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Cambridge University Science Magazine
The next generation of lateral flow tests (LFTs) will use a drop of blood to detect specific white blood cells. These disease-fighting cells, called neutrophils, help the body to fight infections.

Immunocompromised people, such as those on chemotherapy, can have low levels of neutrophil cells. If they develop an infection and this is not treated rapidly with antibiotics, they are at greater risk of life-threatening complications like sepsis.

However, patients on chemotherapy do not always have low neutrophil levels and therefore do not always need to immediately attend hospital for antibiotics if they believe they may develop an infection.

In fact, up to half of hospital visits made by chemotherapy patients thought to be developing an infection, around 50,000 per year in the UK may be unnecessary. Clinical assessments and lengthy blood tests showed that their neutrophil levels were normal and they were not at risk of sepsis.

Dr Pietro Sormanni’s group at the University of Cambridge develops technologies to discover antibody molecules used as detection markers on LFTs. Thanks to a newly established partnership with a Cambridge-based startup, 52 North Health, the group will now develop antibodies that will underpin LFTs to accurately detect an individuals’ neutrophil levels and risk of sepsis in an at-home test.

Sormanni summarises the ethos behind this project: ‘Patients on immunosuppression therapy, like chemotherapy, are extremely vulnerable to infection. If they develop a little bit of fever or any sort of sign of potential infection they are rushed to the hospital and given a lot of antibiotics while doctors do a blood test which takes time.

Sometimes this means that they didn't need any of those antibiotics if there was no biomarker for infection. This contributes to the rise of antibiotic resistance, is stressful for the patient, and costly to the healthcare system, so we are trying to turn the readout of this relatively lengthy blood test into a lateral flow test: a faster point of care.’

Dr Saif Ahmad, an academic consultant oncologist at Addenbrooke’s Hospital, has first-hand experience with this problem. As a response to patient distress, he co-founded 52 North Health, the company developing these LFTs, called Neutrocheck, that tests for neutrophils.

‘I realised that this was something I saw every day when I was on call in the hospital,’ commented Ahmad in a BBC interview in 2020. Since then, the company has been busy designing and testing this LFT.

It takes around ten minutes to produce a result and will help patients and doctors quickly decide who needs antibiotics and hospital care. This has the benefit of reducing the rise in antibiotic-resistant bacteria, allowing resources to be focused on the sickest patients. It also increases the quality of life for patients, allowing them to stay out of the hospital with peace of mind.

‘We have tested our device performance from over 200 blood samples from Addenbrooke’s Hospital, Cambridge, and we have performed user testing with patients interacting with the device in around 40 individuals,’ said Ahmad.

A clinical study will commence in 2023 at Addenbrooke’s Hospital to test the device and apply for UKCA and CE marking, a label of meeting high safety, health, and environmental protection requirements.

LFTs were a huge component of the testing strategy to manage COVID-19 and this public awareness campaign has energised research into LFTs and their use in other diagnostics. Using the principle, a target in a liquid can quickly be detected. In LFTs, a set of stationary antibodies bind the specific molecule, releasing a dye. Therefore, a result appears within the time it takes for the molecule, like the smartie colours, to move. For the person using the test, this looks like a line appearing on the strip.

Of course, the reality of designing this technology for medical use is a little more complicated than a drop of liquid on a stick. The real challenges are in finding biomarkers that will accurately reflect the clinical condition you are testing for, whether or not to seek further treatment for patients using NeutroCheck, and then obtaining suitable antibodies binding to these biomarkers. Proteins, our complicated building blocks, provide both the challenge and the answer.

Proteins make up around half of our dry body weight, every single cell in the human body contains proteins. The human genome encodes more than 20,000 different proteins, of which most are expressed in all cell types, but a few are unique to specific types of cells. To design LFTs that detect one cell type, like neutrophils, among the many that are present in the blood, antibodies have to be obtained that bind to one of these unique proteins.

The Sormanni lab is going to tackle this problem using 3D computer modelling to predict which antibodies will react with a specific protein. Traditionally, this process would be done with experimental trial and error using lab resources and time, whereas a computer can make these predictions much more quickly. In the case of COVID-19, the LFT contains detection antibodies initially modelled on a computer that bind to the viral spike on the surface of the coronavirus protein, which is unique to this virus.

While faster than their human counterparts, computers still have their limitations. Recently, in the Baker Lab at the Institute of Protein Design at the University of Washington, there have been advances in computational design that can create proteins that bind to specific molecular targets in a similar way to antibodies. The program needs to be able to scan a target molecule, identify the potential binding sites, then generate proteins that can target those sites.The protein that is generated by a computer might not exist in reality, so the computer then screens millions of proteins in its database to find the candidates that are the most promising, which are then further optimised in the laboratory.

‘When it comes to creating new drugs, there are easy targets and there are hard targets,’ said Dr Longxing Cao, who worked on the project as a PhD student and is now an assistant professor at Westlake University. ‘Even very hard targets are amenable to this approach. We were able to make binding proteins to some targets that had no known binding partners or antibodies.’

Designing a test that is no larger than a stick of chewing gum can require teams of scientists working together all over the world, as well as someone inside who knows which tests are needed. Diverse experiences and specialities, from doctors to computer scientists, are needed to figure out what tests are needed and how to make them. The future of LFTs are broad and exciting and will require problem-solvers from all walks of life of all specialties to help design them.

‘In principle,’ adds Sormanni, ‘you can get fancier and you can have different bands with different targets on a single lateral flow test. Or even bands that are printed with different densities so that you could get a kind of gradient that gives you information about the quantity of your target protein. So if you have a lot of protein, you will probably see a lot of bands. And if you have a little of your protein, you may only see very few bands.’

A device like NeutroCheck has the potential to streamline the healthcare journey for thousands of people. As Dr Ahmed showed, innovation can stem from the right person noticing a problem. When you step back from this article, what will you notice?

Caroline Reid started in physics and, although she left the equations behind, loves all things that bubble, beep, and bang in communications. Artwork by Caroline Reid.