ve given them an experience to remember, as well as a better understanding of research in a biomedical institute.” commented Paula at the end of the day.

 

Although this was a high-paced tutorial in protein production and structure determination – a process that usually takes at least several weeks, and in some extreme cases an entire career – the students received a hands-on demonstration of some real-life research techniques. We all hope that this experience, even at such an early age, might just implant the idea of a future in science for some of these young people.

But from my own perspective, I can say that their enthusiasm has been infectious (no pun intended), and is a timely reminder of why I got into science in the first place – because at school I always found science classes more interesting than any others. I would have loved such an opportunity when I was that age.

Thanks go to Phil Aldridge, ICaMB’s Leading the Way coordinator, all of the members of the Waldron, Salgado and Bolam labs who helped out during the visit, the staff of George Stephenson High, and most of all to the members of the AU team, for making the day a success.

 


George Stephenson High School http://www.gshs.org.uk/home

 

You don’t always want what your mother gives you! – can we prevent mitochondrial disease?

 

By Professor Robert Lightowlers

In 1988, scientists in the UK and US recognised that certain diseases were caused by mutations in mtDNA . Over the following 20 years, mtDNA defects have been shown to cause a range of debilitating diseases many affecting different parts of the body. However, the main disorders relate to your muscle tissue and the brain.

Human muscle fibres stained for mitochondrial function. As can be seen in B, some of the fibres show no activity. This is because these fibres have high levels of mutated mitochondrial DNA.

It is estimated that at least 1:10,000 people suffer from disorders associated with defects in Mitochondrial DNA (mtDNA) – that’s more than 6,000 people in the UK. Even so, it is only recently that the importance of mitochondrial diseases have hit the general media.

Many of you will have seen the debate on correcting mitochondrial diseases in the newspapers (for example, see the Guardian, Telegraph) and on television recently, but not be aware of the central role that Newcastle researchers have played in making this exciting, or to some, controversial, new therapy closer to becoming a reality.  Here, Bob Lightowlers ICAMB Director and senior member of the Wellcome Trust Centre for Mitochondrial Research (WTCMR) reflects on the role mitochondrial research in Newcastle has played in this process over the last 20 years and tells us some of the story behind the headlines.

What are Mitochondria?

Electron micrograph of a cell (coloured blue) revealing part of the mitochondrial structure (orange) within. The entire length of the mitochondrion is about 5 micrometres.

 

These crucial structures found in all the trillions of cells in our body have many essential functions. One very important role they play is to take our common foodstuffs such as fats and sugars and turn them into energy for our body’s to function.

A single human cell showing the nucleus (green), the mitochondrial network (red) and the mitochondrial DNA within the network (yellow)

 

 

 

One surprising element of these structures is that they contain their own genetic element, mitochondrial (mt) DNA. Much smaller than our chromosomes, mtDNA is essential for energy production.

 

 

 

OK, so this is important, but why have mitochondria and mtDNA begun to work their way into the common conversation of the nation?

Answer: Our mothers!

What has this got to do with our mothers ? Mitochondrial DNA is only transmitted to babies by their mothers. This is different to all our other DNA where copies are made and transmitted from both parents. Unfortunately, as you inherit your mothers mitochondria, diseases caused by mtDNA mutations are inadvertently transmitted from the mother.

How does this relate to Newcastle based Mitochondrial Research?

My colleague Doug Turnbull, a neurologist here in Newcastle (and Director of the WTCMR) and I have been intrigued by these mtDNA mutations since it first became clear that they could cause disease. Back in the early ‘90’s, we discussed whether some day it would be possible to try and prevent the transmission of the faulty mtDNA from the mothers to their children. Of course, at that stage, it was just wishful thinking. As the Mitochondrial Research Group (MRG) began to grow and mature in Newcastle, we often returned to one question:

What if the nucleus from the diseased egg could be transferred to a healthy egg whose nucleus had been removed, in essence leaving all the affected mtDNA behind ?

If it was indeed possible, this reconstituted egg could be fertilised and implanted back into the mother by standard techniques used routinely in fertility clinics throughout the world. We also would consider when would such a technique be most efficient: before or after fertilisation of the egg? On paper both options looked possible, but there are many complications.

Technical Concept: achieving the switch of nuclei without some of the faulty mtDNA being inadvertently taken along for the ride.

Towards the end of the 90’s, scientists working in Canada were able to show that the level of mtDNA inadvertently transferred when the nucleus was switched into a recipient cell lacking a nucleus, was low. This was a promising result, but it led to two central questions:

•   Could this be repeated with human cells?

•   Was this technique morally and ethically acceptable to everyone?

The ethical debate: Debate raged as to whether this technique would constitute genetic manipulation of humans, which of course would be illegal. Further, it was not possible to perform these types of reconstruction experiments in man, as using viable human fertilised cells for research was also, understandably, illegal.

Professor Mary Herbert working at the nearby Human Fertility Centre came up with an intriguing proposal. She explained that unfortunately, during the standard process of in vitro fertilisation, many eggs became incorrectly fertilised. These eggs are unable to grow correctly and have to be discarded. One way of determining whether it would be possible to swap mtDNA in humans, she suggested, was to use these incorrectly fertilised eggs. As this procedure would still require the manipulation of fertilised human eggs, a licence would need to be applied for from the Human Fertilisation and Embryological Authority (HFEA). Following lengthy and extensive debate, including members of the research team being called to the House of Commons, a licence was eventually awarded in 2005.  Five years later, with the essential help of colleagues in the Fertility Centre, Mary, Doug and a group of us from the MRG were able to show that such a swap could be performed without any or very low levels of the defective mtDNA being transferred. Importantly, there was also no defect detectable in the reconstituted cells . In 2011, this very promising result, along with many other important contributions made by the Newcastle MRG to understanding mitochondrial biology in health and disease was recognised by the Wellcome Trust who funded the establishment of a new Research Centre in Newcastle, the Wellcome Trust Centre for Mitochondrial Research.

Getting acceptance of the technique

It was important to know whether the people of the UK agreed that such reconstitution technology was ethically acceptable. In August 2012, the government asked the Human Fertility and Embryological Authority (HFEA) to find out what the general public thought of the procedure .  The results were collated last month and the Human Fertility and Embryological Authority made a recommendation to Government. There was an overall support for the new technology with only 10% being fairly or strongly against the concept of mitochondrial gene replacement ) This is an endorsement of the method but there is still a long way to go before the technique can be performed in the clinic.

Its amazing to think how far this concept has come in 20 years. Perhaps in another 20 years we may be able to look back and celebrate how this dream has helped to provide a realistic method to help prevent the transmission of a debilitating disease for many couples.

 

Wellcome Trust Centre for Mitochondrial Research http://www.newcastle-mitochondria.com/
Human Fertility and Embryological Authority (HFEA) http://www.hfea.gov.uk/index.html
HFEA mitochondria puclib consultation 2012 http://www.hfea.gov.uk/6896.html