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Two UK DRI researchers shortlisted for the 2021 MRC Max Perutz Science Writing Award

PhD students Catherine Heffner and Imogen Swift from UK DRI at UCL, have been recognised in this year’s MRC Max Perutz Writing Award, an initiative designed to encourage outstanding science communication among early career researchers.

At a virtual awards ceremony on the evening of 21 October, the MRC recognised the science-writing efforts of 10 PhD students shortlisted for their annual prize. Now in its 24th year, the Max Perutz Writing Award, aims to encourage outstanding written communication by MRC PhD students. It challenges students to explain why their research matters in 1,100-words for a non-scientific audience. The award is named after the eminent scientist and Nobel Laureate Dr Max Perutz, an accomplished and natural communicator who died in 2002.

Catherine and Imogen, based in the labs of Dr Adrian Isaacs and Prof Jonathan Rohrer (Dementia Research Centre, UCL)/Prof Henrik Zetterberg respectively, brilliantly capture the aims of their PhD projects investigating the underlying causes of dementia. In addition to successfully translating the complexities of their science to a lay audience, the pair crucially convey why this research is so important to the millions of people affected by these devastating diseases. You can read both articles below in full.

The overall winner of this year’s award was Vicky Bennett from the GW4 BioMed MRC Doctoral Training Partnership at the University of Bath. Vicky’s article ‘Cranberry juice won’t cut it anymore’ is about identifying potential drugs that could be re-purposed to target drug-resistant bacteria that cause urinary tract infections (UTIs). In addition to receiving a cash prize of £1500, the article was featured in The Observer. Catherine’s article ‘Teatime at grandma’s’, about her investigations into the genetic causes of dementia, picked up a £750 runners-up prize.

In the afternoon before the ceremony, the shortlisted students had the chance to attend a virtual science writing masterclass led by Dr Claire Ainsworth from SciConnect, and all 10 shortlisted students will receive a year free membership from the Association of British Science Writers (ABSW).

UK DRI shortlisted articles

Teatime at Grandma’s - Catherine Heffner

I had just learnt how to make a decent cup of tea; taking orders from this lot was a challenge. Alice was constantly laughing about something and could barely take breath to give her order. Doris would sit sulking and stare at her tea until it turned cold. Peter would silently accept his cup with a smile and then, when you weren’t looking, would scurry over to the sugar pot and heap in extra teaspoons.

These were the characters of my grandma’s new nursing home. Although they all had dementia, I was struck by how differently each individual was affected, with members of the group displaying a range of memory, speech and behavioural changes. As the months and years passed, I also noticed how time affected each of them differently. While most remained more or less the same, some would go through sudden and rapid declines in their mental functioning. Perhaps most jarringly of all, others even experienced dramatic personality changes, morphing from their bright and bubbly selves into silent and brooding figures.

The variety of change I saw amongst these patients reflected a small part of a much larger reality. Dementia is an umbrella term for a multitude of different disorders, together affecting 50 million people around the world. There is currently no cure for any of these disorders. Part of the reason for this is because we don’t yet fully understand the processes going on in the brain that lead to dementia.

Whilst spending time at my grandma’s nursing home as a teenager, my curiosity grew. What accounted for the differences in these behaviours? Why did the health of some patients decline so rapidly whilst others lived stably for many years? Feeling strongly indifferent towards science at that time, I was surprised to find my burgeoning questions were addressed in biology class.

Here we learnt that stretches of DNA called genes act as the instructions for the cell to make different proteins. These proteins form the toolkit for the cell to use in all sorts of functions. Changes in the genetic instructions are known as mutations and can affect the proteins produced so they can’t properly perform their functions. Sometimes these proteins have such important functions that their mutation can affect the health of cells in the body, and consequently the health of the body as a whole.

I was immediately intrigued. These genetic mutations seemed like clues. If we could study the mutations that were found in people with dementia and determine how they affect brain cell function, we might be able to understand the processes in the brain that go awry in dementia. If we understood these processes, maybe someday we could use them as targets for medicines!

Fast forward a few years, and my current work towards my PhD has led me to study one of these rare genetic clues. As almost always in science, this lead was established from many years of work from researchers before me. In the 1990s, scientists analyzed the genetic code from a large family with a peculiarly high prevalence of dementia. They identified a particular genetic mutation that was seen only in the family members with dementia and not in the unaffected members. The clue was found.

The next step for me is to figure out how this genetic mutation affects the protein it relates to. We know that this protein has the crucial task of repairing holes in the fatty membrane layer that coats cells. In the body, cells are under constant attack from different materials which can puncture tiny holes in this membrane. This is bad news for cells. Even tiny holes can allow the contents of the cell to flood out and material outside the cells to flood in, which can be enough to kill them. We think that brain cells might be particularly vulnerable to this kind of attack. Whilst cells in the body come in all shapes and sizes, brain cells tend to be long and spindly, forming a large surface area with a lot of potential for damage to the membrane. Thankfully, our cells come equipped with proteins that can quickly repair punctures, such as our protein in question.

In my PhD I am investigating whether the dementia associated mutation prevents this protein from properly repairing membranes. To test this, I have been using a high-powered laser to zap very small holes in cell membranes. I do this under a microscope and watch the protein as it repairs the hole I zapped. At this point in my PhD, I have spent many happy

hours zapping and filming cells with either normal repair proteins or mutated ones. I have noticed that the mutated proteins take much longer to respond to the lasered hole and may not repair membranes as effectively. While this is a subtle difference to the cells that I zap, one can easily imagine the implications it might have when scaled to thousands of cells in a person’s brain, encountering damage every day across the decades.

Since we know that the genetic mutation I am studying is directly linked to dementia, we know this is a powerful clue. Most other kinds of dementias seem to be more complicated, as they are influenced by a combination of genetic and lifestyle factors that vary between patients, making it difficult to pinpoint the cause of the disease. However, as technological advances are increasing the ease at which genetic information can be gathered and analyzed we are continually identifying more clues, making this is such an exciting time to be in dementia research.

My hope is that by studying these clues and how they affect cell functions, we can build an understanding of the processes that occur in brains with dementia. From here, we could create medicines that directly target these processes and prevent them from ever taking hold of a person’s mind. Perhaps then we would be in a better position to focus on the important things in life, like enjoying teatime at grandma’s.
It’s in the blood: the race to treat frontotemporal dementia - Imogen Swift

“The look he gave me, I can only describe it as a look like there was no one home”

This striking moment is the first memory Hannah has of her father’s dementia. She recalls how he started to go missing, making obscure financial decisions or laughing when his grandchildren were upset. In 2017, at the age of 60, he was diagnosed with frontotemporal dementia (FTD).

Few people have heard of FTD. Unlike Alzheimer’s disease, this form of dementia mainly affects your personality, behaviour and language. It is the second most common form of young-onset dementia, usually affecting people in their 50s but symptoms can start from any age. Patients often lose empathy for their loved ones, lose their ability to speak and lose their sense of self. Currently there is no cure.

For Hannah’s family, the news got worse still. Around a third of people with FTD have a genetic component, meaning it can be passed down from generation to generation. Hannah had suspected this as she recalls similarities between the look in her father’s eyes and that of her grandfather years before. Her grandfather had passed away, aged 57, with what was recorded as complications of Alzheimer’s disease. At the time, little was known about FTD.

Hannah was told that she has a 50% chance of carrying the faulty gene and developing FTD. Over the next 10 months, whilst watching her father’s condition deteriorate, she deliberated as to whether she wanted to find out if she is also a gene carrier. Eventually, she concluded that she could not live with the uncertainty and decided to get genetically tested. It was not good news. Hannah carries the same version of the gene as her father and will develop FTD. Each of her young daughters has a 50% chance of the same fate.

For Hannah, and many others in her position, the only solution is finding a treatment. In other words, finding something that will stop the disease from developing in the first place.

Yet hope is on the horizon. Clinical trials have started for this form of dementia.

Hannah carries the faulty version of a gene called progranulin. This gene is an instruction booklet for creating the progranulin protein, which in the world of brain cells, is a Jack of all trades. It fights viruses, heals wounds, recycles and repairs cell machinery and grows the cell. However, in people like Hannah, the faulty gene means that only half the required amount of this protein is created.

This is where the clinical trials come in. They aim to increase the levels of the progranulin protein in the brain and stop the disease from developing in people like Hannah, who do not currently have symptoms, but carry the faulty gene. However, if these trials are in people without symptoms, how will we know if the treatment is working? For this, we need definitive measures to test the treatment’s success. One way to do this is to look in body fluids, like blood and urine, or even better, the fluid your brain sits in: cerebrospinal fluid (CSF).

For my PhD, I am developing tests to measure different molecules in blood, urine and CSF and assessing whether there are differences in people who carry the faulty gene and those who do not. For this, it is important to first establish what we already know. We know that people with this gene have lower progranulin protein levels and we can actually measure this in their blood. We also know that this reduced level leads to the complex symptoms of FTD. However, we need to understand what happens in between.

One way to work this out is to think about what the progranulin protein does in the cell. In order to carry out its extensive responsibilities, we know it recruits other proteins, such as prosaposin. Together these two proteins move into cells and carry out key functions. In fact, according to research, progranulin cannot do many of its jobs without its trusted sidekick, prosaposin.

Therefore, in my PhD, I want to ask: are prosaposin levels different in people with the faulty gene? And can we measure this in their CSF?

The first step in developing this test is to find another type of protein, known as an antibody, that sticks specifically to the prosaposin protein. We could then use two of these specific antibodies to make a prosaposin sandwich (not as appetising as it sounds). By also attaching a label onto one of the antibodies (or “bread slices”), we can measure how much prosaposin is in the CSF (i.e. how many “sandwiches”).

One of the biggest challenges when developing these tests, is that some proteins are not present in high enough levels in the blood or CSF. To overcome this, we use ultra-sensitive machinery to detect very low quantities. To give some scale to this, if you had 18 million Olympic swimming pools, our machines could detect the equivalent of a single golf ball.

So, at 8AM on a Tuesday morning I was in the lab starting my experiment. This was the fifth trial and I was hoping that the subtle changes I’d made to the method would yield positive findings. Over the next nine hours I would pipette, shake, wait, wash and repeat. I was hoping to show that we can detect the elusive prosaposin protein in CSF. By 5PM, I was anxiously waiting as the numbers start to show up on the screen. I looked in amazement as the results suggested the experiment had worked. I had developed a test in CSF for the prosaposin protein.

One week later, I ran the experiment again, this time testing our precious CSF samples from people who carry the faulty gene. With another anxious wait and some eager graph creation, I found that prosaposin was higher in these carriers. This exciting result could help explain why these people develop FTD, adding a crucial piece to the puzzle of our understanding of this form of dementia. It could also be a useful measure in clinical trials to help establish whether treatments are working.

However, this is only the first step in a long journey of discovery and there is much more to find. For Hannah and many other families like hers, life is a ticking time bomb, knowing that at some point this disease will take them from their loved ones. I am hopeful that we will beat FTD but it is vital that we find the right treatment to save lives before more generations are affected.

Article published: 11 November 2021