̽��ֱ�� of Cambridge - proteomics

Study highlights potential for ‘liquid health check’ to predict disease risk

cjb250 — Mon, 02 Dec 2019 16:00:36 +0000

Preventative medicine programmes such as the UK National Health Service’s Health Check and Healthier You programmes are aimed at improving our health and reducing our risk of developing diseases. While such strategies are inexpensive, cost effective and scalable, they could be made more effective using personalised information about an individual’s health and disease risk.

̽��ֱ��rise and application of ‘big data’ in healthcare, assessing and analysing detailed, large-scale datasets makes it increasingly feasible to make predictions about health and disease outcomes and enable stratified approaches to prevention and clinical management.

Now, an international team of researchers from the UK and USA, working with biotech company SomaLogic, has shown that large-scale measurement of proteins in a single blood test can provide important information about our health and can help to predict a range of different diseases and risk factors.

Our bodies contain around 30,000 different proteins, which are coded for by our DNA and regulate biological processes. Some of these proteins enter the blood stream by purposeful secretion to orchestrate biological processes in health or in disease, for example hormones, cytokines and growth factors. Others enter the blood through leakage from cell damage and cell death. Both secreted and leaked proteins can inform health status and disease risk.

In a proof-of-concept study based on five observational cohorts in almost 17,000 participants, researchers scanned 5,000 proteins in a plasma sample taken from each participant. Plasma is the single largest component of blood and is the clear liquid that remains after the removal of red and white blood cells and platelets. ̽��ֱ��study resulted in around 85 million protein targets being measured.

̽��ֱ��technique involves using fragments of DNA known as aptamers that bind to the target protein. In general, only specific fragments will bind to particular proteins – in the same way that only a specific key will fit in a particular lock. Using existing genetic sequencing technology, the researchers can then search for the aptamers and determine which proteins are present and in what concentrations.

̽��ֱ��researchers analysed the results using statistical methods and machine learning techniques to develop predictive models – for example, that an individual whose blood contains a certain pattern of proteins is at increased risk of developing diabetes. ̽��ֱ��models covered a number of health states, including levels of liver fat, kidney function and visceral fat, alcohol consumption, physical activity and smoking behaviour, and for risk of developing type 2 diabetes and cardiovascular disease.

̽��ֱ��accuracy of the models varied, with some showing high predictive powers, such as for percentage body fat, while others had only modest prognostic power, such as for cardiovascular risk. ̽��ֱ��researchers report that their protein-based models were all either better predictors than models based on traditional risk factors or would constitute more convenient and less expensive alternatives to traditional testing.

Many of the proteins are linked to a number of health states or conditions; for example, leptin, which modulates appetite and metabolism, was informative for predictive models of percentage body fat, visceral fat, physical activity and fitness.

One difference between genome sequencing and so-called ‘proteomics’ – studying an individual’s proteins in depth – is that whereas the genome is fixed, the proteome changes over time. It might change as an individual becomes more obese, less physically active or smokes, for example, so proteins will be able to track changes in an individual's health status over a lifetime.

“Proteins circulating in our blood are a manifestation of our genetic make-up as well as many other factors, such as behaviours or the presence of disease, even if not yet diagnosed,” said Dr Claudia Langenberg, from the MRC Epidemiology Unit at the ̽��ֱ�� of Cambridge. “This is one of the reasons why proteins are such good indicators of our current and future health state and have the potential to improve clinical prediction across different and diverse diseases.”

“It’s remarkable that plasma protein patterns alone can faithfully represent such a wide variety of common and important health issues, and we think that this is just the tip of the iceberg,” said Dr Stephen Williams, Chief Medical Officer of SomaLogic, who led the study. “We have more than a hundred tests in our SomaSignal pipeline and believe that large-scale protein scanning has the potential to become a sole information source for individualised health assessments.”

While this study shows a proof-of-principle, the researchers say that as technology improves and becomes more affordable, it is feasible that a comprehensive health evaluation using a battery of protein models derived from a single blood sample could be offered as routine by health services.

“This proof of concept study demonstrates a new paradigm that measurement of blood proteins can accurately deliver health information that spans across numerous medical specialties and that should be actionable for patients and their healthcare providers,” said Peter Ganz, MD, co-leader of this study and the Maurice Eliaser Distinguished Professor of Medicine at the UCSF and Director of the Center of Excellence in Vascular Research at Zuckerberg San Francisco General Hospital and Trauma Center. “I expect that in the future we will look back at this Nature Medicine proteomic study as a critical milestone in personalising and thus improving the care of our patients.”

Reference
Williams, SA et al. Plasma protein patterns as comprehensive indicators of health; Nat Med; 2 Dec 2019; DOI: 10.1038/s41591-019-0665-2

Competing interests
̽��ֱ��research was a collaboration with SomaLogic Inc, which has a commercial interest in the results. Several co-authors were or are employees of SomaLogic. ̽��ֱ��company has provided funding to the ̽��ֱ�� of Cambridge. Dr Peter Ganz is a member of the SomaLogic Medical Advisory board, for which he receives no remuneration of any kind.

Funding
̽��ֱ��research was supported by the UK Medical Research Council, US National Institutes on Aging, British Heart Foundation, National Institute for Health Research, the Norwegian Ministry of Health, Norwegian ̽��ֱ�� of Science and Technology and Norwegian Research Council, Central Norway Regional Health Authority, Nord-Trondelag County Council, Norwegian Institute of Public Health, US National Heart, Lung and Blood Institute. SomaScan assays and the Covance study were funded by SomaLogic, Inc.

Proteins in our blood could in future help provide a comprehensive ‘liquid health check’, assessing our health and predicting the likelihood that we will we will develop a range of diseases, according to research published today in Nature Medicine.

Proteins circulating in our blood are a manifestation of our genetic make-up as well as many other factors, such as behaviours or the presence of disease, even if not yet diagnosed

Claudia Langenberg

Geralt

Blood plasma

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Cambridge joins EU partners in ten-million-euro proteomics project

ta385 — Tue, 15 Jan 2019 22:41:40 +0000

̽��ֱ��European Union has awarded ten million euros to a consortium of 18 research groups in the field of mass spectrometry based proteomics research.

̽��ֱ��European Proteomics Initiative Consortium (EPIC-XS), funded as part of the Horizon 2020 Work programme, is coordinated by Albert Heck, professor of biomolecular mass spectrometry and proteomics at Utrecht ̽��ֱ��. ̽��ֱ��project began on 1 January 2019 and will run for four years.

Proteomics, the large-scale study of proteins and their role in living cells and organisms, is an important technology used to gain insight into the function of biological systems. Proteomics has been applied in many different types of studies. These include understanding how cells of the body respond to drug treatment and discovering new biomarkers in body fluids such as blood serum that can be used to detect disease but also monitor how patients respond to treatment.

Proteomics research requires state of the art technology, in-house technical know-how, sustainable and robust workflow practices, successful and correct data interpretation, and data management. ̽��ֱ��EPIC-XS initiative will support researchers by providing them with access to state of the art proteomics equipment, and allowing them to submit research proposals that make use of the proteomics technology offered by the project.

This initiative is a follow-up of the previous European proteomics infrastructure project PRIME-XS, which was completed in 2015. EPIC-XS will again provide access to proteomics facilities throughout Europe, supporting and expanding the European proteomics community with its expertise. ̽��ֱ��provision of courses and training programs will enable new research communities to be schooled in advanced proteomics technologies.

̽��ֱ��EPIC-XS consortium consists of partners from fifteen nations: Great Britain, France, Spain, Italy, Switzerland, Germany, the Netherlands, Estonia, Sweden, Belgium, Denmark, Greece, Czechia, Austria and Norway. All partners share a common goal: to facilitate the development and sustainability of proteomics exploration to all life science researchers within the European Union.

̽��ֱ��British partner of EPIC-XS is the Cambridge Centre for Proteomics (CCP). CCP was established in 2000 in the Department of Biochemistry. Since then, CCP has become a world-leading facility applying its technology to a wide variety of biological questions. ̽��ֱ��Centre is comprised of a core facility that offers full quantitative analysis on virtually any sample of any complexity and a research group that creates and applies novel proteomics technology. Its Director, Professor Kathryn Lilley, said:

“I am delighted that CCP is involved in EPIC-XS, having been a partner in its highly successful forerunner, PRIME-XS. As part of consortium, we develop technology, combining our expertise in determining where proteins are located within living cells, with that of our European colleagues who are using proteomics to investigate protein structure.

“This kind of international partnership is essential. There is a vast array of proteomics methods and each research laboratory can only become expert in a sub-set of these. By working together, we can unite and finesse our methodologies to uncover important cellular processes inaccessible with current approaches. This will make us greater than the sum of our parts.”

̽��ֱ�� ̽��ֱ�� of Cambridge has joined European partners in a major study of proteins which will shed light on the role played by biological systems in health and disease.

This kind of international partnership is essential

Kathryn Lilley

̽��ֱ��Lilley research group, Cambridge Centre for Proteomics

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Neighbourhood watch: New technique helps identify proteins involved in immune response

cjb250 — Fri, 23 May 2014 13:13:18 +0000

When our bodies are under attack from foreign organisms, such as bacteria and viruses, our immune system orchestrates a complex fight-back involving many separate parts. One important component of this response is a type of cell called the B-lymphocyte – it is this cell that is at the forefront of our defence as it identifies and attempts to neutralise invaders.

̽��ֱ��B-lymphocyte produces a protein called the B-cell receptor on its surface. ̽��ֱ��receptor recognises and attaches itself to molecules from the invading organisms, known as antigens. This triggers the B-lymphocyte to divide and to release specialised proteins called antibodies which neutralise the antigens.

There are many aspects of this process that are still not well understood. One reason is because the B-cell receptor does not exist in isolation on the B-lymphocyte surface. Rather, it forms localised clusters together with a number of ‘molecular neighbours’. It is these local interactions that control how the lymphocytes divide and replicate and determine the strength of the antibody response. A better understanding of these interactions could ultimately lead to better control of the immune response – for example in vaccine development. However, the molecular contacts within the clusters are relatively weak, and so they are technically difficult to identify.

Now, in an international collaboration, scientists at the ̽��ֱ�� of Cambridge’s Department of Biochemistry, the Cambridge Centre for Proteomics and the Institute of Biophysics in Beijing have developed a technique that allows some of these molecules to be detected. ̽��ֱ��experiments were performed primarily by Li Xue-Wen in Beijing and Dr Jo Rees in Cambridge, and are published in the Journal of Biological Chemistry. ̽��ֱ��method enables proteins in the immediate vicinity of the B-cell receptor to be chemically tagged in such a way that they can be more easily isolated. ̽��ֱ��tagged molecules can then be identified using a method called mass spectrometry.

For this initial ‘proof of principle’ experiment, the researchers looked at the B-cell receptor on the surface of a chicken B-lymphocyte and identified molecules that were hitherto not thought to be involved in regulation of the receptor. They show that these molecules combine with the receptor to activate a class of proteins called integrins that are known to play an important role in the response of B-lymphocytes to antigens. Similar molecules occur on the human B-lymphocyte surface, and drugs active against integrins are already used to modulate the immune response. So a long-term implication of this work may be to identify new therapeutic targets for immune regulation.

Professor Sarah Perrett from the Institute of Biophysics said: “In applying this technique, we have addressed a particularly challenging issue: how do we identify weak and transient, but potentially important, interactions between membrane proteins, which are notoriously difficult to work with?”

Dr Tony Jackson from the Department of Biochemistry, ̽��ֱ�� of Cambridge said: “There are many problems in cell-biology where we would like to identify proteins that group together on the cell surface, and our method could also be applied in these cases. It should therefore be of interest to a wide group of researchers in both the academic and industrial biomedical communities.”

Funding for the research included the Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Wellcome Trust.

A new technique developed at the ̽��ֱ�� of Cambridge allows researchers to identify clusters of proteins on immune cells which are key to fighting off the body’s invaders.

There are many problems in cell-biology where we would like to identify proteins that group together on the cell surface

Tony Jackson

Bruce Blaus

B-lymphocyte

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Location, location, location: finding out where proteins live and with whom

bjb42 — Sat, 01 May 2010 09:16:50 +0000

̽��ֱ��Biotechnology and Biological Sciences Research Council (BBSRC) has been a long-term funder and supporter of the Cambridge Centre for Proteomics (CCP) since the beginnings of this cross-departmental facility almost a decade ago. ̽��ֱ��large-scale study of proteins, called proteomics, was still in its infancy when CCP first opened its doors to the research community, offering a range of services to separate, identify and quantify proteins in complex samples.

‘Working out what the limitations were with the technology, and solving them, has always been a major consideration,’ explained Dr Kathryn Lilley, who headed the team that set up CCP and is its Director. ‘In fact, two-thirds of the lab focuses on the development of methods, influenced by projects that can’t be handled by the high-throughput pipelines we have in place. In turn, the technical advances benefit the core facilities.’

Techniques being used at CCP are able to identify changes in a cell’s proteins under different conditions, helping colleagues in many university departments including Biochemistry, Genetics, Pathology, Pharmacology and Plant Sciences to answer complex biological questions. ̽��ֱ��expertise at CCP also underpins research at the Cambridge Systems Biology Centre, and complements imaging methods under development at the Centre for the Physics of Medicine.

In a decade, the technology has progressed immeasurably from the early days of simply providing a catalogue of as many proteins as possible in a sample. Today, more sophisticated approaches such as Localization of Organelle Proteins by Isotope Tagging (LOPIT), developed by CCP, enable the accurate determination of the subcellular location of proteins, and rely heavily on the use of complex statistical methodologies.

‘LOPIT provides a snapshot of spatial information,’ explained Dr Lilley. ‘From this, we are beginning to tell where proteins live, who with, and how this changes depending on what’s happening to the cell. In the foreseeable future, with integration of complementary technologies, we will be able to build three-dimensional dynamic maps of the cell’s proteins, helping us to understand more fully how cells work.’

For more information, please contact Dr Kathryn Lilley (ksl23@cam.ac.uk) at the Cambridge Centre for Proteomics (www.bio.cam.ac.uk/proteomics/).

̽��ֱ��Cambridge Centre for Proteomics is internationally recognised for pioneering technology that helps us to understand what proteins do inside cells.

We are beginning to tell where proteins live, who with, and how this changes depending on what’s happening to the cell.

Dr Kathryn Lilley

CCP

Gel electrophoresis

Biotechnology and Biological Sciences Research Council

̽��ֱ��Biotechnology and Biological Sciences Research Council (BBSRC) is the UK’s principal research funder across the biosciences. Its current Chair is Sir Tom Blundell, who is also Director of Research and Emeritus Professor in Cambridge’s Department of Biochemistry.

Over the past decade, BBSRC has helped achieve a step change in bioscience. Descriptive, single-problem research is increasingly being replaced by generic, predictive and systems approaches, informed by the physical, computational and social sciences. ̽��ֱ��result is that the UK has kept its world-lead in fundamental bioscience, and enhanced its capability to generate the new knowledge needed to tackle global challenges such as food security, sustainable energy and healthier ageing.

BBSRC research at Cambridge exemplifies this combination of excellence and impact. A grants and fellowships portfolio of over £50 million supports research in more than 20 departments, ranging from predictive modelling of disease epidemiology, the role of short interfering RNAs in cell regulation, data standards and software for macromolecular analysis, to mechanisms of predator vision and defensive colouration in birds. BBSRC also funds around 100 postgraduate research students including some registered with the ̽��ֱ�� at the Babraham Institute.

Cambridge hosts one of six programmes that comprise the BBSRC Sustainable Bioenergy Centre, which is a £26 million investment bringing together academics and industry to investigate sustainable methods for producing biofuels. Dr Paul Dupree in the Department of Biochemistry leads the Cambridge programme, with partners at Newcastle ̽��ֱ�� and Novozymes A/G, which seeks to improve the release of sugars from plant cell walls. An important resource for the Dupree lab, and many others across Cambridge, has been the protein-analysis capabilities of the Cambridge Centre for Proteomics, a long-term recipient of BBSRC funding.

Research projects requiring ‘big’ science approaches and longer timescales are supported by BBSRC under its strategic longer and larger (LoLa) grant scheme. One such grant to develop a pig super-vaccine was recently awarded to a consortium of researchers based at five universities, including Cambridge’s Department of Veterinary Medicine.

Ways to improve the manufacturability of viral vectors for therapeutics are currently being pursued with funding from the BBSRC-led Bioprocessing Research Industry Club.

BBSRC-funded research at Cambridge has also turned into notable innovations. One example is the massively parallel Solexa sequencing technology invented by Professor Shankar Balasubramanian and Professor David Klenerman in the Department of Chemistry, resulting in the spin-out company Solexa, which was purchased by Illumina for $600 million in 2007. ̽��ֱ��technology is revolutionising bioscience by improving the cost and speed of DNA sequencing by 1,000–10,000 fold on previous technologies. In recognition of this work, Professor Balasubramanian was recently named BBSRC Innovator of the Year 2010.

For more information and to download the BBSRC 2010–2015 Strategic Plan, please visit www.bbsrc.ac.uk/

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