Misfolding
Image by Louise Serpell
“Misfolding” is a public engagement collaboration between the Centre for Research in Opera and Music Theatre and the Serpell Lab in the School of Life Sciences at the University of Sussex.
The Lab has made some important discoveries about the particular malfunctionings of the brain that lead to dementia, which significantly alter our understanding of the illness. Proteins are at the core of life as we know it, and their malfunctioning can lead to disease. For over 100 years scientists have known that there are proteins that can stick together and build up in the brains of people with Alzheimer’s disease. This process is called “misfolding” and can be studied in a laboratory with the aim of finding out why it happens, and what can be done to stop or reverse it so that diseases can be treated.
The project employs music, performance and digital arts to communicate these developments in brain science and dementia research in an imaginative and poetic way.
Project Team
Professor Nicholas Till – Centre for Research in Opera and Music Theatre
Frances M Lynch – Artistic Director, electric voice theatre and Minerva Scientifica Women in Music and Science
Professor Louise Serpell – Serpell Lab, School of Life Sciences
Dr Karen Marshall – Serpell Lab, School of Life Sciences
- Video transcript
I'm professor Louise Serpell and I'm Dr Karen Marshall and we work in the School of Life Sciences at the University of Sussex dementia affects millions of people throughout the world and the most common form of dementia is Alzheimer's disease there are many misconceptions about Alzheimer's disease it's not a part a natural part of getting old like losing your keys or forgetting people's names it's a disease of the brain as scientists our role is to try and find out what causes Alzheimer's disease the work we do in the laboratory can sometimes seem a long way from those living with dementia but basic research is at the core of scientific discovery and treatment the brain is obviously very complex and there will be many factors at play in the initiation and development of Alzheimer's disease for over a hundred years we have known that there are proteins that can stick together and build up in the brains of people with Alzheimer's disease we call this process misfolding and we can make these proteins in the lab to examine them and their effects we can observe them sticking together moving into and around cells and we can see that the cells become damaged and eventually die our task is to find out how this process works then how to prevent or reverse it science like art requires an inquiring and creative mind both seek to explain sometimes abstract and intangible Concepts so that we can envisage and perceive information in an imaginative ways the artist's impressions of Alzheimer's disease that we see here embody complicated ideas and allow us to transcend beyond the rigid framework scientists work by bringing a new but recognisable perspective in these works the repeating patterns sounds symmetry different materials as well as the invocation of feelings of Despair but also of Hope for how research Endeavors to help people all resonate with us as researchers it is compelling to see the work we do in the lab reflected in an audio visual format the pieces capture the Intrigue of research and help us all to understand the mystery of protein misfolding
We are all now familiar with the role of viruses in human diseases, and have for some time known about good & bad bacteria. But how many of us know that proteins are also involved in human disease? When certain proteins, known as amyloid proteins, misfold things can go very wrong.
Misfolding for Dummies by Frances M Lynch
Misfolding for Dummies comprises a comprehensive spoken text which seeks to explain the complicated science of amyloid folding and its relationship to Alzheimer’s disease, and music. Text and music were completed in June 2021. The instrumental music is a direct translation of coding in the proteins as they fold or misfold and was originally scored for wind quintet and 2 violins, but I converted these to purely electronically generated instruments with quite different sounds!
The video, created by Herbie Clarke, was recorded in a lecture theatre at the University of Sussex in the form of an introductory lecture by a fictional and slightly eccentric professor of Microbiology and Memory loss (played by myself) at the equally fictional University of Hope. She appears to have put up chalk diagrams on the board behind her – but don’t be fooled, these were created by proper scientists, Drs Marshall and Copsey from the Serpell Lab.
Electric voice theatre has provided a BSL version of the video with interpreter, Sarah Ankers.
Although there is still a long way to go in this research there is hope for the future:
A mystery remains, but we are not blindfold
Misfolding is slowly unfolding
Surely and steadily
Step by Step
The mysterious misfolding proteins
Are giving their secrets away.
- Video transcript
It all begins with DNA
Deoxyribonucleic Acid
That beautiful double helix
The secret of Life
The secret of Photo 51 and Rosalind Franklin
4 bases in sequence
Adenine, guanine, cytosine, thymine
Adenine, guanine, cytosine, thymine
With a sweet sugar coating, a backbone
Not where you’d expect it, strongly supporting from deep insideBut no, on the outside
Two of them,
Running in parallel motion
And inside the bases are weaving
3 of them coding (tri-nucleotide units called codons)
Computing, coding, messaging
Computing, coding, messaging
A beautiful string of pearls
A chain of 20 amino acids
Ordered and numbered
Folding and shaping
Making each type of Protein
Creating a structure for each special function
Each shape must fit exactly its profile
To function precisely as needed
No square pegs in round holes
No duodecahedron can fit its flat faces
Inside rows of heptagonal spaces
No
Proteins are cleverly prescribed
The exquisite origami of living cells
Each making a match to their everyday
Extraordinary, exceptional functions
Proteins
The essentials of lifeBut no, on the outside
Two of them,
Running in parallel motion
And inside the bases are weaving
3 of them coding (tri-nucleotide units called codons)
Computing, coding, messaging
Computing, coding, messaging
A beautiful string of pearls
A chain of 20 amino acids
Ordered and numbered
Folding and shaping
Making each type of Protein
Creating a structure for each special function
Each shape must fit exactly its profile
To function precisely as needed
No square pegs in round holes
No duodecahedron can fit its flat faces
Inside rows of heptagonal spaces
No
Proteins are cleverly prescribed
The exquisite origami of living cells
Each making a match to their everyday
Extraordinary, exceptional functions
Proteins
The essentials of lifeYou need to eat them too of course
I hope you eat enough
Chicken, fish, nuts
Tofu, quinoa, cheese
And humans
I hope you don’t eat those
Proteins are more than just nourishment
Essential for life
Essential for living
For keeping our bodies working and thrivingThat line of coding from DNA to protein
Making shapes that help us
Digest our food with chemical reactions
Or
Presenting as warriors, antibodies valiantly fighting off viruses
Maintaining the structures of hair skin and nails
Helping muscles contract, grow and relax
And many are hormones...well we certainly need those!
Proteins fold into patterns, repeating, repeating, repeating
Keeping things going everywhere
Our feet, our hands
Our stomachs and headsBut what happens
When things go wrong?
What if they should be found to
Misfold?
Create the wrong shape
That won’t fit anywhere
That must make its own placeSome tiny proteins, rogues in the pack
Receive the wrong code?
So instead of forming fantastical structures
They stick
And fix to each other
So hard to see
Assembling themselves
So hard to find
Making oligomers
Nasty and dangerous ‘Orrible oligomers
Killers of cells
Bad apples
Rotting and sticking fast
A stodgy cluster
Growing and building a ladder of threads
Of strands of fibres
Twisting, misfolding
Stretching, extending
Until it becomes
A fine cross beta rope ladder
Of amyloid fibres
Amyloid fibrils
Threads wound under a microscope
They group into Amyloid Plaques
With no inscriptions for heroes
But prisons for oligomers
Holding them fast in their stony mass
And inside the killers wait
Causing many diseases
Oligomers killers of cells
Oligomers killers of cells
Cells in our bodies
Cells in our brains
Look out
In the brain if an Amyloid Plaque
Is made up of a protein named Amyloid Beta
Yes I know that’s confusing so I’ll say it again
In the brain if an Amyloid Plaque
A structure you’d recognise if stuck in your teeth
Full of amyloid fibrils, and outside the cells
Is made up of a protein named Amyloid Beta
Well then you’re in trouble
On Alzheimer’s ground
Look out
In the brain if a Tangle of Fibres
Is made up of a protein named Tau
Yes I know that’s confusing so
I’ll say it again
In the brain if a Tangle of Fibres
Formed of pairs of helical threads
And lurking inside the cells
Is made up of a protein named Tau
Well then you’re in trouble
On Alzheimer’s ground
Two things to look out for in Alzheimer’s
Two pathological
Hallmarks of death
Those Amyloid Plaques and Tangles of Fibres
Neurofibrillary Tangles
to be more precise
Betray the presence of brain disease....
BUT
Why is it there?
Genetics?
Downs Syndrome?
Or just getting older?
Losing your memory
Your capacity to learn
As your hippocampus is eaten away
Leaving holes
Where your keys
And your socks
Once resided
Our brains all have amyloid beta inside
But what of those toxic, repulsive wee oligomers?
It’s still to be proven you know, that they are quite that deadly
Not proven the verdict could be
Some folk with Alzheimers have amyloid plaques
But
There are people whose amyloid plaques are benign
And what if it forms very early in life
Would you want a test for it, say just five?
A mystery remains
But we are not blindfold
Misfolding is slowly unfolding
Surely and steadily
Step by Step
The mysterious misfolding proteins
Are giving their secrets away
Misfolding Through the Looking Glass by Shu Yang
"Misfolding Through the Looking Glass is a short video that I created to convey the harms of protein misfolding and hope for curing the disease. To achieve the sensual feeling both visually and vividly, I hybridised real objects (the plant, the wooden-wired handicrafts and the cloudy steam) with virtual effects: the constant evolving organic structures, the cytoplasm, the cell-like creatures, the golden light, the folding lines, and the signal waves.
Alice Through the Looking Glass has been the perfect summary and contour of my ideas for the video, combining fantasy with science. I applied this narrative to the whole process of making: the generating and selection of music, the creation of sound effects, and the visual presentation of the video." - Shu Yang
Scarbled Words by Antonia Redding
"In my piece Scarbled Words I wanted first to explore the language used to convey the science of misfolding proteins in the brain, and to show the symptoms that are caused by them. Specifically, I have focused on how this affects memory and in particular verbal recall, communication, and shifting perceptions of time in individuals affected by dementing illness. I have attempted to demonstrate how this can be distressing and difficult, whilst at the same time showing the enduring human ability to create happiness and joy even within reduced capacity. I also wanted to express a sense of hope in the advancements in the field, both in scientific research, as well as an improved understanding of social care needs for individual sufferers.
I have tried to convey the internal, biological and neurological mechanisms within a person suffering from Alzheimer's. We start by looking at how the disease progresses, from when it is first diagnosed to its most advanced stages, and finishes with living with the disease." - Antonia Redding
- Video transcript
[Applause]
thank you
protein Building inside cells making chains life folding folding life unfolding time unfolding folding
unfolding [Music] [Applause] Miss misfolding folding folding [Music]
Miss misfolding
story unfolding [Music] thank you
making sense
[Music] unfolding time unfolding misfolding this ease this ease
[Music]
[Laughter]
[Music]
ah
forget stories history memories remember Miss yes remember remember my story remember misfolding my story Miss Miss folding lost folding Miss ions folding mysterious
Miss human who lives unfold mystery
cellular memory folding how do I do this folding must remember
mystery unraveling that bind history don't mystery don't know unraveling
[Applause] lost my history
forget
folding
Miss flawless
[Music]
don't know misfolding I don't know a story miss miss miss miss my story fullness folding my story mystery
mystery mystery
foreign
In Here by Kira Ramchaitar-Husbands (Subsis)
"The soundscape employs recordings of found sounds such as tissue paper, cardboard and tinfoil (contrasting with starkly synthesised textures) whilst the visuals combine minimalistic and organic 3D shapes juxtaposed with dark and primary colours. These elements represent the influence of genetics and environment. By mapping the timeline of the disease through sound and image, I have sought to create an environment that conveys the ephemerality of memory and life.
With the focal point of a strand of DNA pulsating and simulating life throughout the piece, we end on a final note of hope. I wish to express the hope of curing this disease through the colourful organic structures, which represent the fundamental balance of our bodies' healthiest everchanging, evolving, fluid, and natural state." - Kira Ramchaiter-Husbands
Miss Amy-Lloyd Folding (The Amyloid Hypothesis) by Frances M Lynch
Miss Amy-Lloyd Folding is a setting for 3 female voices of a poem I wrote on May 9 2019 as a response to initial discussions with Professor Louise Serpell and Dr Karen Marshall from the School of Life Sciences, University of Sussex. I was struck particularly by how much they felt that the causes of Alzheimer’s were there from birth, so that no research could be complete without studying people at various stages of their life.
The animated film (including text display) is by Hannah Fox, the sound was produced by Herbie Clarke and Frances M Lynch and the singers from electric voice theatre are Frances M Lynch, Soprano, and Samantha Houston and Margaret Cameron, Mezzos.
- Video transcript
She was Miss Folding all her life
The proteins in her brain
The blanket ruffled in the cot
The arms not holding her securely
Paper planes and paper games that never flew and never played
The proteins in her brain - Miss Folding
The birthday cake that did not rise
The folding seat that wouldn’t stay
The chairs and tables stacked away
The crash of wood on polished floor
The proteins in her brain - Miss Folding
The crisp pound notes misplaced
No help for rainy days
Umbrellas failed to open
The proteins in her brain - Miss Folding
The ironing board snapped shut on hands that neatly folded clothes
Which somehow came undone
Like proteins in her brain - Miss Folding
Until in later life the paper would not fit
The envelope was blocked
The letters could not sit at peace upon the page
Like proteins in her brain - Miss Folding
The napkins - try and try again -
Were never folded properly
Like deckchairs in a storm
Like proteins in her brain - Miss Folding
White sheets await a final fold
How many others led her here
To lie at peace before her time
As year on year she was misfolding
Proteins in her brain
- Previous work
An exploratory workshop with three members/ex-members of the Sussex Music department took place on 1 and 2 June 2021, with a public showing of the outcomes, described as “sketches” for finished pieces, by Kira Ramchaitar-Husbands, Antonia Redding and Shu Yang.
The three pieces were introduced by Frances Lynch’s contribution “Misfolding for Dummies”.
“Folding and Misfolding” by Kira Ramchaitar-Husbands for sampled paper folding sounds and audio-visual electronics
“Virus, Bacteria, Protein” by Antonia Redding for recorded soundscape (Predators as virus, birds for bacteria, mechanical sounds as proteins), my mum’s voice (she is living with dementia), my voice, paper aeroplane and Scrabble
“Hope for ReFolding” by Shu Yang - biochemistry inspired soft-crafts, sound, music, and mini-performance
"Miss Amy-Lloyd Folding” by Frances M Lynch
She was Miss Folding all her life
The proteins in her brain
The blanket ruffled in the cot
The arms not holding her securely
Paper planes and paper games that never flew and never played
The proteins in her brain – Miss Folding
The birthday cake that did not rise
The folding seat that wouldn’t stay
The chairs and tables stacked away
The crash of wood on polished floor
The proteins in her brain – Miss Folding
The crisp pound notes misplaced
No help for rainy days
Umbrellas failed to open
The proteins in her brain – Miss Folding
The ironing board snapped shut on hands that neatly folded clothes
Which somehow came undone
Like proteins in her brain – Miss Folding
Until in later life the paper would not fit
The envelope was blocked
The letters could not sit at peace upon the page
Like proteins in her brain – Miss Folding
The napkins – try and try again –
Were never folded properly
Like deckchairs in a storm
Like proteins in her brain- Miss Folding
White sheets await a final fold
How many others led her here
To lie at peace before her time
As year on year she was Mis-Folding
Proteins in her brain