探花直播 of Cambridge - Tom Blundell

10 Cambridge spinouts changing the story of cancer

skbf2 — Thu, 17 Oct 2024 12:57:43 +0000

10 Cambridge spinouts聽on putting their research into practice to improve outcomes for cancer patients - and why Cambridge is a great place to do this.聽聽聽聽

New innovation hub aims to take a 'moon shot' at cystic fibrosis

cjb250 — Wed, 18 Apr 2018 14:01:05 +0000

John Winn鈥檚 office at Microsoft Research looks like that of any typical academic: on one wall is a whiteboard graffitied with impenetrable equations and mathematical scribblings, on the opposite wall books and files line shelves, and on his desk are photos of his family.

His desk, however, is somewhat different: it can rise or fall, depending on whether he wants to work standing or sitting 鈥� and underneath is a treadmill for walking and working at the same time. 鈥淭here have been times when I鈥檝e been deep in thought and almost fallen off it,鈥� he jokes.

Winn has cystic fibrosis (CF) and keeping fit is an important part of managing his condition: the stronger his lung function, the better equipped he is to fight the potentially life-threatening infections that plague people living with the condition.

CF occurs when an individual inherits two copies of a single genetic variant, one from each parent. 探花直播disease causes a build-up of thick, sticky mucous in the lungs, intestines and organs, and those affected by the condition are particularly susceptible to lung infections leading to progressive inflammatory lung damage. Although life expectancy for people with CF has almost doubled in recent decades, it is still significantly below average.

Winn is a machine learning specialist and is using his expertise to fight the condition that affects his everyday life. Together with Professor Andres Floto from the Department of Medicine at Cambridge, he is turning data from the daily lives of people with cystic fibrosis into potentially life-saving information.

As part of this study, funded by the Cystic Fibrosis Trust and Royal Papworth Hospital, participants have been submitting data 鈥� everything from heart rate and lung function through to self-reported wellbeing 鈥� via an app that also monitors their activity levels. Machine learning then sifts through the data, looking for patterns and 鈥� it鈥檚 hoped 鈥� building a model that can predict when a patient鈥檚 health is about to deteriorate and advise them to seek medical help.

鈥� 探花直播overarching principle is about giving people control over their own health data and making it work for them,鈥� says Winn. 鈥淭here鈥檚 some informal feedback that just participating in the study and taking these readings has already improved health outcomes for some individuals: for example, it鈥檚 helped with adherence with taking their medications as they noticed that if they missed taking certain medicines, their readings got worse.鈥�

探花直播project is just one strand of a major new Cystic Fibrosis Innovation Hub based on the Cambridge Biomedical Campus and run by Floto. 探花直播Hub is supported through a 拢5 million commitment from the Cystic Fibrosis Trust and matching funds from the 探花直播 of Cambridge. It will strengthen existing collaborations across the 探花直播 and with the Wellcome Trust Sanger Institute, as well as build new collaborative research networks with CF centres around the UK. 探花直播Trust鈥檚 Chief Executive, David Ramsden, said it will 鈥減rovide聽in CF research across the country鈥�.

Floto agrees with this sentiment: 鈥淲e have an opportunity to uplift UK CF research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology.鈥�

A major part of the Hub鈥檚 activities will be around developing new drugs that target chronic inflammation in CF, in collaboration with the pharmaceutical company GSK as part of the GSK/Cambridge Strategic Partnership, as well as new antibiotic therapy for the main causes of lung infection in the condition.

Finding new drugs against these bacteria is becoming increasingly urgent 鈥� Floto and Professor Julian Parkhill at Sanger recently showed that Mycobacterium abscessus, the pathogen behind one of the most serious infections, is becoming increasingly multi-drug resistant and spreading globally. This is one reason why people with CF are advised not to meet each other.

鈥淐learly the techniques that we develop 鈥� and the drug-like molecules that come out of it 鈥� will have more general applicability to patients with other multi-drug resistant infections,鈥� Floto says. This will be welcome news to England鈥檚 Chief Medical Officer, Professor Dame Sally Davies, who has warned of a future where 鈥渁ny one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can鈥檛 be treated by antibiotics.鈥�

探花直播timing of all this is particularly good: Papworth Hospital, whose Adult Cystic Fibrosis Centre has gained a national and international reputation for its treatment of patients and its contribution to research, is due to move to the Biomedical Campus later in 2018. 探花直播CF wards will feature state-of-the-art air flow systems, designed with Floto鈥檚 work on the spread of multi-drug resistant CF pathogens in mind.

This close proximity between the patients and the researchers will help Floto test the new treatments he is pioneering. He is particularly excited about the potential for new cellular therapies he鈥檚 developing with Professor Ludovic Vallier at the Department of Surgery. Floto describes these as their 鈥渕oon shot鈥�. These would involve taking cells from a CF patient, re-programming them 鈥� correcting the genetic defect along the way 鈥� and then re-injecting them into patients. 鈥淭his could provide a way to regenerate damaged lungs,鈥� he says.

Floto knows his plans for the Hub are ambitious, but given that it鈥檚 almost 30 years since the gene that causes CF was discovered and there is still no cure for the disease, believes it鈥檚 time to take this shot at the moon.

Floto鈥檚 collaborators in the CF Innovation Hub include Chris Abell (Chemistry), Sir Tom Blundell (Biochemistry), Julian Parkhill and Ludovic Vallier.

Almost 30 years on from the discovery of the genetic defect that causes cystic fibrosis, treatment options are still limited and growing antibiotic resistance presents a grave threat. Now, a team of researchers from across Cambridge, in a major new centre supported by the Cystic Fibrosis Trust, hopes to turn fortunes around.

We have an opportunity to uplift UK cystic fibrosis research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology

Andres Floto

Cambridge Biomedical Campus

A no-strings-attached scientific relationship

Professor Claire Bryant, like Floto, works on an inflammatory lung disease as part of the GSK/Cambridge Strategic Partnership. In her case, she鈥檚 looking at chronic obstructive pulmonary disease (COPD).

COPD is a condition caused by smoking, pollution and severe asthma. Bryant is looking in particular at how COPD makes the lungs 鈥榮tickier鈥� to bacteria, increasing the risk of infections.

She holds two grants under the GSK/Cambridge Strategic Partnership, which aims to develop the next wave of 鈥榞ame-changing鈥� medicines by bringing academic and industrial expertise together to tackle often intractable disease. Based at Cambridge鈥檚 Department of Veterinary Medicine, Bryant currently has a three-day-a-week sabbatical at GSK鈥檚 headquarters in Stevenage. As such, it鈥檚 arguable whether anyone embodies the partnership more than she does.

探花直播three-year sabbatical provides Bryant with three postdocs, two PhD students and budget, with access to GSK resources, but with 鈥渘o strings attached鈥�. 探花直播only proviso is that if she works with a GSK reagent, they have first rights on what she does with this. Crucially, she says, it gives her 鈥渢he space to think鈥�.

Bryant is embedded in GSK鈥檚 Respiratory Drug Discovery Unit and attends its lab meeting every week. 鈥淚鈥檝e met really smart, clever scientists at GSK, with different skills to those of us in academia,鈥� she says. 鈥淚 get to see all aspects of what happens at GSK, everything from how a target is identified to how drugs are developed to target it, through to taking these drugs to clinical trials. I see the whole spectrum.鈥�

It is, though, a mutually beneficial programme, she stresses. Bryant brings her knowledge of innate immunity and her experience of multi-disciplinary collaborations, particularly in imaging. 鈥淚t鈥檚 effectively like being a consultant,鈥� she says. 鈥淚 want them to get as much out of me as I do out of them.鈥�

探花直播text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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A whole host of options

cjb250 — Fri, 09 Oct 2015 08:30:04 +0000

Professor Lalita Ramakrishnan is, it鈥檚 fair to say, a world authority on the biology of TB. She studies the disease 鈥� one which most people will know of as a disease of the lungs 鈥� using what at first sight seems an unusual model: the zebrafish.

鈥淲hat most people don鈥檛 realise is that about 40% of human TB occurs outside the lungs,鈥� explains Ramakrishnan. 鈥淚t can infect the brain, bone, heart, reproductive organs, skin, even the ear. In fact, TB infection is a basic biology question, and this is the same in zebrafish as it is in humans.鈥�

TB is caused by Mycobacterium tuberculosis, which is generally transmitted from person to person through the air. It has been around since at least the Neolithic period, but its prevalence in 19th-century literature led it to be considered something of a 鈥榬omantic鈥� disease. 探花直播truth is a long way from this portrayal. 探花直播disease can cause breathlessness, wasting and eventual death. And while treatments do exist, the drug regimen is one of the longest for any curable disease: a patient will typically need to take medication for six months.

Ramakrishnan is involved in a new trial due to start soon that might allow doctors to reduce the length of this treatment. She is cautiously optimistic that it can be reduced to four months; if successful, however, it may eventually lead to treatments more on a par with standard antibiotic treatments of a couple of weeks.

探花直播trial builds on work in zebrafish carried out by Ramakrishnan and colleagues at the 探花直播 of Washington, Seattle, before she moved to the Department of Medicine in Cambridge in September 2014. These small fish, which grow to the length of a little finger, helped her and collaborator Professor Paul Edelstein from the 探花直播 of Pennsylvania (currently on sabbatical in Cambridge) to make an important discovery that could explain why it takes a six-month course of antibiotics to rid the body of the disease (rather than seven to ten days that most infections take) and yet in the lab can easily be killed.

Within our bodies, we have a host of specialist immune cells that fight infection. One of these is the macrophage (Greek for 鈥榖ig eater鈥�). This cell engulfs the TB bacterium and tries to break it down. This, together with powerful antibiotics, should make eliminating TB from the body a cinch. Ramakrishnan鈥檚 breakthrough was to show why this wasn鈥檛 the case: once inside the macrophages, TB switches on pumps, known as 鈥榚fflux pumps鈥�. Anything that we throw at it, it just pumps back out again.

鈥淥nce we鈥檇 identified the pumps, we started to look for drugs that are out there in the market and tested a few of them,鈥� she explains. 鈥淲e found that verapamil, an old drug, made the bacteria susceptible to two of the antibiotics we use to fight TB.鈥�

探花直播trial of verapamil, which is commonly used to treat high blood pressure, is due to start soon at the National Institute for Research in Tuberculosis (NIRT) in Chennai, India.

Ramakrishnan is one of a number of brilliant minds working as part of a collaboration between the NIRT and the 探花直播 of Cambridge to apply the very latest in scientific thinking and technology to the problem of TB.

An expansion of this collaboration has now become possible through the recent award of a 拢2 million joint grant from the UK Medical Research Council (MRC) and the Department of Biotechnology (DBT) in India, which will enable the exchange of British and Indian researchers. For Professor Sharon Peacock, the UK lead on the proposal, this means an opportunity to train a new cohort of early-career researchers in an environment where they will have access to outstanding scientific facilities and training, at the same time as becoming familiar with the clinical face and consequences of TB for people in India.

鈥淚ndia is home to a large pool of talented young people with the potential to help fight back against this deadly disease,鈥� says Peacock. 鈥淒eveloping a close collaboration between Cambridge and Chennai involving two-way traffic of scientists and ideas is an exciting opportunity to start to tap into this.鈥�

There are few places more suitable for the proposed work than India. According to the World Health Organization, India is home to almost one in four of all worldwide cases of TB, with over two million newly diagnosed cases in 2014.

Not only that, but it is one of the countries that has seen an increase in the number of cases of drug resistance to TB 鈥� including 鈥榤ulti-drug鈥�-resistant, and even more worrying, 鈥榚xtremely鈥� drug-resistant strains of TB against which none of our first- and second-line drug treatments work. In part, this increase reflects improved access to diagnostic services, but the situation highlights why new approaches to tackling the disease are urgently needed, says Professor Soumya Swaminathan, Director of NIRT and the India lead in the collaboration.

鈥淪o far, the treatment of TB has focused almost exclusively on using drugs to try to kill the bacteria directly, but there鈥檚 increasing evidence that there may be benefits to targeting the host. TB is very clever and it manipulates the host immune system to its own advantage, so if we could use drugs to help the immune system, then we may be able to make it more effective.鈥�

This is the approach that Professors Ken Smith and Andres Floto from the Department of Medicine at Cambridge, also part of the collaboration, are taking. Smith is looking at the role that specialist immune cells known as T cells play in the persistence of multi-drug-resistant strains of TB. His group has evidence that around two thirds of the population have T cells which have a tendency to become 鈥榚xhausted鈥� when activated.

鈥淚t might be that exhausted T cells can鈥檛 fight multi-drug-resistant TB effectively, in which case we need to find a way to overcome this exhaustion and spur the T cells on to rid the body of the disease,鈥� says Smith.

For Floto, the key may lie in the role played by the macrophages and their otherwise voracious appetites. As their Greek name suggests, macrophages 鈥榚at鈥� unwanted material (surprisingly similar in action to Pac-Man), effectively chewing it up, breaking it down and spitting it out again.

This process, known as autophagy (鈥榮elf-eating鈥�), is a repair mechanism for clearing damaged bits of cells and recycling them for future use, but also works as a defence mechanism against some invading bacteria. So why, when it engulfs TB, does the bacterium manage to avoid being digested?

鈥淎utophagy is partially inhibited by TB itself, but we found that if you overstimulate this mechanism 鈥� like flooring the accelerator of a car 鈥� you can overcome the bacteria,鈥� explains Floto. 鈥淐learly this will be applicable to normal TB, but we already have drugs that are effective against this. We want to know if this would work against multi-drug-resistant strains.鈥�

Floto and colleagues already have a list of potential drugs that can stimulate autophagy, drugs that have already been licensed and are in use to treat other conditions, such as carbamazepine, which is used to treat epileptic seizures. These drugs are safe to use: the question is, will they work against TB?

鈥淲e鈥檝e already shown that carbamazepine stimulates autophagy in cells to kill TB 鈥� even multi-drug-resistant TB. We now want to refine it and test it in mice and in fish, alongside a shortlist of around 30 other potential drugs,鈥� he adds.

TB evolves through 鈥榩olymorphisms鈥� 鈥� spontaneous changes in the letters of its DNA to create variants. Because the drug regimen to fight the disease lasts so long, many patients do not take the full course of their medicines. If the TB is allowed to relapse, it can evolve drug resistance.

These patterns of resistance can be detected using genome sequencing 鈥� reading the DNA of the bacteria. Peacock believes this technique may be able to help doctors more easily diagnose drug resistance in patients.

鈥淭B is very slow to grow in the laboratory, which means that testing an organism to confirm which antibiotics it is susceptible or resistant to can take several weeks, especially in the case of more resistant strains,鈥� she says. 鈥淭here is increasing evidence that antibiotic resistance can be predicted from the genome sequence of the organism, and we want to establish and evaluate this technology in India, where it is needed.鈥�

This sequencing data could also then help inform the search for new drugs, explains Professor Sir Tom Blundell from the Department of Biochemistry. He is no stranger to TB: his grandfather died from the disease shortly after the war 鈥� though, as Blundell points out, this strain of TB is far less common now, as the organism has evolved in different communities throughout the world.

鈥淲e can take the polymorphisms and ask questions such as 鈥榃hat does this mean for the use of current drugs?鈥欌€� says Blundell. 鈥� 探花直播nature of the polymorphisms in the TB genome sequence of an infected individual can give us information on where that person was infected and聽what are the drugs that might be most effective. We can then begin to look at new targets for particular polymorphisms.鈥�

Blundell plans to take the information gathered through the Chennai partnership and feed it into his drug discovery work. He takes a structural approach to solving the problem: look at the shape of the polymorphism and its protein products and try to find small molecules that can attach to and manipulate them. In essence, it鈥檚 akin to picking a lock by analysing the shape of its mechanism and trying to identify a key that could turn it, thus opening the door.

Yet even if the Chennai venture is successful, and research from the partnership leads to a revolution in how we understand and treat TB, the team recognise that this is unlikely to be enough to eradicate the disease for good.

鈥淭B is as much a public health issue as one of infectious diseases,鈥� says Ramakrishnan, pointing to Europe, where even before the introduction of antibiotics, the disease was already on the decline. 鈥淲e need better nutrition, better air, less smoking, reductions in diabetes.鈥�

Swaminathan agrees. 鈥淭B is very much associated with poverty and all the risk factors that go with it,鈥� she says. 鈥淲hen people are living in very crowded conditions, when they鈥檙e malnourished, TB is going to continue to spread. This is happening in the slums of Mumbai, for example, where we鈥檙e seeing a mini-epidemic of multi-drug-resistant TB. Unless we see a rapid improvement in the living standards of people we鈥檙e not going to see a very major effect. There鈥檚 only so much we can do biomedically.鈥�

Inset image:聽Macrophage engulfing Tuberculosis pathogen (ZEISS Microscopy).

Almost one in four of the world鈥檚 cases of tuberculosis (TB) are in India and the disease is constantly adapting itself to outwit our medicines. Could the answer lie in targeting not the bacteria but its host, the patient?

What most people don鈥檛 realise is that about 40% of human TB occurs outside the lungs ... It can infect the brain, bone, heart, reproductive organs, skin, even the ear

Lalita Ramakrishnan

Calcutta Rescue

Picture to educate people in villages that have no medical service about the spread of TB

探花直播Next Generation

If there鈥檚 one thing on the side of science v. TB, it鈥檚 the wealth of talent available in India.

Professor Sir Tom Blundell is quick to praise the Indian postdocs that come to work in his lab. 鈥淭hey tend to be naturally very inquisitive and interactive, with very enquiring minds,鈥� he says.

This is something with which Professor Ashok Venkitaraman, Director of the Medical Research Council (MRC) Cancer Unit at Cambridge, wholeheartedly agrees. He has helped establish the Center for Chemical Biology and Therapeutics (CCBT) in Bangalore in part, he says, because 鈥渢he number of really bright, well-trained young scientists in India is huge. 探花直播level of enthusiasm and commitment is something I find quite exceptional.鈥�

探花直播CCBT is an inter-institutional centre that links the Institute for Stem Cell Biology and Regenerative Medicine and the National Center for Biological Sciences, both of which are world-class Indian research institutes studying fundamental biology. However, argues Venkitaraman, India needs the capacity to translate fundamental research to clinical application.

It is to help bridge this gap that the CCBT was established, with funding from the Department of Biotechnology (DBT) in India, recently supplemented by a 拢2 million joint award from the UK MRC and the DBT. 探花直播idea is to find innovative ways to discover 鈥榥ext-generation鈥� medicines against human diseases, by coupling biological research that reveals novel drug targets with approaches in chemistry and structural biology that create potential drug candidates.

Although Venkitaraman鈥檚 interest is in cancer, he predicts the work of the CCBT will be 鈥渄isease agnostic鈥�, because similar types of novel drug targets have been implicated in infectious diseases, cancer and even developmental defects.

鈥淲e desperately need to develop new medicines not just for currently problematic diseases like cancer and TB, but also for the new challenges that are being thrown at us all the time 鈥� antibiotic resistance, new infections, metabolic syndromes and diseases of ageing, for example. Nowhere is this need more critical than in emerging nations like India where the spectrum of disease is distinct from countries like the UK.鈥�

探花直播text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Cambridge partners with India to fight multidrug resistant TB

Anonymous — Fri, 13 Feb 2015 16:30:42 +0000

探花直播Cambridge-Chennai Centre Partnership on Antimicrobial Resistant Tuberculosis will bring together a multidisciplinary team of international researchers, and will be led by Professor Sharon Peacock and Dr Soumya Swaminathan.聽探花直播team, including Professors Lalita Ramakrishnan, Ken Smith, Tom Blundell and Andres Floto, will focus on developing new diagnostic tools and treatments to address the sharp rise in cases of multidrug resistant tuberculosis (TB).

This will include research into:

the use of emerging sequence-based diagnostics to improve the accuracy of individual patient treatment for drug resistant TB
predicting the impact of genetic mutations on drug resistance based on modelling of bacterial genome data
the development of an in-depth understanding of bacterial genes associated with so-called 鈥榙rug-tolerance鈥�, where the drug鈥檚 ability to kill the bacteria gradually weakens
novel approaches to treatment of TB based on enhancing the body鈥檚 immune system to enable it to fight infection.

探花直播partnership will generate a rich and lasting clinical and genomic dataset for studying TB, and the transfer of scientific training and technology will foster future international collaborative projects.

鈥淚 am delighted that Cambridge has been given the opportunity to work on a disease of global importance through the development of this partnership,鈥� said Professor Sharon Peacock. 鈥淐hennai was the site for many of the early MRC-funded TB treatment trials, and the chance to explore new therapies and diagnostics to improve patient outcome through the use of state-of-the-art technologies represents an exciting opportunity.鈥�

探花直播funding is part of a landmark collaboration between the MRC and the Government of India DBT. Nearly 拢3.5million will be invested by the UK, through the MRC and the Newton Fund, a new initiative intended to strengthen research and innovation partnerships between the UK and emerging knowledge economies, with matched funding provided by DBT.

Prof K. VijayRaghavan, Secretary, Department of Biotechnology added: 鈥� 探花直播Department of Biotechnology, Government of India is delighted to partner with the MRC in creating research centres which will address vexing challenges in medicine through quality science and collaboration. India is committed to working with the best in the world, for India and for the world. We are acutely aware that the fruits of our partnership can mean better lives for the most- needy everywhere and are committed to make the collaboration succeed.鈥�

探花直播探花直播 of Cambridge has been awarded 拢2 million from the UK Medical Research Council and the Government of India鈥檚 Department for Biotechnology to develop a partnership with the National Institute for Research in Tuberculosis (NIRT) in Chennai.

I am delighted that Cambridge has been given the opportunity to work on a disease of global importance through the development of this partnership

Sharon Peacock

CDC/ Melissa Brower

This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of rod-shaped drug-resistant Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB). 探花直播artistic recreation was base

探花直播text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

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