The MRC’s annual science writing competition, the Max Perutz Science Writing Prize, challenges MRC-funded PhD students to communicate the importance of their research to a non-scientifically trained audience in 800 words or less. This year, Lizzie Horton from the WIMM/HIU submitted the following excellent entry. Lizzie Horton is a DPhil student in the Rehwinkel Group.
Machines alarming. Doctors, nurses, physios and carers shouting though masks. Whirring breathing apparatuses. These are the sounds you hear as you walk through a noisy Covid-19 High Dependency Unit. Populated by some of the sickest patients, they are here because, for one reason or another, their bodies can’t cope with the attack of the virus without support. What’s making them so sick?
As an immunologist, I haven’t actually heard the sounds coming from a Covid-19 ward; in fact, I had to ask my sister, who is a doctor, to describe it. Instead, I look at the tiny parts of our bodies that help- but sometimes hinder- recovery from infections. I am researching the immune response to viruses.
Most of us never consider our immune system. We are exposed to germs all the time, but only occasionally succumb to one of those ghastly colds. Even then, we are quick to recover. This is not the case for all; sadly, many die each year from virus infections. Indeed, the Covid-19 pandemic saw the hospitalisation of previously healthy patients as well as patients with pre-existing conditions. How can this be? My research is aiming to better understand the body’s response to viral infection.
The human immune system has two main prongs. The innate response is an initial, reasonably non-specific response of the body to any foreign attack. The adaptive response is highly specific to each virus encountered and creates an immune memory. This immune memory remembers the virus so that when you next ‘see’ it, your body can react more quickly. They work as a team so that when you’re infected with a virus, the innate response holds off the infection until the adaptive response kicks in, which it does much faster if it has seen the virus before. Sars-CoV-2, the virus which causes Covid-19 disease, was a new virus to humans, and so no one had specific immune memory. The Covid-19 pandemic is therefore a very strong example of just how important your innate response is. But if nobody’s body had seen Sars-CoV-2 before, then why did only some people get sick?
Trouble arises when this innate response overshoots and doesn’t turn off. An unchecked innate response can create an inflammatory storm, which can lead to damaging not only the virus but also the body’s own tissue. It is a deadly defence, and our bodies must walk the tightrope between too much and too little.
This brings us back to my cells. Like a pet, they need frequent care, except the food is slightly less smelly. Every two days I give them fresh bright red food, occasionally served with a side of virus. I use these cells to study one part of the innate immune response to infection: interferon-stimulated genes. Genes act as the body’s instruction manual and can be turned off and on in individual cells. Interferon-stimulated genes are usually only active in cells that are infected with virus and have a role in protecting cells against infection. Conversely, these genes can be switched on in the cells of some patients with chronic autoimmune disorders. However, while there are hundreds of these genes, we only know the functions of a handful of them.
During my PhD, I am discovering new ways in which our bodies defend against viral infection, through characterising these interferon-stimulated genes. This knowledge will help us to understand the tight balance between anti-viral defence and autoimmunity. This could aid in making new vaccines, anti-virals and anti-inflammatory medicines.
To study interferon-stimulated genes, I create cells that have the genes ‘deleted’ using technology called CRISPR-Cas9 (which won the Nobel Prize for chemistry in 2020). I can then compare cells with and without the genes, to see if they respond differently to viral infection. I have seen that different levels of these genes in cells lead to differential responses to viral infections. The next steps for the remaining two years of my PhD are to determine the mechanisms by which these interferon-stimulated genes act; how they restrict virus infection, which viruses they work on, and whether too much of these genes can contribute towards autoimmune and inflammatory disorders.
This all sounds very technical; let me assure you that my day-to-day life involves donning a white lab coat, culturing viruses, throwing it on some cells and then waiting to see how they react. Think large red vials of virus, spinning tubes, and of course, pipetting (using a syringe to pick up tiny amounts of liquid) all day every day.
Discovering the mechanism of action of these interferon-stimulated genes is very similar to detective work. I look for clues to generate ideas and then test these ideas in experiments. For instance, I can see under a microscope where in the cell these interferon-stimulated genes act by putting a fluorescent tag on them- they then glow! I use these glowing tags to look at which other parts of the cell they interact with. Knowing where in the cell the genes are needed helps me to work out what they do. This breadcrumb-like trail of clues requires lots of piecing together, but after generating an idea (we call this a hypothesis), I test it again and again until I know whether it is true. If it isn’t I must re-think!
This work at my lab bench is far removed from patients in the Covid-19 High Dependency Unit. Cells in culture are not even a whole organ, let alone a person with a specialised and complex immune response. However, understanding these delicate workings is critical if we are to be better equipped to heal diseases. It is crucial for scientists to first gain a fundamental understanding of all the different ways our cells fight off viruses, through work like mine. We can learn from cells what is happening in our bodies when we have a sore throat and headache from a cold.
Scientists have been researching the immune response to infection since the discovery that germs cause illness in the 1800s, but there is still so much to discover. This is the part of my research that enthuses me: that the defence system shared between you and I is so complex that after decades of research by thousands of scientists, we still have much to learn, with the potential to save lives.
And so, I eagerly put on my lab coat every day and am spending four years trying to understand a minuscule, minute detail of our complex immune system in the hope that in the next pandemic we can better harness our body’s deadly defence.
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October 2021 saw the MRC WIMM’s first in-person Public Engagement event since March 2020. The IF Oxford Festival aimed to engage people from across Oxford with current academic research. Gulnar Abdullayeva, a DPhil student in the Bodmer Group, volunteered at the MRC WIMM stall. In this piece she describes her experience.