̽��ֱ�� of Cambridge - stem cells

New way to extend ‘shelf life’ of blood stem cells will improve gene therapy

lmp58 — Thu, 15 Aug 2024 14:47:37 +0000

Researchers have identified a drug already used for cancer patients, that, when applied to current gene therapy protocols can improve blood stem cell function threefold.

One trillion blood cells are produced every day in humans, and blood stem cells are the only cell types in our body capable of producing all blood cell types over our lifespan, giving them immense regenerative potential.

Blood stem cell gene therapy is a ground-breaking treatment that currently provides the only cure to more than ten life-debilitating genetic diseases and has already saved the lives of more than two million people with blood cancers and other diseases.

These therapies take blood stem cell samples from patients, where their genetic defect is corrected in a dish before being delivered back to the patient. However, limitations persist in blood stem cell therapies because of the shelf life of the cells outside the body. When removed from their environment in the human body and cultured in a dish, most blood stem cells lose their function. ̽��ֱ��exact timing and cause of this function loss has not previously been well understood.

Now, scientists in the Laurenti Group and others at the ̽��ֱ�� of Cambridge’s Cambridge Stem Cell Institute (CSCI) and Department of Haematology have pinpointed a timeline for the blood stem cells under the current gene therapy protocols, which typically take place over three days. After the first 24 hours in a dish, more than 50% of the blood stem cells can no longer sustain life-long blood production, which is before therapy would even begin in a clinical setting.

During those first 24 hours, the cells activate a complex molecular stress response in order to adapt to the dish. By studying this stress response, the team identified a solution. Through repurposing a cancer growth blocker drug (Ruxolitinib), already in use for cancer treatments, they were able to improve stem cell function in a dish by three times its former capabilities.

̽��ֱ��group is now aiming to modify current gene therapy protocols to include this drug, providing patients with the highest number of high-quality blood stem cells and improving their outcomes.

̽��ֱ��study is published today in the journal Blood.

Professor Elisa Laurenti at the ̽��ֱ�� of Cambridge Stem Cell Institute, and senior author of the study, said: “This is really exciting because we are now in a position where we can begin to understand the huge stress that these stem cells sense when they are manipulated outside of our body. Biologically it is really fascinating because it affects every aspect of their biology. Luckily, we were able to identify a key molecular pathway which governs many of these responses, and that can be targeted by a drug which is already in use and is safe to use.

“I hope our findings will enable safer treatments for gene therapy patients. Our discovery also opens up many possibilities to better expand blood stem cells ex vivo and expand the set of disease where we can use blood stem cells to improve patients’ lives.”

Dr Carys Johnson at the ̽��ֱ�� of Cambridge Stem Cell Institute, and first author of the study, said: “Although we expected that removing these cells from the body and culturing them on a plastic surface would alter gene expression, the extent of change we found was surprising, with over 10,000 genes altered and a significant stress response detected. It was also striking to discover that the majority of blood stem cells are functionally lost during gene therapy protocols, before transplantation back to the patient.

“We have identified a key bottleneck where function is lost and clinical culture could be improved. I hope that our work will drive advancements in culture protocols to better harness the power of blood stem cells and improve the safety and efficacy of clinical approaches.”

Reference

C.S. Johnson, M.J. Williams, K. Sham, et al. ‘Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle.’ Blood 2024; DOI: 10.1182/blood.2023021426

Story written by Laura Puhl, Cambridge Stem Cell Institute.

Researchers have discovered a way to extend the shelf life of blood stem cells outside the body for use in gene therapy, providing patients with better options and improving their outcomes.

We were able to identify a key molecular pathway...that can be targeted by a drug which is already in use and is safe to use.

Elisa Laurenti

Philippe Delavie from Pixabay

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Lab-grown ‘mini-guts’ could change how we treat Crohn’s disease

cjb250 — Tue, 11 Jun 2024 09:31:24 +0000

Cambridge scientists have grown ‘mini-guts’ in the lab to help understand Crohn’s disease, showing that ‘switches’ that modify DNA in gut cells play an important role in the disease and how it presents in patients.

Cambridge ReseARch Trail

zs332 — Thu, 14 Mar 2024 16:34:06 +0000

A new augmented reality trail, launched as part of the Cambridge Festival, is showcasing the world leading research of the ̽��ֱ�� of Cambridge in a new light.

‘Mini-placentas’ help scientists understand the causes of pre-eclampsia and pregnancy disorders

cjb250 — Wed, 17 Jan 2024 16:00:37 +0000

̽��ֱ��study, published today in Cell Stem Cell, shows that it is possible to experiment on a developing human placenta, rather than merely observe specimens, in order to study major disorders of pregnancy.

Successful pregnancy depends on the development of the placenta in the first few weeks of gestation. During this period, the placenta implants itself into the endometrium – the mucosal lining of the mother’s uterus.

Interactions between the cells of the endometrium and the cells of the placenta are critical to whether a pregnancy is successful. In particular, these interactions are essential to increase the maternal blood supply to the placenta, necessary for fetal growth and development.

When these interactions do not work properly, they can lead to complications, such as pre-eclampsia, a condition that causes high blood pressure during pregnancy. Pre-eclampsia occurs in around six in 100 first pregnancies and can put at risk the health of both the mother and the baby.

Professor Ashley Moffett from the Department of Pathology at the ̽��ֱ�� of Cambridge said: “Most of the major disorders of pregnancy – pre-eclampsia, still birth, growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study – the period after implantation, when the placenta embeds itself into the endometrium, is often described as a ‘black box of human development’.

“Over the past few years, many scientists – including several at Cambridge – have developed embryo-like models to help us understand early pre-implantation development. But further development is impeded because we understand so little about the interactions between the placenta and the uterus.”

Professor Moffett and colleagues at the Friedrich Miescher Institute, Switzerland, and the Wellcome Sanger Institute, Cambridge, have used ‘mini-placentas’ – a cellular model of the early stages of the placenta – to provide a window into early pregnancy and help improve our understanding of reproductive disorders. Known as ‘trophoblast organoids’, these are grown from placenta cells and model the early placenta so closely that they have previously been shown to record a positive response on an over-the-counter pregnancy test.

In previous work, Professor Moffett and colleagues identified genes that increase the risk of or protect against conditions such as pre-eclampsia. These highlighted the important role of immune cells uniquely found in the uterus, known as ‘uterine natural killer cells’, which cluster in the lining of the womb at the site where the placenta implants. These cells mediate the interactions between the endometrium and the cells of the placenta.

In their new study, her team applied proteins secreted by the uterine natural killer cells to the trophoblast organoids so that they could mimic the conditions where the placenta implants itself. They identified particular proteins that were crucial to helping the organoids develop. These proteins will contribute to successful implantation, allowing the placenta to invade the uterus and transform the mother’s arteries.

“This is the only time that we know of where a normal cell invades and transforms an artery, and these cells are coming from another individual, the baby,” said Professor Moffett, who is also a Fellow at King’s College, Cambridge.

“If the cells aren’t able to invade properly, the arteries in the womb don’t open up and so the placenta – and therefore the baby – are starved of nutrients and oxygen. That's why you get problems later on in pregnancy, when there just isn't enough blood to feed the baby and it either dies or is very tiny.”

̽��ֱ��researchers also found several genes that regulate blood flow and help with this implantation, which Professor Moffett says provide pointers for future research to better understand pre-eclampsia and similar disorders.

Dr Margherita Turco, from the Friedrich Miescher Institute in Switzerland and co-lead of this work, added: “Despite affecting millions of women a year worldwide, we still understand very little about pre-eclampsia. Women usually present with pre-eclampsia at the end of pregnancy, but really to understand it – to predict it and prevent it – we have to look at what's happening in the first few weeks.

“Using ‘mini-placentas’, we can do just that, providing clues as to how and why pre-eclampsia occurs. This has helped us unpick some of the key processes that we should now focus on far more. It shows the power of basic science in helping us understand our fundamental biology, something that we hope will one day make a major difference to the health of mothers and their babies.”

̽��ֱ��research was supported by Wellcome, the Royal Society, European Research Council and Medical Research Council.

Reference
Li, Q et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell; 17 Jan 2024; DOI: doi.org/10.1016/j.stem.2023.12.013

Volunteers wanted for women's health study

̽��ֱ�� of Cambridge researchers at Addenbrooke’s Hospital are looking for volunteers who are planning their first pregnancy, to take part in a new study focussing on pregnancy and women’s long-term health (the POPPY study).

̽��ֱ��POPPY study aims to understand why some women develop pre-eclampsia and other placental complications and why these conditions have an adverse effect on women’s future heart health.

If you are aged 18-45 years and are planning your first pregnancy, you may be eligible to participate. We are also looking for similar aged volunteers who are not actively planning a pregnancy, for a control group.

Reimbursement is provided for time, inconvenience and travel.

To find out more, please visit the POPPY study website or email the POPPY study team.

18 January 2024

Scientists have grown ‘mini-placentas’ in the lab and used them to shed light on how the placenta develops and interacts with the inner lining of the womb – findings that could help scientists better understand and, in future, potentially treat pre-eclampsia.

Most of the major disorders of pregnancy – pre-eclampsia, still birth, growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study.

Ashley Moffett

Friedrich Miescher Institute/ ̽��ֱ�� of Cambridge

Placental organoid (circle in the centre). Trophoblast cells are invading out of the organoid, mimicking placental cells invading the uterus in the early weeks of pregnancy.

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Early-stage stem cell therapy trial shows promise for treating progressive MS

cjb250 — Mon, 27 Nov 2023 16:00:22 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, ̽��ֱ�� of Milan Bicocca and Hospital Casa Sollievo della Sofferenza (Italy), is a step towards developing an advanced cell therapy treatment for progressive MS.

Over 2 million people live with MS worldwide, and while treatments exist that can reduce the severity and frequency of relapses, two-thirds of MS patients still transition into a debilitating secondary progressive phase of disease within 25-30 years of diagnosis, where disability grows steadily worse.

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord.

Key immune cells involved in this process are macrophages (literally ‘big eaters’), which ordinarily attack and rid the body of unwanted intruders. A particular type of macrophage known as a microglial cell is found throughout the brain and spinal cord. In progressive forms of MS, they attack the central nervous system (CNS), causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that stem cell therapies might help ameliorate this damage. These involve the transplantation of stem cells, the body’s ‘master cells’, which can be programmed to develop into almost any type of cell within the body.

Previous work from the Cambridge team has shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, can help reduce inflammation and may be able to help repair damage caused by MS.

Now, in research published in the Cell Stem Cell, scientists have completed a first-in-human, early-stage clinical trial that involved injecting neural stem cells directly into the brains of 15 patients with secondary MS recruited from two hospitals in Italy. ̽��ֱ��trial was conducted by teams at the ̽��ֱ�� of Cambridge, Milan Bicocca and the Hospitals Casa Sollievo della Sofferenza and S. Maria Terni (IT) and Ente Ospedaliero Cantonale (Lugano, Switzerland) and the ̽��ֱ�� of Colorado (USA).

̽��ֱ��stem cells were derived from cells taken from brain tissue from a single, miscarried foetal donor. ̽��ֱ��Italian team had previously shown that it would be possible to produce a virtually limitless supply of these stem cells from a single donor – and in future it may be possible to derive these cells directly from the patient – helping to overcome practical problems associated with the use of allogeneic foetal tissue.

̽��ֱ��team followed the patients over 12 months, during which time they observed no treatment-related deaths or serious adverse events. While some side-effects were observed, all were either temporary or reversible.

All the patients showed high levels of disability at the start of the trial – most required a wheelchair, for example – but during the 12 month follow up period none showed any increase in disability or a worsening of symptoms. None of the patients reported symptoms that suggested a relapse and nor did their cognitive function worsen significantly during the study. Overall, say the researchers, this points to a substantial stability of the disease, without signs of progression, though the high levels of disability at the start of the trial make this difficult to confirm.

̽��ֱ��researchers assessed a subgroup of patients for changes in the volume of brain tissue associated with disease progression. They found that the larger the dose of injected stem cells, the smaller the reduction in this brain volume over time. They speculate that this may be because the stem cell transplant dampened inflammation.

̽��ֱ��team also looked for signs that the stem cells were having a neuroprotective effect – that is, protecting nerve cells from further damage. Their previous work showed how tweaking metabolism – how the body produces energy – can in turn reprogram microglia from ‘bad’ to ‘good’. In this new study, they looked at how the brain's metabolism changes after the treatment. They measured changes in the fluid around the brain and in the blood over time and found certain signs that are linked to how the brain processes fatty acids. These signs were connected to how well the treatment works and how the disease develops. ̽��ֱ��higher the dose of stem cells, the greater the levels of fatty acids, which also persisted over the 12-month period.

Professor Stefano Pluchino from the ̽��ֱ�� of Cambridge, who co-led the study, said: “We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS.

“We recognise that our study has limitations – it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example – but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials.”

Co-leader Professor Angelo Vescovi from the ̽��ֱ�� of Milano-Bicocca said: “It has taken nearly three decades to translate the discovery of brain stem cells into this experimental therapeutic treatment This study will add to the increasing excitement in this field and pave the way to broader efficacy studies, soon to come.”

Caitlin Astbury, Research Communications Manager at the MS Society, says: “This is a really exciting study which builds on previous research funded by us. These results show that special stem cells injected into the brain were safe and well-tolerated by people with secondary progressive MS. They also suggest this treatment approach might even stabilise disability progression. We’ve known for some time that this method has the potential to help protect the brain from progression in MS.

“This was a very small, early-stage study and we need further clinical trials to find out if this treatment has a beneficial effect on the condition. But this is an encouraging step towards a new way of treating some people with MS.”

Reference
Leone, MA, Gelati, M & Profico, DC et al. Intracerebroventricular Transplantation of Foetal Allogeneic Neural Stem Cells in Patients with Secondary Progressive Multiple Sclerosis (hNSC-SPMS): a phase I dose escalation clinical trial. Cell Stem Cell; 27 Nov 2023; DOI: 10.1016/j.stem.2023.11.001

An international team has shown that the injection of a type of stem cell into the brains of patients living with progressive multiple sclerosis (MS) is safe, well tolerated and has a long-lasting effect that appears to protect the brain from further damage.

I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS

Stefano Pluchino

Early-stage stem cell therapy trial shows promise for treating progressive MS

eyecrave productions (Getty Images)

Mature Adult Female with Disability

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Lab-grown ‘small blood vessels’ point to potential treatment for major cause of stroke and vascular dementia

cjb250 — Thu, 16 Nov 2023 16:00:19 +0000

̽��ֱ��study, published today in Stem Cell Reports, also identifies a drug target to ‘plug’ these leaks and prevent so-called small vessel disease in the brain.

Cerebral small vessel disease (SVD) is a leading cause of age-related cognitive decline and contributes to almost half (45%) of dementia cases worldwide. It is also responsible for one in five (20%) ischemic strokes, the most common type of stroke, where a blood clot prevents the flow of blood and oxygen to the brain.

̽��ֱ��majority of cases of SVD are associated with conditions such as hypertension and type 2 diabetes, and tend to affect people in their middle age. However, there are some rare, inherited forms of the disease that can strike people at a younger age, often in their mid-thirties. Both the inherited and ‘spontaneous’ forms of the disease share similar characteristics.

Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute, ̽��ֱ�� of Cambridge, used cells taken from skin biopsies of patients with one of these rare forms of SVD, which is caused by a mutation in a gene called COL4.

By reprogramming the skin cells, they were able to create induced pluripotent stem cells – cells that have the capacity to develop into almost any type of cell within the body. ̽��ֱ��team then used these stem cells to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.

Dr Alessandra Granata from the Department of Clinical Neurosciences at Cambridge, who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease. Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”

Our blood vessels are built around a type of scaffolding known as an extracellular matrix, a net-like structure that lines and supports the small blood vessels in the brain. ̽��ֱ��COL4 gene is important for the health of this matrix.

In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called ‘tight junctions’, which ‘zip’ cells together. This leads to the small blood vessels becoming leaky – a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.

̽��ֱ��researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure – similar to how in ̽��ֱ��Sorcerer’s Apprentice, a single broom can help mop the floor, but too many wreak havoc.

When the team treated the blood vessels with drugs that inhibit MMPs – an antibiotic and anti-cancer drug – they found that these reversed the damage and stopped the leakage.

Dr Granata added: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”

̽��ֱ��study was funded by the Stroke Association, British Heart Foundation and Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.

Reference
Al-Thani, M, Goodwin-Trotman, M. A novel human 1 iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases. Stem Cell Reports; 16 Nov 2023; DOI: https://doi.org/10.1016/j.stemcr.2023.10.014

Cambridge scientists have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that supports these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke.

Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease

Alessandra Granata

Alessandra Granata/ ̽��ֱ�� of Cambridge

Disease mural cells stained for calponin (mural cells marker, green), collagen IV (magenta) and DAPI (nuclei, blue)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Developing ‘kinder’ treatments for a devastating childhood cancer

cjb250 — Wed, 20 Sep 2023 15:00:35 +0000

Neuroblastomas can be devastating to children and their families and the treatments can be harsh. But thanks to scientists, some tadpoles and a little poetry, improved treatments could soon be on their way.

Scientists develop test to identify people at risk of developing acute myeloid leukaemia and related cancers

jg533 — Thu, 24 Aug 2023 15:14:28 +0000

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), the ̽��ֱ�� of Cambridge’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analysed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists created 'MN–predict', a platform for predicting the risk of developing blood cancers such as acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10- to 15-year period.

̽��ֱ��test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukaemia prevention.

Professor George Vassiliou, senior author of the study, said: “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukaemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.”

̽��ֱ��myeloid neoplasms are a group of related cancers encompassing acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists have discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells - the cells responsible for normal blood formation. ̽��ֱ��mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukaemia.

While mutations that promote cell growth are common, leukaemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

̽��ֱ��work is published today in the journal Nature Genetics.

Dr Muxin Gu, first author of the paper, said: “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers, and use novel treatment to prevent the cancers developing.”

Dr Pedro M Quiros, joint senior author of the study, said: “Despite some recent advances in their treatment, unfortunately these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favour of treating the full-blown disease.”

̽��ֱ��research and development of MN-Predict was funded by Cancer Research UK and the Leukaemia and Lymphoma Society. Scientists from the Early Cancer Institute, ̽��ֱ�� of Cambridge, ̽��ֱ�� of Bristol, ̽��ֱ�� of Oviedo (Spain), ̽��ֱ�� of York, AstraZeneca (UK), German Cancer Research Center (DKFZ, Germany), St James's Hospital, Leeds (UK) and ̽��ֱ�� of Pavia (Italy) also participated in the study.

Reference

Gu M, Cheloor-Kovilakam S, Dunn W, Marando L, Barcena C, Mohorianu I, Smith A, Kar S, Fabre M, Gerstung M, Cargo C, Malcovati L, Quiros P, Vassiliou G: 'Multiparameter prediction of myeloid neoplasia risk.' Nature Genetics. 2023. DOI: 10.1038/s41588-023-01472-1

Adapted from a press release by the Wellcome-MRC Cambridge Stem Cell Institute.

̽��ֱ��new ‘MN-predict’ platform will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.

George Vassiliou

Nguyễn Hiệp on Unsplash

Person having a blood test

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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