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Prof Ziad Mallat leads Cambridge effort to win £30m to tackle leading cause of heart attacks and strokes




It is the world’s biggest killer – and yet we don’t fully understand the leading cause behind it.

Cardiovascular diseases claimed an estimated 17.9 million lives in 2016 – 31 per cent of all deaths around the globe.

And 85 per cent of these were due to heart attacks and stroke, most commonly caused by a blockage of the arteries – known as atherosclerosis.

Professor Ziad Mallat in the Department of Medicine. Picture: Keith Heppell
Professor Ziad Mallat in the Department of Medicine. Picture: Keith Heppell

Now an international team led by a Cambridge professor of cardiovascular medicine is competing for a £30million prize from the British Heart Foundation to unravel its secrets.

If they beat the other three shortlisted teams in the charity’s Big Beat Challenge, they will create the world’s first 3D map of atherosclerosis at single cell resolution, giving unparalleled insight into this hardening or blocking of the arteries.

Prof Ziad Mallat, of the Department of Medicine at the University of Cambridge, tells the Cambridge Independent:“We are excited about the prospect of this. We hope we have assembled the right team.

“Atherosclerosis is very debilitating. If it happens in the arteries that supply the brain, it causes stroke. If it happens in the arteries supplying the heart, it causes heart attacks.

“It is really common across the world. Every five minutes in the UK there is one heart attack and one stroke.

“Why is this having such a huge impact on the quality of life of people? We believe something is not being treated or understood.”

Clinicians currently treat the risk factors for the disease, which include high blood cholesterol, high blood pressure and diabetes.

“What we don’t do is really treat what causes the disease, which is the malfunctioning of the immune system,” says Prof Mallat.

“When you have high blood pressure or cholesterol, this injures the arteries. Initially, the immune system sends immune cells to the injured vessel to try to heal the artery.

“However, what we know is that most of the time the immune system doesn’t operate properly and this prevents the healing, and so the disease progresses.

“We have good understanding of how this happens in pre-clinical models, like mouse models, but very limited understanding of how it happens in humans.

“We think this is what is preventing doctors and scientists from finding a treatment that would transform the way patients are treated.”

Through their iMap, as they are calling it, Prof Mallat and the team of global experts he has assembled want to understand what is happening in the accumulations, known as plaques, that block the arteries and affect blood flow to the heart and other parts of the body. The plaques can be made up of fat, cholesterol, calcium and other substances.

“These plaques obstruct the lumen [the interior space in the artery] and even burst into the lumen, leading to clot formation, which obstructs the blood flow. This causes the heart attacks and strokes,” says Prof Mallat.

“Our idea is to build the first 3D map of these fatty plaques, at

. We would like to know what each immune cell and each cell in the vessel wall is doing. What is its genetic make-up? What is its protein make-up? What is the fuel that it is using? Why, when the immune cell comes along to do a good job, does it stop doing it?

“We want to interrogate each cell and work out how it is interacting and communicating with other cells.

“Only with this 3D map of the plaques will we be able to understand what is happening inside. Once we have done this, we will be able to harness this knowledge to find new protective methodologies and therapies.”

These therapies could harness the immune system, which raises the possibility of vaccinating against atherosclerosis.

“If we understand how the immune cells react, we can use the information to re-educate them with vaccination,” suggests Prof Mallat. “If they are overreacting to fat components or protein components, we can educate them to make them do the right job when they see this in the arteries, to reduce the inflammation and limit the development of the disease.”

Arteries can be narrowed by plaques
Arteries can be narrowed by plaques

The scale of this challenge, however, is vast and requires a multi-disciplinary approach.

“It needs a lot of different expertise around the world,” says Prof Mallat. “You need good cardiologists, good molecular biologists, immunologists, mathematicians and computer scientists – because the information will be huge and needs to be integrated together. You need people who know a lot about genomics, lipidomics and proteomics, so we have gathered world-leading experts in each of these areas to come together and look at this problem from every angle possible.”

Among those helping Prof Mallat is Sarah Teichmann, from the Wellcome Sanger Institute at Hinxton, who is the co-founder of the global consortium working on the Human Cell Atlas – a hugely ambitious and important project creating comprehensive reference maps of all human cells in the human body.

“They are looking at the make-up of healthy organs,” notes Prof Mallat. “Some of the investigators are mapping some of the arteries and are looking at vascular cells like endothelial cells. It is intriguing but nobody else is looking at other cells in the artery. We are looking at both the healthy arteries and the diseased arteries. It is building on the work of the Human Cell Atlas.”

Also on the team are experts from Imperial College London, Germany, France, Spain, the La Jolla Institute of Immunology in San Diego and from Icahn School of Medicine at Mount Sinai in New York.

Key to their work is the need for data and samples, and the group has multiple sources available.

Professor Ziad Mallat and some of his team. Picture: Keith Heppell
Professor Ziad Mallat and some of his team. Picture: Keith Heppell

“We have organ donors from the Cambridge bio-repository and the clinical school at Mount Sinai, so we have access to healthy and diseased arteries from the same individuals.

“We have access to blood from these individuals and to immune cells from other parts of the body, so we can compare what the immune cells are doing in different compartments.

“The other source is from a cohort of thousands of individuals, through a collaboration with Professor Valentin Fuster in Madrid, who have been followed for more than 10 years, and they will be followed for another 10 years.

“We have blood samples and microbiota from them. We also have access to imaging of their arteries. They are followed for cardiovascular outcomes, so if someone has a heart attack or stroke, it is documented.

“We will be able to look at the ageing of the immune system in these individuals and how this correlates to changes in their arteries and the occurrence of disease.

“All of this is being done at very high resolution, which has not been done before. Integrating the information from the genes, the proteins, the lipids and so on, to have a broad view, has never been possible.”

There are parallels with the work being carried out at Cancer Research UK Cambridge Institute under Prof Greg Hannon, where the first virtual 3D tumour is being created using a multi-disciplinary team.

“We are discussing with him how we can integrate some of the technologies he is developing. It will be fantastic to collaborate with him on this,” says Prof Mallat.

What is known already is that our arteries are sensitive to changes in blood flow.

“Even subtle perturbations in the micro-environment are sensed by the arteries and can be considered as a danger,” explains Prof Mallat.

“When it interprets this as a danger, it sends signals to the immune system to react. I would say this is happening almost continuously, and is aggravated of course when you have additional stimuli like high blood cholesterol or exposure to smoke.”

Stages of atherosclerosis
Stages of atherosclerosis

While the use of imaging and monitoring of biomarkers is helping us diagnose atherosclerosis earlier, Prof Mallat describes this as “not optimal, because we don’t understand the disease in a comprehensive manner”. A 3D map would aid diagnosis, prediction and prevention of disease, as well as opening up new therapeutic avenues.

“Nobody knew 10 or 15 years ago that the immune system could play such a huge role in cancer,” Prof Mallat points out. “Now cancer immunotherapy is advancing enormously. We are convinced that atherosclerosis is highly motivated by the immune system but no-one is targeting the immune system to treat it. That’s why we want to understand it and we think this could really induce a revolution in our understanding and how we treat it.”

Cambridge Cardiovascular to host events at Cambridge Science Festival

Visitors to Cambridge Science Festival will have a chance to find out more about the iMap project and the work of cardiovascular researchers.

Cambridge Cardiovascular, an umbrella group for the field, is involved in organising activities once again at this year’s festival, which runs from March 9 to 22.

At 6-7pm on Wednesday, March 18 at the Mill Lane lecture rooms in Cambridge, a talk titled ‘More than a blocked pipe: The hardening of the arteries and their role in stroke and heart attacks’ will be delivered by Dr Nick Evans, of the Department of Medicine, and Prof Melinda Duer, of the Department of Chemistry.

At 6-7pm on Friday, March 20, also at Mill Lane lecture rooms, Dr Sanjay Sinha, of Cambridge Stem Cell Instituteand the Department of Medicine will discuss ‘Mending broken hearts: stem cells for heart disease’.

Then, from 11am to 4pm on Sunday, March 22, ‘A View of the Heart’ will be on offer at the Cambridge Academy for Science and Technology, in Long Road, where cardiovascular scientists will help you explore the organ and visualise heartbeats.

Book at sciencefestival.cam.ac.uk.

The Big Beat Challenge

The British Heart Foundation’s £30million Big Beat Challenge is designed as the charity’s ‘moon-shot’ to propel our understanding of cardiovascular disease into a new era.

Some 75 applications were received from 40 countries following its launch in August 2018, and these have been whittled down to four, including the one led by Prof Mallat to map and treat atherosclerosis. The other ideas are:

Hybrid heart

Led by Jolanda Kluin, professor of translational cardiothoracic surgery at the University of Amsterdam in the Netherlands, this team plans to create a solution for heart failure by developing a soft robotic heart. They intend to design, build, test and implant a hybrid heart that consists of a soft robotic shell forming the soft artificial muscles and sensors to enable natural motion, and a tissue-engineered lining to make sure all the surfaces in contact with blood are safe. With wireless energy transfer, the vision is that this could replace the need for human heart transplantation.

Echoes

Led by Professor Frank Rademakers, chief medical technology officer at University Hospitals Leuven, Belgium, this team would develop wearable technology that can be used in daily life to capture more data than ever before. This information – ranging from symptoms and physical activity to heart function and air quality – could be used alongside genetic and healthcare data to transform diagnosis, monitoring and treatment of heart and circulatory diseases through the creation of a digital twin.

Cure heart

This project aims to provide a cure for inherited, killer heart muscle diseases. Led by Professor Hugh Watkins, BHF chair of cardiovascular medicine at the University of Oxford, these researchers will develop a treatment that targets and silences the faulty genes responsible for cardiomyopathies – diseases of the heart muscle that can lead to sudden death at an early age. They intend to combine a deep understanding of underlying genetic mechanisms with new technologies, to stop the progression of the damage caused by genetic heart muscle diseases, or even reverse the damage.

Professor Sir Nilesh Samani, medical director at the British Heart Foundation, said: “Heart and circulatory diseases remain the number one cause of death worldwide.

“We’re taking small steps forward every year but what’s needed is a giant leap, which won’t be achieved by a business-as-usual approach.

“The Big Beat Challenge embodies our ambition to turbo-charge progress and could lead to its own ‘man on the moon’ moment. I have absolutely no doubt the winning idea will define the decade in their area.”

The teams will prepare their final applications by June 14, with interviews in early September and a decision expected by the end of the year.

Read more

Our guide to the Cambridge Science Festival 2020

Can HIV be cured? Evelyn Trust-funded research at University of Cambridge probes viral latency

Inside the Cambridge lab in pole position to create a new coronavirus vaccine

Sanger Institute scientist helps unveil blueprint for extraordinary Human Cell Atlas

Prof Greg Hannon on taking over at the Cancer Research UK Cambridge Institute and creating the world’s first virtual reality tumour



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