̽��ֱ�� of Cambridge - cell

Cartographers of the human body: the Human Cell Atlas

cjb250 — Wed, 20 Nov 2024 16:00:45 +0000

̽��ֱ��Human Cell Atlas is an ambitious project to map every cell in the human body. Its co-lead, Professor Sarah Teichmann, explains how the initiative is already changing our understanding of our bodies.

Immune cell characteristics mapped across multiple tissues

cjb250 — Fri, 13 May 2022 15:41:02 +0000

̽��ֱ��research, from the ̽��ֱ�� of Cambridge, Wellcome Sanger Institute, and collaborators, has created an open-access atlas of the immune cells in the human body and focuses on those found within tissues, which are understudied, compared to those circulating in the blood.

This study is part of the international Human Cell Atlas (HCA) consortium, which is aiming to map every cell type in the human body as a basis for both understanding human health and for diagnosing, monitoring, and treating disease.

Published in Science, the research explores the similarities and differences of the same types of immune cells across 16 different tissues. Knowing more about immune cell traits and reactions in these tissues could help future research into therapies that aim to produce or enhance an immune response to fight disease, such as vaccinations or anti-cancer treatments.

It is one of a trio of milestone collaborative papers published together in Science this week, which have created comprehensive and openly available cross-tissue cell atlases. ̽��ֱ��complementary studies shed light on health and disease, and will contribute towards a single Human Cell Atlas.

̽��ֱ��human immune system is made up of many different types of cells that can be found throughout the body, all playing crucial roles. They not only fight off pathogens when they appear, but remember them so they can be eliminated in the future.

In this new research, scientists simultaneously analysed immune cells across 16 tissues from 12 individual organ donors. ̽��ֱ��team developed a database that automatically classifies different cell types, called CellTypist, to handle the large volume and variation of immune cells. Through this, they were able to identify around 100 distinct cell types.

Using CellTypist and further in-depth analysis, the researchers created a cross-tissue immune cell atlas that revealed the relationship between immune cells in one tissue and their counterparts in others. They found similarities across certain families of immune cells, such as macrophages, as well as differences in others. For example, some memory T cells show unique features depending on which tissue they are in.

̽��ֱ��team also uncovered new insights into immune system memory by sequencing the antigen receptors that are found on T and B cells. This part of the study showed the different states that T and B cells undergo if they are exposed to an antigen, such as those found on bacteria and viruses.

̽��ֱ��wider research community can use this cross-tissue immune cell atlas to help interpret and inform future research. It could also serve as a framework to identify which immune cells could be useful to activate when designing new therapeutics that focus on guiding or supporting the immune system, such as vaccination and immunotherapies, for both infectious diseases and solid tumours.

Dr Cecilia Domínguez Conde, co-first author from the Wellcome Sanger Institute, said: “We have created a novel catalogue of immune cells within the human body, allowing us to automatically identify cell types across multiple tissues. By using single-cell sequencing data we have been able to reveal around a hundred different kinds of immune cells including macrophages, B cells, and T cells, uncovering crucial information about how the immune system works. We would like to thank the donors and their families for making this research possible.”

Dr Joanne Jones, co-senior author from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said: “In this research, we not only identified distinct types of immune cells, we also found that certain immune cell types follow specific tissue distribution patterns. Understanding the varying behaviours of the same type of immune cell in multiple areas of the body can help inform research into disease and how treatments that target these cells might impact other tissues.”

Dr Sarah Teichmann from the Wellcome Sanger Institute and the Department of Physics at the ̽��ֱ�� of Cambridge, co-founder of the Human Cell Atlas, said: “Our multi-tissue immune cell atlas is a step towards understanding how the immune system functions throughout the entire body and is an important contribution towards the Human Cell Atlas. In addition to creating a new resource for researchers to classify different cell types, our work will have many translational implications, including serving as a framework for developing therapies to fight immune-related diseases and managing infections.”

Reference
Domínguez Conde. C, Xu. C, Jarvis. LB, Rainbow. DB, Wells. SB, et al. (2022) Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science. DOI: 10.1126/science.abl5197

Adapted from a press release by the Wellcome Sanger Institute

Previously underexplored immune cell populations have been genetically mapped across multiple tissues to provide new insights into how our immune systems work.

Understanding the varying behaviours of the same type of immune cell in multiple areas of the body can help inform research into disease and how treatments that target these cells might impact other tissues

Joanne Jones

Chenqu Suo, Sophie Pritchard, Nadav Yayon (Wellcome Sanger Institute)

Developing immune cells (B cells) from prenatal gut tissue

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 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.

Yes

HeLa: the cells that changed science

zs332 — Thu, 25 Feb 2021 09:14:42 +0000

Discover the incredible story of Henrietta Lacks, an African American woman whose cells enabled a scientific revolution and contributed to numerous incredible developments and life-saving treatments in a special book club as part of the Cambridge Festival.

Mathematics explains how giant ‘whirlpools’ form in developing egg cells

sc604 — Wed, 13 Jan 2021 16:35:52 +0000

Egg cells are among the largest cells in the animal kingdom. Unpropelled, a protein could take hours or even days to drift from one side of a forming egg cell to the other. Luckily, nature has developed a faster way: scientists have spotted cell-spanning whirlpools in the immature egg cells of animals such as mice, zebrafish and fruit flies. These vortices make cross-cell commutes take just a fraction of the time. But scientists didn’t know how these crucial flows formed.

Using mathematical modeling, researchers say they now have an answer. ̽��ֱ��gyres result from the collective behavior of rodlike molecular tubes called microtubules that extend inward from the cells’ membranes. Their results are reported in the journal Physical Review Letters.

“While much is not understood about the biological function of these flows, they distribute nutrients and other factors that organise the body plan and guide development,” said study co-lead author David Stein, a research scientist at the Flatiron Institute’s Center for Computational Biology (CCB) in New York City. And given how widely they have been observed, “they are probably even in humans.”

Scientists have studied cellular flows since the late 18th century, when Italian physicist Bonaventura Corti peered inside cells using his microscope. What he found were fluids in constant motion, however scientists didn’t understand the mechanisms driving these flows until the 20th century.

̽��ֱ��culprits, they found, are molecular motors that walk along the microtubules. Those motors haul large biological payloads such as lipids. Carrying the cargo through a cell’s relatively thick fluids is like dragging a beach ball through honey. As the payloads move through the fluid, the fluid moves too, creating a small current.

Sometimes those currents aren’t so small. In certain developmental stages of a common fruit fly’s egg cell, scientists spotted whirlpool-like currents that spanned the entire cell. In these cells, microtubules extend inward from the cell’s membrane like stalks of wheat. Molecular motors climbing these microtubules push downward on the microtubule as they ascend. That downward force bends the microtubule, redirecting the resulting flows.

Previous studies looked at this bending mechanism, but only for isolated microtubules. Those studies predicted that the microtubules would wave around in circles, but their behavior didn’t match the observations.

“ ̽��ֱ��mechanism of the swirling instability is disarmingly simple, and the agreement between our calculations and the experimental observations by various groups lends support to the idea that this is indeed the process at work in fruit fly egg cells,” said Professor Raymond Goldstein from Cambridge’s Department of Applied Mathematics and Theoretical Physics. “Further experimental tests should be able to probe details of the transition between disordered and ordered flows, where there is still much to be understood.”

In the new study, the researchers added a key factor to their model: the influence of neighboring microtubules. That addition showed that the fluid flows generated by the payload-ferrying motors bend nearby microtubules in the same direction. With enough motors and a dense enough packing of microtubules, the authors found that all the microtubules eventually lean together like wheat stalks caught in a strong breeze. This collective alignment orients all the flows in the same direction, creating the cell-wide vortex seen in real fruit fly cells.

While grounded in reality, the new model is stripped down to the bare essentials to make clearer the conditions responsible for the swirling flows. ̽��ֱ��researchers are now working on versions that more realistically capture the physics behind the flows to understand better the role the currents play in biological processes.

Stein serves as the co-lead author of the new study along with Gabriele De Canio, a researcher at the ̽��ֱ�� of Cambridge. They co-authored the study with CCB director and New York ̽��ֱ�� professor Michael Shelley and ̽��ֱ�� of Cambridge professors Eric Lauga and Raymond Goldstein.

This work was supported by the US National Science Foundation, the Wellcome Trust, the European Research Council, the Engineering and Physical Sciences Research Council, and the Schlumberger Chair Fund.

Reference:
D.B. Stein, G. De Canio, E. Lauga, M.J. Shelley, and R.E. Goldstein, “Swirling Instability of the Microtubule Cytoskeleton”, Physical Review Letters (2021). DOI: 10.1103/PhysRevLett.126.028103

̽��ֱ��swirling currents occur when the rodlike structures that extend inward from the cells’ membranes bend in tandem, like stalks of wheat caught in a strong breeze, according to a study from the ̽��ֱ�� of Cambridge and the Flatiron Institute.

̽��ֱ��mechanism of the swirling instability is disarmingly simple, and the agreement between our calculations and experimental observations supports the idea that this is indeed the process at work in fruit fly egg cells

Raymond Goldstein

Yes

Driving force behind cellular ‘protein factories’ could have implications for neurodegenerative disease

erh68 — Wed, 16 Dec 2020 19:00:00 +0000

In a study published today in Science Advances, researchers from the ̽��ֱ�� of Cambridge show that tiny components within the cell are the biological engines behind effective protein production.

̽��ֱ��endoplasmic reticulum (ER) is the cell’s protein factory, producing and modifying the proteins needed to ensure healthy cell function. It is the cell’s biggest organelle and exists in a web-like structure of tubes and sheets. ̽��ֱ��ER moves rapidly and constantly changes shape, extending across the cell to wherever it is needed at any given moment.

Using super-resolution microscopy techniques, researchers from Cambridge’s Department of Chemical Engineering and Biotechnology (CEB) have discovered the driving force behind these movements – a breakthrough that could have significant impact on the study of neurodegenerative diseases.

“It has been known that the endoplasmic reticulum has a very dynamic structure – constantly stretching and extending its shape inside the cell,” said Dr Meng Lu, research associate in the Laser Analytics Group, led by Professor Clemens Kaminski.

“ ̽��ֱ��ER needs to be able to reach all places efficiently and quickly to perform essential housekeeping functions within the cell, whenever and wherever the need arises. Impairment of this capability is linked to diseases including Parkinson’s, Alzheimer’s, Huntington’s and ALS. So far there has been limited understanding of how the ER achieves these rapid and fascinating changes in shape and how it responds to cellular stimuli.”

Lu and colleagues discovered that another cell component holds the key – small structures, that look like tiny droplets contained in membranes, called lysosomes.

Lysosomes can be thought of as the cell’s recycling centres: they capture damaged proteins, breaking them down into their original building blocks so that they can be reused in the production of new proteins. Lysosomes also act as sensing centres – picking up on environmental cues and communicating these to other parts of the cell, which adapt accordingly.

There can be up to 1,000 or so lysosomes zipping around the cell at any one time and with them, the ER appears to change its shape and location, in an apparently orchestrated fashion.

What surprised the Cambridge scientists was their discovery of a causal link between the movement of the tiny lysosomes within the cell and the reshaping process of the large ER network.

“We could show that it is the movement of the lysosomes themselves that forces the ER to reshape in response to cellular stimuli,” said Lu. “When the cell senses that there is a need for lysosomes and ER to travel to distal corners of the cell, the lysosomes pull the ER web along with them, like tiny locomotives.”

From a biological point of view, this makes sense: ̽��ֱ��lysosomes act as a sensor inside the cell, and the ER as a response unit; co-ordinating their synchronous function is critical to cellular health.

To discover this surprising bond between two very different organelles, Kaminski’s research team made use of new imaging technologies and machine learning algorithms, which gave them unprecedented insights into the inner workings of the cell.

“It is fascinating that we are now able to look inside living cells and see the marvellous speed and dynamics of the cellular machinery at such detail and in real time,” said Kaminski. “Only a few years ago, watching organelles going about their business inside the cell would have been unthinkable.”

̽��ֱ��researchers used illumination patterns projected onto living cells at high speed, and advanced computer algorithms to recover information on a scale more than one hundred times smaller than the width of a human hair. To capture such information at video rates has only recently become possible.

̽��ֱ��researchers also used machine learning algorithms to extract the structure and movement of the ER networks and lysosomes in an automated fashion from thousands of datasets.

̽��ֱ��team extended their research to look at neurons or nerve cells – specialised cells with long protrusions called axons along which signals are transmitted. Axons are extremely thin tubular structures and it was not known how the movement of the very large ER network is orchestrated inside these structures.

̽��ֱ��study shows how lysosomes travel easily along the axons and drag the ER along behind them. ̽��ֱ��researchers also show how impairing this process is detrimental to the development of growing neurons.

Frequently, the researchers saw events where the lysosomes acted as repair engines for disconnected or broken pieces of ER structure, merging and fusing them into an intact network again. ̽��ֱ��work is therefore relevant for an understanding of disorders of the nervous system and its repair.

̽��ֱ��team also studied the biological significance of this coupled movement, providing a stimulus – in this case nutrients – for the lysosomes to sense. ̽��ֱ��lysosomes were seen to move towards this signal, dragging the ER network behind so that the cell can elicit a suitable response.

“So far, little was known on the regulation of ER structure in response to metabolic signals,” said Lu. “Our research provides a link between lysosomes as sensors units that actively steer the local ER response.”

̽��ֱ��team hopes that their insights will prove invaluable to those studying links between disease and cellular response, and their own next steps are focused on studying ER function and dysfunction in diseases such as Parkinson’s and Alzheimer’s.

Neurodegenerative disorders are associated with aggregation of damaged and misfolded proteins, so understanding the underlying mechanisms of ER function is critical to research into their treatment and prevention.

“ ̽��ֱ��discoveries of the ER and lysosomes were awarded the Nobel Prize many years ago – they are key organelles essential for healthy cellular function,” said Kaminski. “It is fascinating to think that there is still so much to learn about this system, which is incredibly important to fundamental biomedical science looking to find the cause and cures of these devastating diseases.”

Reference:
Meng Lu et al. ' ̽��ֱ��structure and global distribution ofthe endoplasmic reticulum network is actively regulated by lysosomes.' Science Advances (2020). DOI: 10.1126/sciadv.abc7209

Researchers have identified the driving force behind a cellular process linked to neurodegenerative disorders such as Parkinson’s and motor neurone disease.

There is still so much to learn about this system, which is incredibly important to fundamental biomedical science

Clemens Kaminski

Inducing lysosome (green) anterograde motion with light leads to a rapid and significant extension of ER network (magenta).

Yes

New virtual reality software allows scientists to ‘walk’ inside cells

sc604 — Mon, 12 Oct 2020 15:00:15 +0000

̽��ֱ��software, called vLUME, was created by scientists at the ̽��ֱ�� of Cambridge and 3D image analysis software company Lume VR Ltd. It allows super-resolution microscopy data to be visualised and analysed in virtual reality, and can be used to study everything from individual proteins to entire cells. Details are published in the journal Nature Methods.

Super-resolution microscopy, which was awarded the Nobel Prize for Chemistry in 2014, makes it possible to obtain images at the nanoscale by using clever tricks of physics to get around the limits imposed by light diffraction. This has allowed researchers to observe molecular processes as they happen. However, a problem has been the lack of ways to visualise and analyse this data in three dimensions.

“Biology occurs in 3D, but up until now it has been difficult to interact with the data on a 2D computer screen in an intuitive and immersive way,” said Dr Steven F Lee from Cambridge’s Department of Chemistry, who led the research. “It wasn’t until we started seeing our data in virtual reality that everything clicked into place.”

̽��ֱ��vLUME project started when Lee and his group met with the Lume VR founders at a public engagement event at the Science Museum in London. While Lee’s group had expertise in super-resolution microscopy, the team from Lume specialised in spatial computing and data analysis, and together they were able to develop vLUME into a powerful new tool for exploring complex datasets in virtual reality.

“vLUME is revolutionary imaging software that brings humans into the nanoscale,” said Alexandre Kitching, CEO of Lume. “It allows scientists to visualise, question and interact with 3D biological data, in real time all within a virtual reality environment, to find answers to biological questions faster. It’s a new tool for new discoveries.”

Viewing data in this way can stimulate new initiatives and ideas. For example, Anoushka Handa – a PhD student from Lee’s group – used the software to image an immune cell taken from her own blood, and then stood inside her own cell in virtual reality. “It’s incredible - it gives you an entirely different perspective on your work,” she said.

̽��ֱ��software allows multiple datasets with millions of data points to be loaded in and finds patterns in the complex data using in-built clustering algorithms. These findings can then be shared with collaborators worldwide using image and video features in the software.

“Data generated from super-resolution microscopy is extremely complex,” said Kitching. “For scientists, running analysis on this data can be very time-consuming. With vLUME, we have managed to vastly reduce that wait time allowing for more rapid testing and analysis.”

̽��ֱ��team is mostly using vLUME with biological datasets, such as neurons, immune cells or cancer cells. For example, Lee’s group has been studying how antigen cells trigger an immune response in the body. “Through segmenting and viewing the data in vLUME, we’ve quickly been able to rule out certain hypotheses and propose new ones,” said Lee. This software allows researchers to explore, analyse, segment and share their data in new ways. All you need is a VR headset.”

Reference:
Alexander Spark et al. ‘vLUME: 3D Virtual Reality for Single-molecule Localization Microscopy.’ Nature Methods (2020). DOI: 10.1038/s41592-020-0962-1

Virtual reality software which allows researchers to ‘walk’ inside and analyse individual cells could be used to understand fundamental problems in biology and develop new treatments for disease.

Biology occurs in 3D, but up until now it has been difficult to interact with the data on a 2D computer screen in an intuitive and immersive way

Steven Lee

Alexandre Kitching

DBScan analysis being performed a mature neuron in a typical vLUME workspace.

Yes

Women in STEM: Dr Stephanie Höhn

sc604 — Thu, 14 Nov 2019 07:00:00 +0000

I work in an interdisciplinary research group including biologists, physicists, mathematicians and engineers. I path to this stage of my career was a little off the beaten track. Before my academic career, I worked as a legal clerk. This provided me with life experience but, seeking more intellectual diversity, I decided at the age of 25 to leave the safety of my job and to study molecular cell biology at Bielefeld ̽��ֱ�� in Germany.

My biology teacher inspired me by going beyond the curriculum and discussing recent discoveries in life sciences with me. I wanted to contribute to increasing our knowledge of the incredible microcosmos of cells and their countless functions in life.

I took a leap of faith at the start of my postdoctoral career. I joined a biophysics group at Cambridge and started engaging with scientific methods that were well outside of my comfort zone at first. ̽��ֱ��effort required on both sides to communicate across disciplines has been worth it, though. I am now combining mathematical analyses and computational simulations with advanced imaging techniques. This combination enables me to provide missing puzzle pieces to explain how cells manage to self-assemble into functional organs and tissues.

I think it’s important to keep an open mind and consider changes as opportunities. Whichever path you choose to pursue next, you can always change directions, add and combine different fields. Network with people with different backgrounds: discussing things from different angles can be very motivating.

An entirely new world of opportunities opened up to me when I learned how concepts from physics and mathematics can explain the development of living organisms. When observing a growing organism, one naturally wonders how each of the cells ‘knows’ where to go and what to do. It turns out that often very few parameters can lead to very complicated patterns, and it’s interesting looking for equations that explain how these parameters interact.

My work sets out to reveal how cells generate forces that shape developing tissues. When an embryo develops, its cells move and change their shape in an astoundingly coordinated way to form tissues and organs. Errors in this self-organisation can lead to severe birth defects. Many tissues, including our retina, are formed through the folding of cell sheets, like a sheet of paper can be folded into different shapes.

I am using a fascinating and beautiful model organism called Volvox to study how these folding events work. This aquatic micro-organism is almost entirely transparent which allows me to observe the development of its embryos microscopically. Amazingly, its spherical embryos fold in a way that literally turns them inside out. This peculiar process is a normal part of Volvox development and gives me the chance to study the fundamental mechanisms that can cause a cell sheet to fold.

I am using a custom-built microscope to observe this process through time-lapse recordings. I also measure the physical forces in different regions of the cell sheet to reveal which parts are being pulled or pushed into a new shape. I use computer-generated simulations to test my hypotheses on which cells are actively forming the tissue and which ones are just being pushed around by others. Determining the location and mechanical properties of cells that actively shape a tissue might help us in the future to diagnose and find remedies for associated birth defects.

Day-to-day, I could be doing any number of things. My work involves growing model organisms in little water tanks; staring at and recording time-lapse videos of developing organisms with different microscopy techniques and designing optical devices to improve imaging. I also write code for image processing and analysis, process microscopy images and videos with specialised software, and measure shape changes of cells and tissues. I run computer simulations of folding cell sheets and compare them to microscopic observations, measure physical forces in developing tissues, and supervise students.

One of the most exciting days for me was when I managed to visualise the three dimensional shape changes of living Volvox embryos for the first time with our self-built microscope. It was really great to have overcome all the challenges that led up to this. It was then that I realised the potential these under-studied organisms possess to help us understand our own development.

I can be the first person in the world to see so-far unknown microscopic worlds, every time I observe a new species, a new developmental stage or try a different microscopy technique. These are very special moments even before sharing my new findings with the scientific and non-scientific community. A key moment for me was when I started discussing my biological questions with physicists and mathematicians. It was a real eye-opener to see their different perspectives and approaches towards similar questions. It really made me aware of the power of interdisciplinary work.

There are supportive networks for women in STEM in Cambridge. These include, for example; CamAWiSE and the Emmy Noether Society for Women in Mathematics. There are also opportunities for outreach work, such as ̽��ֱ��Science Festival, the Plant Festival, Open Days and seminars that are open to the public. ̽��ֱ�� ̽��ֱ�� also provides ample opportunities to network with international scientists through local conferences and seminar series in inter-disciplinary fields relevant to my research (e.g. Physics of Living Matter Symposium, the Physics Meets Biology Conference, Building an Organisms Symposium, Evolution and Development seminar series). There are many imaging facilities and networks for imaging facilities (e.g. Cambridge Advanced Imaging Centre, CRUK and EPSRC Cancer Imaging Centre).

Dr Stephanie Höhn is a postdoctoral researcher in the Department of Applied Mathematics and Theoretical Physics, and a member of Trinity Hall. Here, she tells us about her unusual path to an academic career, the advantages of being a biologist in a mathematics department, and how an organism that can turn itself inside out might one day help us prevent certain birth defects.

Yes

Interplay between mitochondria and the nucleus may have implications for changing cell’s ‘batteries’

cjb250 — Thu, 23 May 2019 18:00:47 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, suggests that matching mitochondrial DNA to nuclear DNA could be important when selecting potential donors for the recently-approved mitochondrial donation treatment, in order to prevent potential health problems later in life.

Almost all of the DNA that makes up the human genome – the body’s ‘blueprint’ – is contained within our cells’ nuclei. This is referred to as ‘nuclear DNA’. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as the ‘batteries’ that provide the energy for our cells to function. Each of these mitochondria is coded for by a tiny amount of ‘mitochondrial DNA’. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

Until now, scientists had thought that mitochondria were readily interchangeable, serving only to power our bodies, and so an individual’s mitochondria could be replaced with those from a donor with no consequences. However, in the first major population study to use data from the UK-wide 100,000 Genomes Project and its National Institute for Health Research (NIHR)-funded pilot project, researchers compared mitochondrial and nuclear DNA from tens of thousands of people and found that mitochondria may be fine-tuned to the nucleus.

̽��ֱ��researchers studied over 1,500 mother-child pairs and found that just under a half (45%) of individuals within these pairs harboured mutations affecting at least 1% of their mitochondrial DNA. Mutations in certain parts of mitochondrial DNA were more likely to be transmitted, such as those in the so-called D-loop region, which controls how mitochondrial DNA copies itself. Conversely, mutations in other parts of mitochondrial DNA were more likely to be suppressed, such as the code for how mitochondria produce their own proteins.

“Children inherit their DNA exclusively from their mother and we wanted to see how this explains the origins of mitochondrial diseases,” says first author Dr Wei Wei from the Medical Research Council (MRC) Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge. “What we found was that there is some kind of selection taking place when mitochondrial DNA is transmitted down a generation, allowing some mutations to be passed on and others to be blocked.”

Genetic variants that had previously been observed around the world were more likely to be passed on than completely new ones, the team found. This implies that there is a mechanism that filters the mitochondrial DNA when it is being passed down from mother to child, influencing the likelihood that a particular variant becomes established in the human population.

DNA can give us clues to our ancestry – for example, the pattern of genetic variants in an individual’s DNA might be more common in people of European ancestry than it is in people of Asian ancestry. In most people, genetic variants in both our nuclear and mitochondrial DNA come from the same part of the world. However, in around one in 40 people in the UK sample, the mitochondrial DNA and nuclear DNA did not have matching ancestries. For example, the nuclear DNA could be European whilst the mitochondrial DNA is Asian. This happens because at some point in the maternal lineage, there was a mother from a different ethnic background.

“As mitochondrial DNA has a much higher mutation rate than nuclear DNA, mutation of the mitochondrial genome is a common occurrence. We wanted to study the natural selective forces determining the fate of these mutations,” says Dr Ernest Turro of the Department of Haematology and the MRC Biostatistics Unit, and one of the senior authors of this study.

“Our statistical analysis suggests that, in people with differing mitochondrial and nuclear ancestries, recent mitochondrial mutations are more likely to have been seen before in populations with the same nuclear ancestry than the same mitochondrial ancestry.”

Crucially, these results suggest that changes in our mitochondrial DNA are shaped by our nuclear DNA.

“This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand,” says Professor Patrick Chinnery, Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and Wellcome Trust Principal Research Fellow. “What this suggests to us is that swapping mitochondria might not be as straightforward as just changing the batteries in a device.”

̽��ֱ��evidence mirrors that from previous studies in fruit flies and mice, where a mismatch between their mitochondrial and nuclear DNA affected how long the organisms lived for and caused cardiovascular and metabolic complications later in life (diseases in humans that might include heart disease and type 2 diabetes, for example).

̽��ֱ��findings could have implications for mitochondrial donation treatment (also known as mitochondrial replacement therapy), says Professor Chinnery, who previously worked with the team at Newcastle ̽��ֱ�� pioneering this treatment. This technique is now licenced for use in the UK to prevent the transmission from mother to child of potentially devastating mitochondrial diseases. It involves substituting a mother’s nuclear DNA into a donor egg while retaining the donor’s mitochondria.

“Mitochondrial replacement therapy is an important new treatment to enable mothers to have children free from terrible mitochondrial diseases, which arise because of severe mutations in mitochondrial DNA,” says Professor Chinnery.

“Our work suggests we’ll need to look carefully at this new treatment to make sure it does not cause unexpected health problems further down the line. It may mean that doctors will need to match the nuclear genome and mitochondrial genome of mitochondrial donors, similar to an organ transplant.”

̽��ֱ��team has now begun work looking at those people whose mitochondrial DNA does not match their nuclear DNA to see if this mismatch increases the likelihood that they will be affected by health problems later in life.

̽��ֱ��research is the first major population study to arise from data collected as part of the 100,000 Genomes Project, which collects genetic data from patients through the NHS with the aim of transforming the way people are cared for and providing a major new resource for medical research. Pilot data for the study was collected through the NIHR Cambridge Biomedical Research Centre.

“ ̽��ֱ��involvement of the 100,00 Genomes Project in major discoveries demonstrates the importance of large-scale, carefully collected datasets with whole genome sequences, which provide new biological insights and pave the way for major healthcare transformations,” says Professor Mark Caulfield, Chief Executive of Genomics England and Co-Director of the William Harvey Research Institute at Queen Mary ̽��ֱ�� of London.

̽��ֱ��research was largely funded by the NIHR, Wellcome, the MRC and Genomics England.

Reference
Wei, W et al. Germline selection shapes human mitochondrial DNA diversity. Science; 24 May 2019; DOI: 10.1126/science.aau6520

Mitochondria, the ‘batteries’ that produce our energy, interact with the cell’s nucleus in subtle ways previously unseen in humans, according to research published today in the journal Science.

This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand

Patrick Chinnery

Dr David Furness (Wellcome Images)

Three mitochondria surrounded by cytoplasm

Yes

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