The genetic lottery: self-destruction or survival?

Illustrated strand of DNA

As one of the many scientists who contributed to our Settlers exhibition, geneticist Dr Calliope Dendrou from the Wellcome Centre for Human Genetics ran a Spotlight talk as part of the exhibition’s event programme, where she explained more about her research into genetics and autoimmune diseases…

Our genes make us who we are – they are what unite us a single species, Homo sapiens – but they are also what make us unique individuals, with a particular set of characteristics. Genes are made up of DNA inherited from one individual to the next, transmitting the code for life through time.

The DNA ‘alphabet’ comprises four letters, A, C, G and T, and three billion of these letters make up the complete human genome. Comparing two unrelated individuals, on average around one in 1,000 of the three billion letters will differ. Genetically speaking, each of us is 99.9 percent the same as every other unrelated person.

Studying our genetic composition and the similarities and differences between individuals is of interest from a historical, geographic and sociological perspective, as the Settlers exhibition at the Museum shows. But it can also have medical implications for our understanding of the types of diseases we are susceptible to.

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Immune cell (yellow) engulfing anthrax bacteria (orange). Image: Volker Brinkmann [CC BY 2.5], via Wikimedia Commons
My lab works on the genetics of autoimmune diseases, which affect some ten percent of people worldwide and include relatively common conditions such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes.

Autoimmune diseases arise when the cells of the immune system function inappropriately. The immune system is made up of millions of immune cells patrolling the body, sensing their environment and sending signals to each other.

If the body has been injured due to physical trauma or an infection, then upon receiving the right signals immune cells help to clear damaged cells or fight off pathogens. But sometimes immune cells can begin to respond to the wrong signals, triggering a self-destruction. When this happens they can destroy the body’s own tissues and organs and then autoimmune start to diseases develop.

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Autoimmune disorders in a nutshell –  illustration by Beatrice the Biologist

The common autoimmune diseases are very complex and are thought to result from a combination of genetic and environmental influences. Hundreds of genetic factors can influence someone’s risk of autoimmune disease development, so having a low or high risk is a genetic lottery – it depends on how many different genetic factors happened to have come together for that person.

We are investigating the biological consequences of these genetic factors to find better ways to target the immune cells that are attacking the body. The trick is to do this without suppressing the immune system’s ability to fight off infection, a problem associated with drugs used treat autoimmune disease patients today.

The winning brainwave

If you could create an experiment to learn more about the human brain, what would you investigate? We posed this question in our Big Brain Competition last year, as part of the Brain Diaries exhibition with Oxford Neuroscience, and received a whopping 800 entries!

For the competition, Oxford University neuroscientists offered people the chance to use the state-of-the-art MRI scanner at Wellcome Centre For Integrative Neuroimaging at the John Radcliffe Hospital to investigate a burning question about the brain. We had ideas from the young and old, and by visitors from all around the world suggesting brilliant questions and some fascinating experiments.

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Functional MRI image of the human brain using the MRI Scanner

To judge all the ideas, entries were split into categories: feasible experiments, unfeasible experiments, under 18s, and questions about the brain. WIN researchers compiled a long-list for each, which was ranked by a panel of neuroscientists and people from the museum to reach the eventual winners.

Sadly, only one experiment could be carried out, so an overall winner was picked from the ‘feasible experiments’ category. The winning experiment was suggested by Richard Harrow, who wanted to understand how the brain identifies voices.

A person is put in the MRI scanner with headphones on.  They are shown a photo of a person familiar to them, either a friend, family member or celebrity.  Then, in their headphones they are played the voice of a person, but the voice is either sped up or slowed down.
They are required to say whether the face on the photo matches the voice they have heard. What happens in the brain when this confusion of audio and visual information is occurring? Will the brain find a way to identify the vocal signature of the voice, even if distorted, and be able to say with conviction if the photo and the voice are a match?
– Richard Harrow, winning competition idea

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Competition winner Richard Harrow was interviewed alongside neuroscientist Dr Stuart Clare during the live streaming of the experiment

On the day of the experiment, the winners and runners-up headed over to the WIN Centre to watch Richard’s winning experiment being conducted. The experiment was streamed live by Oxford Sparks and we had a clear result from the test, as neuroscientist Dr Holly Bridge explains:

The scans show that when you’re getting information that corresponds in both your auditory and your visual system you get a boost in your brain activity. We can detect that the brain does respond differently depending on whether or not you can match the face with the voice; it clearly has a lot to do with expectation.

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The brains behind the Big Brain Competition, Dr Holly Bridge and Dr Stuart Clare explained the results of the experiment on a Facebook Live stream

The scientists also wanted to answer as many of the other great brain questions as possible. So a series of articles picks out some of the broad themes in the competition ideas, including lifestyle, muscle memory and stress. Researchers also answered more big questions live on Facebook during this year’s Brain Awareness Week.

We sorted the many entries in the Big Brain Competition into themes such as vision, lifestyle, and language

Thank you to everyone who suggested an experiment or asked a question; it made for a fascinating conclusion to the Brain Diaries exhibition, and has definitely increased the amount of brain activity from staff across the Museum and Oxford Neuroscience… if only there was an MRI scanner for us to see it!

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Winners of the Big Brain Competition at the Museum of Natural History with the neuroscientists. Left to right: James, Holly, Stuart, Misha, Richard, Lily, and Heidi

You can still get involved with the Big Brain Competition by trying the winning experiment at home.

 

The crucial cortex

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University of Oxford PhD student Lance Millar recently ran one of our Brain Spotlight events as part of the Brain Diaries exhibition programme. Here, Lance explains his research into neurodevelopmental disorders and possible treatments.

The brain has always been a fascinating organ for me. It is the site of our intelligence, our problem-solving and social skills, and it allows us to connect our senses to the world around us.

The large, folded outer part of the human brain is called the cortex, and is responsible for decision-making, language, face recognition, and a lot of the other things that I like to think are what make us human. The word cortex comes from the Greek for husk or outer shell, which underestimates the importance of what the cortex does.

Humans can survive with damage to the cortex, but depending on the part of the cortex that is damaged, a range of disabilities can result. People who have had a stroke can lose part of their cortex, leading to limb paralysis, loss of speech, or loss of memory, depending on the site of the damage.

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Cerebral cortex – Professor Michael R Peres – Wellcome Images

Some people are also born with a developmental problem in the cortex, and are said to have a neurodevelopmental disorder. Such conditions are thought to include autism, schizophrenia, ADHD, and even dyslexia – all fairly common conditions. The damage to the cortex is subtle and complex in these conditions, and scientists are still working out exactly what happens to the brain during its prenatal development.

I am studying one particular neurodevelopmental disorder caused by lack of oxygen at birth. It is known to medical specialists as neonatal hypoxia ischaemia. The image on the right shows a cross-section MRI scan of a normal newborn human brain, alongside some babies who have been damaged by oxygen deprivation. You can see that the brains are smaller, the cortex is less folded and it takes up less space inside the skull.

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MRI scans of normal newborn brains alongside those of babies who have been damaged by oxygen deprivation. Image: Woodward et al., New England Journal of Medicine, 2006

Scientists still don’t know how to protect the newborn brain from these injuries. Some are caused by inflammation which is a normal response to illness, but can wreak havoc in the confined space of the skull. Some is caused by the presence of free radicals, which are thought to contribute to ageing and organ failure, as the newborn brain doesn’t have many antioxidants to fight these chemicals. It’s also possible that the electrical signals that neurons within the brain send to each other contribute to the damage when there isn’t enough oxygen to feed them.

So what can we do to treat oxygen deprivation at birth? One breakthrough treatment currently available is known known as hypothermia. In this technique, the baby is cooled to 33℃ which slows down the brain-damaging chemical reactions which in turn protects the brain. This is currently the only treatment available, but I am involved in the study of possible alternatives.

We don’t want to introduce any drugs to the baby’s system as they might be harmful to normal development. So scientists are currently working on treatments which help the baby’s natural body proteins to protect the brain. I do this by looking at neurons under the microscope, and identifying proteins expressed by these neurons using fluorescent probes known as antibodies.

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An example of neurons under the microscope. Image: Lancelot Millar

These neurons are expressing neuroserpin, a natural brain protein which decreases inflammation and cell death. I’m looking at exactly where neuroserpin is expressed in the brain, how it can be upregulated in response to oxygen deprivation, and how its chemical reactions could be used to protect the brain.

Another way to help people with neurodevelopmental disorders is to better understand how the cortex connects to other parts of the brain and how it can carry out complicated decisions. There is still so much to understand about the complexity of the human brain, and what seems like fundamental research could generate the springboard for new ideas for neurodevelopmental disorder treatments.

To explore the structure of the human brain and compare it to that of other animals see the Brain Diaries Brain Explorer below.

 

Cathedral to nature

To mark National Poetry Day 2017, former Museum poet-in-residence Kelley Swain writes about her residency, getting to know the Museum, and the Guests of Time anthology.  

Throughout 2016, I was one of three fortunate writers to be invited into the Oxford University Museum of Natural History’s first poetry residency. It was our task to engage how we wished with the collections, curators, history and architecture of the Museum, and produce seven new poems each in the first third of the year. The next two-thirds comprised editing and publishing the residency anthology, Guests of Time, and running poetry engagement events.

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Kelley Swain reading from the Guests of Time anthology at the launch event  – December 2016

But this wasn’t the first time poets were inspired by the Museum. The building opened in 1860, an exemplary Victorian ‘cathedral to nature,’ heavily influenced by art critic John Ruskin who involved Pre-Raphaelite artists in its design and decoration.

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Guests of Time anthology

Guests of Time includes new work from the resident poets (myself, John Barnie, and Steven Matthews,) as well as contemporary Victorian poetry related to the Museum. This includes ‘The Lay of the Trilobite’ by May Kendall, a student at Somerville College, Oxford, and ‘A Year and a Day’ by Lizzie Siddal, who was invited to contribute designs for decorative carvings in the building (though, ultimately, decorative work was cut short due to lack of funds).

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Continuing to spend time getting to know the building and its contents, I’ve been able to more fully appreciate the astonishing attention to detail throughout, and the sometimes seemingly ‘superfluous’ garnishes in which the architects indulged, such as this decorative ironwork on one of the Museum towers.

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Decorative ironwork on one of the Museum towers

It is not a weathervane; it is not, of course, any kind of antennae. It is beautiful, seemingly unnecessary, yet somehow integral. It was the Victorians (Darwin, always, is a good example,) who began to understand that many things in nature considered ‘superfluous,’ (such as the blue decoration of a male bowerbird’s bower,)  had in fact evolved through mate preference (sexual selection) or another competitive advantage (camouflage, fitness).

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Blue decoration of a male bowerbird’s bower

Oxford University held an architecture competition to choose a design for the building. The winning team included architect Benjamin Woodward, iron-master Francis Skidmore, and sculptors James and John O’Shea. The Victorians were striving, in Ruskin’s words, towards ‘truth to nature’. They were selecting for what Darwin called ‘grandeur in this view of life’. We do well to remember that no attention to detail, however small, is superfluous: in nature, in architecture, in poetry. On a grander scale, the arts are as essential to humankind as is blue to a bowerbird.

 

 

All about Alzheimer’s

University of Toronto research fellow Jacqueline Zimmermann recently ran one of our Brain Spotlight events as part of the Brain Diaries exhibition programme. To mark World Alzheimer’s Day today, here Jacqueline tells us about the neurophysiology of Alzheimer’s disease and the risk factors we can actively reduce to lead happier, healthier, and longer lives.

Almost all of us have in some way been affected by Alzheimer’s disease, which makes the quest for a cure that much more personal. An estimated one in nine people over the age of 65 will develop the disease, and this risk also increases with age, according to the World Alzheimer’s Report in 2015.

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Jacqueline Zimmerman’s Brain Spotlight on Saturday 16 September as part of the Brain Diaries exhibition series of events.

Due to chemical toxins, and increased longevity, the incidence for Alzheimer’s disease is on the rise. But the good news is that there is a lot that you can do to reduce your risk. At the John Radcliffe Hospital in Oxford, hundreds of scientists are currently working towards identifying the cause and the solution to the disease.

At the Brain Spotlight event at the Museum I presented images of ageing brains, and explained how brains affected by Alzheimer’s have reduced volume in the temporal lobe and the hippocampus, regions critical for language and memory respectively. Diseased brains will also often show reduced frontal lobe volume, which may reflect the changes in personality and the ability to engage in planning which area associated with Alzheimer’s. The overall volume of the brain is also reduced in sufferers because cellular changes lead to the death of neurons.

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Brain Atrophy in Alzheimer’s disease. Note: overall brain volume is reduced, hippocampal regions and frontal regions are particularly affected, and ventricles are enlarged. Image: http://www.lookfordiagnosis.com

Recently, a number of genes have been identified that are related to early onset Alzheimer’s, which is quite rare and much more hereditary than late-onset Alzheimer’s. At the Nuffield Department of Clinical Neurosciences, where I am a visiting researcher, we are investigating a late-onset Alzheimer’s risk gene called Apolipoprotein 4 (APOE4), looking at how it relates to subtle cognitive impairments in middle-aged people. Working with the Oxford Biobank we are trying to determine which cognitive assessments may be most effective in predicting these impairments.

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Functional brain imaging using electroencephalography at Rotman Research Institute in Toronto. Image: Rotman Research Institute

Although some of us may be more susceptible to Alzheimer’s than others, there are a number of environmental factors that contribute, including air pollution or additives in our food, like nitrogen-based chemicals which are used to preserve and flavour processed foods. It is important to reduce cholesterol in the diet, eat plenty of fruits and leafy greens, and engage in frequent physical and mental exercise.

Though there is speculation about the effectiveness of ‘brain games’ and how they translate into improvements in cognition in the real world, there are certainly large benefits of keeping your brain active.

 

Amber time capsules

New Museum Research Fellow Dr. Ricardo Pérez-de la Fuente talks about his fascinating work with a special collection at the Museum of Comparative Zoology, Harvard University, and what he’ll be getting up to at the Museum of Natural History. 

Amber, fossilised resin, has fascinated humanity since prehistoric times due to its mesmerising colour, shine, and fragrance when burned. From a scientific viewpoint however, what makes amber unique is the ability that the resin has to capture small portions of the ecosystem and the organisms living within almost instantaneously, in an unaltered way, preserving them for tens of millions of years. This has an unmatched fidelity among the fossiliferous materials.

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Holotype of Fibla carpenteri Engel, 1995, a snake-fly. Credit: President and Fellows of Harvard College.

During a four-year postdoctoral fellowship at the Museum of Comparative Zoology (MCZ) at Harvard University, I had the chance to curate, identify and digitise one of the premier fossil insect collections worldwide. It holds about 50,000–60,000 specimens, including around 10,000 amber inclusions. One of the unexpected outcomes of my time there was helping to rediscover a forgotten loan of about 400 Baltic amber samples that had been brought to the MCZ from the University of Königsberg during the 1930’s.  This loan ended up sparing the specimens from being destroyed during the bombardment of the city of Königsberg (renamed Kaliningrad thereafter) in World War Two. The full-story as showcased by the Harvard Gazette can be found here.

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Holotype of Lagynodes electriphilus Brues, 1940, a megaspilid wasp. Credit: President and Fellows of Harvard College.

As a researcher specialising in fossil arthropods, one of the most remarkable challenges for me during the digitisation project at the MCZ was to overcome the thrill to learn more about the specimens that we were imaging. In what way were they different from their modern relatives? Were they perhaps new to science? What information were they providing from the ecosystem in which they lived? At present, I can fully embrace these questions and many more thanks to becoming a Museum Research Fellow at the Museum of Natural History.

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Cotype of Hypoponera atavia (Mayr, 1868), an ant. Credit: President and Fellows of Harvard College.

My research at the museum focuses on studying interactions between organisms in deep time and their behaviours, particularly in Cretaceous amber, such as plant-insect pollination relationships around 100 million years ago. During that time, a major shift was taking place in terrestrial ecosystems due to the diversification of angiosperms (flowering plants), which ended up replacing gymnosperms (non-flowering plants) as the dominant flora. There was also the appearance of key groups of organisms from the ecological perspective — ants and bees in the case of insects, for instance.

It is a well-accepted fact that preservation in amber is biased towards small organisms because the larger ones tend to escape the sticky resin more easily. But how easy it is for one to get lost in amber when examining its secrets and trying to unravel its mysteries! Becoming forever trapped within.

Some of the most remarkable Baltic amber specimens (about 40 million years old) returned to the Königsberg collection from the MCZ. Pictures: RPF. Credit: President and Fellows of Harvard College.