̽��ֱ�� of Cambridge - Randall Johnson

Skin found to play a role in controlling blood pressure

cjb250 — Wed, 25 Oct 2017 22:30:22 +0000

In a study published in the open access journal eLife, the researchers show that skin – our largest organ, typically covering two square metres in humans – helps regulate blood pressure and heart rate in response to changes in the amount of oxygen available in the environment.

High blood pressure is associated with cardiovascular disease, such as heart attack and stroke. For the vast majority of cases of high blood pressure, there is no known cause. ̽��ֱ��condition is often associated with reduced flow of blood through small blood vessels in the skin and other parts of the body, a symptom which can get progressively worse if the hypertension is not treated.

Previous research has shown that when a tissue is starved of oxygen – as can happen in areas of high altitude, or in response to pollution, smoking or obesity, for example – blood flow to that tissue will increase. In such situations, this increase in blood flow is controlled in part by the ‘HIF’ family of proteins.

To investigate what role the skin plays in the flow of blood through small vessels, a team of researchers from Cambridge and Sweden exposed mice to low-oxygen conditions. These mice had been genetically modified so that they are unable to produce certain HIF proteins in the skin.

“Nine of ten cases of high blood pressure appear to occur spontaneously, with no known cause,” says Professor Randall Johnson from the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge. “Most research in this areas tends to look at the role played by organs such as the brain, heart and kidneys, and so we know very little about what role other tissue and organs play.

“Our study was set up to understand the feedback loop between skin and the cardiovascular system. By working with mice, we were able to manipulate key genes involved in this loop.”

̽��ֱ��researchers found that in mice lacking one of two proteins in the skin (HIF-1α or HIF-2α), the response to low levels of oxygen changed compared to normal mice and that this affected their heart rate, blood pressure, skin temperature and general levels of activity. Mice lacking specific proteins controlled by the HIFs also responded in a similar way.

In addition, the researchers showed that even the response of normal, healthy mice to oxygen starvation was more complex than previously thought. In the first ten minutes, blood pressure and heart rate rise, and this is followed by a period of up to 36 hours where blood pressure and heart rate decrease below normal levels. By around 48 hours after exposure to low levels of oxygen, blood pressure and heart rate levels had returned to normal.

Loss of the HIF proteins or other proteins involved in the response to oxygen starvation in the skin, was found to dramatically change when this process starts and how long it takes.

“These findings suggest that our skin’s response to low levels of oxygen may have substantial effects on the how the heart pumps blood around the body,” adds first author Dr Andrew Cowburn, also from Cambridge. “Low oxygen levels – whether temporary or sustained – are common and can be related to our natural environment or to factors such as smoking and obesity. We hope that our study will help us better understand how the body’s response to such conditions may increase our risk of – or even cause – hypertension.”

Professor Johnson adds: “Given that skin is the largest organ in our body, it perhaps shouldn’t be too surprising that it plays a role in regulation such a fundamental mechanism as blood pressure. But this suggests to us that we may need to take a look at other organs and tissues in the body and see how they, too, are implicated.”

̽��ֱ��study was funded by Wellcome.

Reference
Cowburn, AS et al. Cardiovascular adaptation to hypoxia and the role of peripheral resistance. eLife; 19 Oct 2017; DOI: 10.7554/eLife.28755

Skin plays a surprising role in helping regulate blood pressure and heart rate, according to scientists at the ̽��ֱ�� of Cambridge and the Karolinska Institute, Sweden. While this discovery was made in mice, the researchers believe it is likely to be true also in humans.

Nine of ten cases of high blood pressure appear to occur spontaneously, with no known cause

Randall Johnson

Matt Reinbold

Skin texture

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̽��ֱ��self-defence force awakens

cjb250 — Tue, 04 Jul 2017 16:50:17 +0000

An army of cells constantly patrols within us, attacking anything it recognises as foreign, keeping us safe from invading pathogens. But sometimes things go wrong: the soldiers mistake benign cells for invaders, turning their friendly fire on us and declaring war.

̽��ֱ��consequences are diseases like multiple sclerosis (MS), asthma, inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis – diseases that are increasing at an alarming rate in both the developed and developing worlds.

Cambridge will be ramping up the fight against immune-mediated and inflammatory diseases with the opening next year of the Cambridge Institute of Therapeutic Immunology and Infectious Disease, headed by Professor Ken Smith. ̽��ֱ��Institute will work at the interface between immunity, infection and the microbiome (the microorganisms that live naturally within us). “We’re interested in discovering fundamental mechanisms that can turn the immune system on or off in different contexts, to modify, treat or prevent both inflammatory and infectious diseases,” says Smith.

But while diseases such as Crohn’s and asthma have long been understood to be a consequence of friendly fire, scientists are starting to see this phenomenon give rise to more surprising conditions, particularly in mental health.

In 2009, Professor Belinda Lennox, then at Cambridge and now at Oxford, led a study that showed that 7% of patients with psychoses tested positive for antibodies that attacked a particular receptor in the brain, the NMDA receptor. This blocked a key neurotransmitter, affecting communication between nerve cells and causing the symptoms.

Professor Alasdair Coles from Cambridge’s Department of Clinical Neurosciences is working with Lennox on a trial to identify patients with this particular antibody and reverse its effects. One of their treatments involves harnessing the immune system – weaponising it, one might say – to attack rogue warriors using rituximab, a monoclonal antibody therapy that kills off B-cells, the cells that generate antibodies.

“You can make monoclonal antibodies for experimental purposes against anything you like within a few days,” explains Coles. “In contrast, to come up with a small molecule – the alternative sort of drug – takes a long, long time.”

̽��ֱ��first monoclonal antibody to be made into a drug, created here in Cambridge, is called alemtuzumab. It targets both B- and T-cells and has been used in a variety of autoimmune diseases and cancers. Its biggest use is in MS, where it eliminates the rogue T- and B-cells that attack the protective insulation (myelin sheath) around nerve fibres. Licensed in Europe in 2013 and approved by NICE in 2014, it has now been used in tens of thousands of MS patients.

As well as treating diseases caused by the immune system, antibody therapies are now widely used to treat cancer. And, as Professor Gillian Griffiths, Director of the Cambridge Institute for Medical Research, explains, antibody-producing cells are not the only immune cells that can be weaponised.

“T-cells are also showing great promise,” she says. “They are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.”

But cancer cells are able to trick T-cells by sending out a ‘don’t kill’ signal. Antibodies that block these signals, which have become known as ‘checkpoint inhibitors’, are proving remarkably successful in cancer therapies. “My lab focuses on what tells a T-cell to kill, and how you make it a really good killer, using imaging and genetic approaches to understand how these cells can be fine-tuned,” Griffiths explains. “This has revealed some novel mechanisms that play key roles in regulating killing.”

A second, more experimental, approach uses souped-up cells known as chimeric antigen receptor (CAR) T-cells programmed to recognise and attack a patient’s tumour.

Neither approach is perfect: antibody therapies can dampen down the entire immune system, causing secondary problems, while CAR T-cell therapies are prohibitively expensive as each CAR T-cell needs to be programmed to suit an individual. But, says Griffiths, “the results to date from both approaches are really rather remarkable”.

One of the problems that’s dogged immunotherapy trials is that T-cells only have a short lifespan. Most of the T-cells transplanted during immunotherapy are gone within three days, nowhere near long enough to defeat the tumour.

This is where Professor Randall Johnson comes in. He’s been working with a molecule (2-hydroxyglutarate), which he says has “become trendy of late”. It’s an ‘oncometabolite’, believed to be responsible for making cells cancerous, which is why pharmaceutical companies are trying to inhibit its action. Johnson has taken the opposite approach.

He’s shown that a slightly different form of the molecule plays a critical role in T-cell function: it can turn them into renewable cells that hang around for a long time and can reactivate to combat cancer. Increasing the levels of this molecule in T-cells makes them stay around longer and be much better at destroying tumours. “Rather than creating killer T-cells that are active from the start, but burn out very quickly, we’re creating an army of cells that can stay quiet for a long time, but will go into action when necessary.”

This counterintuitive approach caught the attention of Apollo Therapeutics, who recognised the enormous promise and has invested in Johnson’s work, which he carried out in mice, to see if it can be applied to humans.

But T-cells face other problems, particularly in pancreatic cancer, explains Professor Duncan Jodrell from the Cancer Research UK Cambridge Institute, which is why immunotherapy against these tumours has so far failed. ̽��ֱ��problem with pancreatic cancer is that ‘islands’ of tumour cells sit in a ‘sea’ of other material, known as stroma. As Jodrell and colleagues have shown, it’s possible for T-cells to get into the stroma, but they go no further. “You can rev up your T-cells, but they just can’t get at the tumour cells.” They are running a study that tries to overcome this immune privilege and allow the T-cells to get to the tumour cells and attack them.

Tim Eisen, Professor of Medical Oncology at Cambridge and Head of the Oncology Translational Medicine Unit at AstraZeneca, believes we can expect great advances in cancer treatment from optimising and, in some cases, combining existing checkpoint inhibitor approaches.

Eisen is working with the Medical Research Council to trial checkpoint inhibitor antibody therapies as a complement – ‘adjuvant’ – to surgery for kidney cancer. Once the kidney is removed, the drug is used to destroy stray tumour cells that have remained behind. But even antibody therapies, which are now widely used within the NHS, are not universally effective and can cause serious complications. “One of the most important things for us to focus on now is which immunotherapeutic drug or particular combination of drugs might be effective in destroying tumour cells and be well tolerated by the patient.”

T-cell therapies – and, in particular, CAR T-cell therapies – are “very exciting, futuristic and experimental,” he says, “but they’re going to take some years to come in as standard therapy.”

̽��ֱ��problem is how to make them cost-effective. “It’s never going to be easier to engineer an individual person’s T-cells than it is to take a drug off the shelf and give it to them,” he says. “ ̽��ֱ��key is going to be whether you can industrialise production. But I’m very optimistic about our ability to re-engineer processes and make it available for people in general.”

We may soon see an era, then, when our immune systems become an unstoppable force for good.

Our immune systems are meant to keep us healthy, but sometimes they turn their fire on us, with devastating results. Immunotherapies can help defend against this ‘friendly fire’ – and even weaponise it in our defence.

T-cells are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.

Gillian Griffiths

̽��ֱ��moment when a T-cell kills

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Apollo's mission to drive therapeutic innovation

lw355 — Tue, 20 Jun 2017 10:50:20 +0000

Over the past year, a four-strong team has had over a hundred meetings with scientists at three UK universities. By the end of this year, they will probably have had another hundred.

̽��ֱ��team is garnering the most comprehensive sense of what’s happening at the bench across three UK universities – Cambridge, Imperial College London and ̽��ֱ�� College London (UCL) – that anyone has ever amassed. Their job is to identify research that has the greatest potential of making it all the way through to becoming a new medicine, and then to help this happen. This is Apollo Therapeutics.

Dr Richard Butt, who heads up the team, explains the drive behind their meetings: “We live in an age of rapidly escalating biomedical innovation – an age where the development of new medicines should be at an all-time high. But the number of new drugs being developed is largely static.”

In drug discovery, the period between getting promising results in an academic lab and receiving real interest from an investor or pharmaceutical company has been called the ‘Valley of Death’ – and not without good reason. Discovering and developing potential new medicines requires not just money but also expertise and the rapid delivery of industrial-type science. Most drug candidates succumb along the way, long before it’s possible to know whether they might have fulfilled an unmet medical need.

In January 2016, the tech transfer offices (TTOs) of Cambridge, Imperial College and UCL joined forces with three global pharmaceutical companies – AstraZeneca (AZ), GSK and Johnson & Johnson – to create a £40m collaboration called Apollo Therapeutics. Their aim is to streamline the academia-to-industry pipeline by “finding the best translatable science, funding it fast and running the right development programme to make it attractive to industry,” says Butt.

In effect, Apollo aims to maximise the chance that a potential drug will be developed from emerging basic science by investing in a state-of-the-art drug discovery programme that a pharma company will find attractive to license.

“ ̽��ֱ��Apollo approach is wholly new and revolutionary,” says Dr Iain Thomas, Head of Life Sciences of Cambridge Enterprise (Cambridge’s TTO). “You could say that Apollo is building reassurance. ̽��ֱ��hardest part of our job at Cambridge Enterprise is selling really good technology to pharma. It relates to the psychology of buying – people don’t buy complicated stuff with lots of risk without a lot of analysis. Reassurance comes from being engaged with an opportunity for a long time.”

Engagement and partnership are at the heart of the Apollo model. First, Butt’s team speaks to the academics and TTOs of the universities to identify exciting prospects, before taking some of the ideas to the wider team of investors (each of the three companies and the TTOs). “As scientists, we will always be very happy to spend time engaging in discussions with any academic about their work. As drug discoverers, we’ve been very picky about what to take forward,” he says. “We filter very aggressively to maximise the chance of success.”

Once a project is selected for investment, Apollo and the academics work together to develop the discovery to a stage that will be attractive to a company to license and take further.

This work might take place in the academic’s laboratory, or in one of the pharma companies, or in a contract company. It might also take place at the Milner Therapeutics Institute – research laboratories that will open on the Cambridge Biomedical Campus in 2018 dedicated to fostering close collaborative interactions between academia and industry.

“ ̽��ֱ��key is bringing together the skill sets, philosophies and expertise of those who discover with those who know what to do with that discovery,” says Dr Ian Tomlinson, Chair of Apollo. “We are all motivated by the goal of finding new medicines for patients.”

Tomlinson adds: “ ̽��ֱ��conventional pipeline works like this: an academic does some great science, takes it as far as they are able to within the confines of the lab and then, if they want to take it further, either forms a spin-out or licenses to pharma. This still has its place, but it takes time and is costly. If Richard’s team brings the investment team an idea that looks good, Apollo can fund it and be working with the academic in a matter of weeks.”

Between them, Butt and his three colleagues have over 60 years of experience of the pharma industry. “We’ve been at the sharp end of drug discovery and failure,” he says. “We saw the boom of the late 80s/early 90s of drug approvals. And then genomics, high-throughput screening and a seeming wealth of targets led to the mindset of ‘we can scale this success’ – if we run three times more projects we’ll be three times more successful’. ̽��ֱ��basic biology almost ceased to matter. Projects were run that shouldn’t have been. R&D costs escalated but the output of new drugs flat-lined or even declined.

“Apollo is led by the science we see. ̽��ֱ��academic fully understands the biology and mechanisms of the disease target, and we understand the milestones that need to be overcome to become a medicine – drug discovery, formulation, toxicology, clinical trial design, regulators, business models.”

Already his team has identified eight projects across the three universities to receive Apollo funding. ̽��ֱ��first to be backed came out of a 20-year search by Dr Ravi Mahadeva at Cambridge’s Department of Medicine for a small molecule drug to treat Alpha-1 trypsin deficiency (AATD). AAT is a protein that normally protects the lungs. In AATD, a single genetic mutation causes it to aggregate in the liver and the resulting effects on the liver and lungs are disabling and ultimately fatal. There is currently no effective long-term treatment for the disease.

“Ravi came to us with an idea and some early compounds,” says Butt. “Quite simply, it wouldn’t have been picked up by a drug company based on the package that he had. We knew we could design a work package to generate more potent, more selective and more drug-like compounds, and create a package of data that pharma would find attractive.”

For Professor Randall Johnson, Apollo funds have meant that his research in Cambridge’s Department of Physiology, Development and Neuroscience has continued seamlessly through to a drug development programme without the stop-start of waiting for funding, licensing or forming a spin-out. “Randall was one of the first Cambridge academics I saw,” says Butt. “He was excited because he was about to publish a key publication on his genuinely novel work highly relevant to the emerging immune-oncology field. Before Randall’s Nature paper was published, we were already working on a project plan and made the commitment to collaborate on the project.

“Because we are embedded in the ̽��ֱ�� and work closely with Cambridge Enterprise, we have fully confidential access to talk to any academic at any of the three universities. When we worked in pharma, it could take months simply to sit around a table and talk about science and look at data with academics.”

Further down the line, potential therapeutics developed from any of the Apollo-funded programmes will first be offered for licensing to AZ, GSK and Johnson & Johnson, and then more widely; the capital gain of any licensing agreements will be divided between the three universities and the three pharma investors. And the interaction with the companies is not just transactional. Each of them is also committing time, resources and expertise to help the projects that are approved for collaboration.

“ ̽��ֱ��cost to license from us will be much lower than the sum cost to have done all that research internally,” says Tomlinson. “At a time when all the pharmas are cutting their costs and doing less R&D, this provides a different model that will be cost-effective to add potential drugs to their pipelines.

“There are very few totally new drugs every year. To get one of those, you’ve got to cast the net very wide and do everything you can to make the most of the opportunities.

“Apollo has the advantage of not being pigeonholed into working only on one disease or therapy area or limited by drug modality, as we would be if we were a pharma company. As a result, we don’t have to consider a ‘strategic fit’ – we’re simply following the best translatable science that should result in a higher success in getting new medicines to patients.”

Inset image: Read more about research on future therapeutics in Research Horizons magazine.

̽��ֱ��stirrings of a revolution are starting to ripple through hundreds of laboratories. It’s a revolution that aims to result in new medicines – faster and with fewer failures – and it’s being led by three UK universities and three global pharmaceutical companies.

̽��ֱ��key is bringing together the skill sets, philosophies and expertise of those who discover with those who know what to do with that discovery.

Ian Tomlinson, Apollo Therapeutics

Taema

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Self-renewable killer cells could be key to making cancer immunotherapy work

cjb250 — Wed, 26 Oct 2016 17:00:35 +0000

In order to protect us from invading viruses and bacteria, and from internal threats such as malignant tumour cells, our immune system employs an army of specialist immune cells. Just as a conventional army will be made up of different types of soldiers, each with a particular role, so each of these immune cells has a particular function.

Among these cells are cytotoxic T-cells – ‘killer T-cells’, whose primary function is to patrol our bodies, programmed to identify and destroy infected or cancerous cells. Scientists are now trying to harness these cells as a way to fight cancer, by growing T-cells programmed to recognise cancer cells in the laboratory in large numbers and then reintroducing them into the body to destroy the tumour – an approach known as adoptive T-cell immunotherapy.

However, this approach has been hindered by the fact that killer T-cells are short-lived – most killer T cells are gone within three days of transfer – so the army may have died out before it has managed to rid the body of the tumour.

Now, an international team led by researchers at the ̽��ֱ�� of Cambridge has identified a way of increasing the life-span of these T-cells, a discovery that could help scientists overcome one of the key hurdles preventing progress in immunotherapy.

In a paper published today in the journal Nature, the researchers have identified a new role for a molecule known as 2-hydroxyglutarate, or 2-HG, which is known to trigger abnormal growth in tumour cells. In fact, the team has shown that a slightly different form of the molecule also plays a normal, but critical, role in T-cell function: it can influence T-cells to reside in a 'memory state’. This is a state where the cells can renew themselves, persist for a very long period of time, and re-activate to combat infection or cancer.

̽��ֱ��researchers found that by increasing the levels of 2-HG in the T-cells, the researchers could generate cells that could much more effectively destroy tumours. Rather than expiring shortly after reintroduction, the memory state T-cells were able to persist for much longer, destroying tumour cells more effectively.

“In a sense, this means that rather than creating killer T-cells that are active from the start, but burn out very quickly, we are creating an army of ‘renewable cells’ that can stay quiet for a long time, but will go into action when necessary and fight tumour cells,” says Professor Randall Johnson, Wellcome Trust Principal Research Fellow at the Department of Physiology, Development & Neuroscience, ̽��ֱ�� of Cambridge.

“So, with a fairly trivial treatment of T-cells, we’re able to change a moderate response to tumour growth to a much stronger response, potentially giving people a more permanent immunity to the tumours they are carrying. This could make immunotherapy for cancer much more effective.”

̽��ֱ��research was largely funded by the Wellcome Trust.

Reference
Tyrakis, PA et al. ̽��ֱ��immunometabolite S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate; Nature; 26 Oct 2016; DOI: 10.1038/nature2016

A small molecule that can turn short-lived ‘killer T-cells’ into long-lived, renewable cells that can last in the body for a longer period of time, activating when necessary to destroy tumour cells, could help make cell-based immunotherapy a realistic prospect to treat cancer.

Rather than creating killer T-cells that are active from the start, but burn out very quickly, we are creating an army of ‘renewable cells’ that can stay quiet for a long time, but will go into action when necessary and fight tumour cells

Randall Johnson

NIAID

T lymphocyte

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