In search of the stroke detector

Stroke, or “brain attack”, is the third biggest killer in the western world, after cancer and heart failure. The life-changing effects associated with this simple, Anglo-Saxon word are readily explained: a stroke occurs when the blood supply to the brain is disrupted by a blood vessel either bursting or blocking, so that the part of the brain supplied by this blood vessel dies.

The brain is a much more complex organ than the heart. While strokes are a common feature of everyday life, precisely how and why they occur is far from straightforward.

Each year in the UK, there will be about 50,000 brain attacks. One-third of those affected will die; one-third will be left severely disabled; and about one-third will make some kind of recovery. In the time it takes to read this article, approximately nine people in Britain, from across all age groups, will have suffered a stroke.

Or did they? For the brain is not only super-sensitive territory – as the human animal’s command HQ – it is also top secret. Despite extraordinary progress in MRI scans, the brain remains essentially mysterious and the symptoms of its dysfunction can be hard to diagnose with certainty. An elderly man presenting himself at A&E with unsteady gait and a slurring of his words could be suffering a stroke – or he might just be intoxicated. Treat him for the former, and you’ll save his life; treat him as a drunk, and he might die.

This is not the only way in which stroke sufferers find themselves trapped in a medical lottery. From the beginning of a stroke, every minute, even every second, becomes a matter of life or death in which the patient’s response is crucial. The onset of a brain attack is bewildering and confusing. For patients in the midst of a medical emergency, the key to the best recovery is rapid recognition of the attack followed by the prompt implementation of brain-saving treatment. But rapid recognition is easier said than done.

All strokes are unique, with a multiplicity of symptoms ranging from a drooping facial muscle to total unconsciousness. But paramedics’ guidelines, such as facial paralysis or slurred speech, do not offer a foolproof diagnostic tool: up to 50% of all pre‑hospital stroke diagnoses turn out to be inaccurate.

The diagnostic predicament is also bedevilled by the phenomenon of “mimics”. For example, a patient might come to A&E with a very bad migraine, exhibiting all the symptoms of stroke. Devoting the resources of stroke treatment to such a mimic is costly in both time and resources, the last thing a cash-strapped NHS can afford.

In A&E, one of the biggest – and potentially most expensive – problems faced by doctors and nurses is how to weed out the mimics and decide if a patient has or has not suffered a stroke. This decision can be fateful. Send the patient for immediate treatment, and all kinds of good outcomes might follow. Delay an hour, and the patient might be on the road to severe disability, even death.

As long ago as 1998, the complex challenges of stroke diagnosis began to intrigue an inquisitive Scottish neuroscientist named Nicholas Dale. He takes up the story: “Some strokes are really obvious. The brain scan shows exactly what’s happened, and everyone is in agreement. But then there are those strokes where the brain scan doesn’t really show anything, even though the symptoms are there. Those are what you might call ‘possible strokes’. What is a clinician supposed to do?” To this last question, Dale would come eventually up with an answer about the size of a thumbnail: the SMARTChip.

Twenty years on, Dale’s tortuous journey into the dark maze of neurological emergency is reaching a climax. After a series of nationwide clinical trials, the Observer can report exclusively that Dale and his biosensor company, Sarissa, an offshoot of Warwick University, are on the threshold of a remarkable breakthrough in stroke diagnosis.

Dale’s pioneering contribution to stroke medicine is a classic tale of scientific innovation replete with accidental discoveries, chance meetings and frustrating setbacks. Add this to the sheer slog of a determined neuroscientist who seems professionally addicted to finding bees in his bonnet, and you begin to approach the story of the smart chip that saves lives.

Dale’s breakthroughs in stroke prevention had mundane beginnings. “My original work,” says Dale with a wry smile, recalling his graduate years in Bristol and St Andrews, was “on how tadpoles swim”.

We need not dwell on Dale’s career in the society of the tadpole. Suffice to say that by 1997, he needed to invent a biosensor to measure the substance adenosine. “I wanted to measure adenosine,” he says, “because I thought that its gradual accumulation in the tadpole’s spinal cord controlled how its swimming slowed over time and ultimately stopped.”

Dale duly published his tadpole findings. It was then, in 1998, articulating a vague thought in the back of his mind, that he uttered to himself the sentence – “This biosensor must be useful for other things” – that would not only change his life, but profoundly influence the fates of many UK stroke patients. At this stage, his aspirations were half-formed, and he had no plan. All he knew was: he was done with tadpoles.

Dale admits that he wanted to do work that did not – as tadpoles always did – provoke smiles of disbelief. “I wanted to find an application for these sensors that was real and important.”

He pauses to recall another turning point. “One of my colleagues in Scotland said: ‘The person you need to talk to is Bruno Frenguelli. He’s interested in models of stroke.’ So I met Bruno,” says Dale, with disarming simplicity, “and told him about my biosensor.”

Dale and Frenguelli were a perfect match. Dale was becoming a master of biosensor technology, whose microchips could measure anything. Frenguelli, a neuroscientist at the University of Dundee, had things he wanted to measure, but no way to make the measurement. Soon, Dale was ferrying his biosensor kit in his car across the Tay Bridge to Dundee, and setting up in Frenguelli’s lab. “We both vividly remember our first joint experiment,” says Dale, “because it was so exciting.”

But then what? The bees in Dale’s bonnet began buzzing again. His biosensor was too cumbersome and fragile for any serious medical applications. “I started to think: could we not make something smaller?”

In 1999, Dale was puzzling over how he might do this – “I realised I would need polymers” – when there was a knock at his door. “And in came this guy I’d never seen before.”

“Hello”, said the newcomer. “I’m Enrique Llaudet.”

Llaudet, a Spanish organic chemist, was a whiz with polymers. Just what Dale needed to create new ways of making tiny biosensors.

So began an eight-year relationship, partly sponsored by seed money from a small Scottish charity, and later by the Wellcome Trust. Now Dale and Llaudet, with Frenguelli in the background, began to develop a tiny biosensor, the ancestor of Sarissa’s smart chip.

There were, inevitably, setbacks. At times, the technology let them down; at times, the funding dried up. But Dale, a natural team player, continued to develop his group, which now included Chris Imray (a heart surgeon at University Hospitals Coventry and Warwickshire NHS Trust), Christine Roffe (a stroke specialist at University Hospitals of North Midlands), Gary Ford (Oxford Academic Health Science Network), Everard Mascarenhas (Sarissa’s CEO), and Faming Tian and Shabin Joshi (both also at the Coventry and Warwickshire).

By now Dale had moved to Warwick to take up a chair in neurosciences. In 2004, Sarissa filed its first biosensor patent, but then Dale found himself in a blind alley. “We had the means, and we had the ideas, but we were getting nowhere. We tried to raise funds for treating foetal hypoxia.” He laughs: “I soon realised that the middle-aged white males who controlled the purse-strings just aren’t interested in babies.”

Finally, Dale returned to stroke. He had puzzled over its mysteries for years, but had never really grappled with the practicalities. Now he began to advance a brilliant hypothesis, developed in collaboration with Chris Imray. This – the measurement of purines in the blood – had the elegance of simplicity. Imray and Dale had begun to prove that, at the onset of stroke, the brain releases a detectable quantity of purines into the blood. If Dale’s smart chip could measure this surge, it could provide positive proof of stroke. For Dale, “elevated purines” would be the criterion by which he would definitively determine the onset of a brain attack.

Today, in the stroke units where Dale’s hypothesis is being tested, nurses have come to recognise that a high purine reading immediately indicates that stroke is a probable diagnosis.

In 2004, that was all in the future. First, Dale had to persuade the medical profession to undertake a clinical trial. It was his contention that Sarissa’s biosensor could weed out the “mimics” that bedevil stroke treatment.

Sarissa made its first commercial sales in 2005. Its biosensors (aka Sarissaprobe) had potential in clinical diagnosis, but, says Dale “we still didn’t have a product that was close to being useful for clinicians and nurses”. In simple terms, Dale’s biosensor would not work in blood.

Blood is the one thing that medics the world over like to test. But blood, as Dale puts it, “is a complex environment. We had to make our sensors a whole lot more selective if we were to measure a surge in purine levels. This was Faming Tian’s brilliant contribution.”

At the same time, Dale was stepping up the presentation of his biosensor to funding bodies. In 2013, he made a pitch to Invention for Innovation, a committee of the National Institute for Health Research. He will probably never forget this moment:

“I made my presentation, and then this clinical biochemist launched into a statement – it was nowhere near an inquiry – which became so hostile that I felt as if I were a delinquent teenager. There was, he told me, no need for this kind of technology. I was stunned by the aggression and the hostility. When this man had finished, I could not think initially how to respond, so I just said, ‘Was there a question?’” The committee burst out laughing. Dale left the meeting with a sense of failure, but he was wrong.

The committee decided to take a punt on his smart chip, after all. Three years ago, Dale and his colleagues began clinical trials in three UK hospitals, Salford, Coventry and Stoke-on-Trent.

Royal Stoke University Hospital, on the west of the city, is just over 10 years old, and a showcase of New Labour’s commitment to a revitalised NHS. Once, in the bad old days, Stoke was served by two separate, Victorian hospitals, with patients ferried between A&E and the stroke unit, which were in different buildings. Now, with A&E just a lift ride away, everything is under one roof with acres of parking space for doctors, nurses, patients and their families.

Inside, long shiny corridors and blinking tiers of lifts take the visitor into the heart of an impressively modern teaching hospital that caters for a population of about 600,000 in Stoke and Stafford. Add Derby, Macclesfield, Wolverhampton, Walsall, and Telford and you are looking at a catchment of 1.5 million. This is Nick Dale’s designated stroke laboratory, and it’s here, for the past three years, that his biosensor has been tested, under Professor Christine Roffe, a dynamic, highly practical director who has placed her team at the forefront of stroke research in the UK, especially as a pioneer of mechanical thrombectomy. She has been here since 1996, heading a unit that consists of six consultants, two specialists and 10 research nurses.

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Roffe has been trialling Sarissa’s chip in Stoke’s acute stroke unit since 2014. It is one of 10 designated hyper-acute stroke centres in the UK, and prides itself on providing a 24/7 response to the emergencies of “brain attack”. Roffe has 26 dedicated stroke beds and another 19 spaces for rehab. The unit will see 1,000-1,200 patients per annum. She also collaborates with Dale at Warwick and teams in Coventry and Salford.

Roffe confirms the starting point of Dale’s initiative: that the first problem in A&E is diagnosis. One-third of all stroke patients are mimics. “Only yesterday,” she says, “we had a patient who turned out to be suffering from migraine.” If they could eliminate the mimics, they could focus all their energies and resources on stroke care.

As we sit in a crowded office adjacent to the acute stroke unit, Roffe reflects on the mystery of the brain. She says, thoughtfully: “There’s still a whole world to be discovered there. We know so little.”

Roffe’s other issue is time. “We want to get them in quick. Time is of the essence. The NHS guidelines suggest that it is vital to treat within four hours.” One problem can be the patients themselves: “They often don’t ring 999 until it’s too late.”

Roffe’s senior research nurse is Holly Maguire, who has been with the unit since 2006. It’s Maguire’s job to integrate the Sarissa’s biosensor with the practice of the stroke unit while at the same time keeping the research separate from the clinical side. Like all medics working in stroke care, Maguire stresses the urgency of her work. Patient consent is a fundamental part of her responsibilities. “Most people are glad to be in the programme”, she says. “We treat first, and then get the consent.”

Maguire and her nursing team will place a pinprick of blood on one of Dale’s biosensors to test for elevated purines, the symptom of a cerebral emergency. She repeats Dale’s stroke-diagnostic mantra: “Normal people (apart from gout patients) don’t have elevated purines.”

At first, the SMARTchip’s performance was rather hit and miss. Now it has become a state-of-the-art device with impressive results. By April 2017, this stage of a three-year trial will be complete. Data from Salford, Coventry, and here at Stoke will be collated by Dale’s team for presentation to the National Institute for Health Research and subsequent publication in clinical journals.

Now that the clinical trials are drawing to a close, Dale can take stock of both its progress and future prospects, contrasting the treatment of brain attack and heart disease. “Survival rates for heart attack victims have risen dramatically over the last 20 years. In part, this has come from faster diagnostic tools such as ECG monitors, and rapid biochemical tests. By comparison, stroke patients have got a raw deal. No equally simple biochemical tests exist in stroke. For neuroscientists, this is depressing.”

“The key to getting the best recovery is rapid recognition of the stroke followed by prompt action to implement brain-saving treatment. This is where SMARTChip is most likely to be transformative.”

In five years’ time, if Dale gets his way, his technology will be a routine part of A&E. He believes that its natural home is “the NHS ambulance, as an indispensable tool in the paramedic’s diagnostic armoury, helping them to recognise stroke patients with greater precision”.

Further, he says, the SMARTChip can be used to monitor the patient’s progress. He concludes with this prediction: “For health providers around the world, enhanced patient recoveries will dramatically reduce the cost of providing stroke care. The resources saved can be diverted to other aspects of quality healthcare as the populations around the globe age and become needier of medical interventions.”

Looking into the future, Dale has ambitious aspirations: “In 10 years time, I’d hope that our SMARTchip would be in the defibrillator boxes that enable the public to treat cardiac arrest. These boxes have been instrumental in saving lives. Upgraded with Sarissa’s SMARTChip, they should become multifunctional, enabling the public to contact the health service with more complete information.”

Dale’s ambition, shared by his team, is that their technology should provide the healthcare professional with a simple and reliable test. Unquestionably, this will have a dramatic impact on the post-stroke life of the patient.

“Personally,” Dale concludes, with quiet satisfaction, “this would be a great source of pride.”