̽��ֱ�� of Cambridge - MRC Laboratory of Molecular Biology (LMB)

First map of every neuron in an adult fly brain complete

jg533 — Wed, 02 Oct 2024 15:04:57 +0000

This landmark achievement has been conducted by the FlyWire Consortium, a large international collaboration including researchers from the ̽��ֱ�� of Cambridge, the MRC Laboratory of Molecular Biology in Cambridge, Princeton ̽��ֱ��, and the ̽��ֱ�� of Vermont. It is published today in two papers in the journal Nature.

̽��ֱ��diagram of all 139,255 neurons in the adult fly brain is the first of an entire brain for an animal that can walk and see. Previous efforts have completed the whole brain diagrams for much smaller brains, for example a fruit fly larva which has 3,016 neurons, and a nematode worm which has 302 neurons.

̽��ֱ��researchers say the whole fly brain map is a key first step to completing larger brains. Since the fruit fly is a common tool in research, its brain map can be used to advance our understanding of how neural circuits work.

Dr Gregory Jefferis, from the ̽��ֱ�� of Cambridge and the MRC Laboratory of Molecular Biology, one of the co-leaders of the research, said: “If we want to understand how the brain works, we need a mechanistic understanding of how all the neurons fit together and let you think. For most brains we have no idea how these networks function.

“Flies can do all kinds of complicated things like walk, fly, navigate, and the males sing to the females. Brain wiring diagrams are a first step towards understanding everything we’re interested in – how we control our movement, answer the telephone, or recognise a friend.”

Dr Mala Murthy from Princeton ̽��ֱ��, one of the co-leaders of the research, said: “We have made the entire database open and freely available to all researchers. We hope this will be transformative for neuroscientists trying to better understand how a healthy brain works. In the future we hope that it will be possible to compare what happens when things go wrong in our brains, for example in mental health conditions.”

Dr Marta Costa from the ̽��ֱ�� of Cambridge, who was also involved in the research, said “This brain map, the biggest so far, has only been possible thanks to technical advances that didn’t seem possible ten years ago. It is a true testament to the way that innovation can drive research forward. ̽��ֱ��next steps will be to generate even bigger maps, such as a mouse brain, and ultimately, a human one.”

̽��ֱ��scientists found that there were substantial similarities between the wiring in this map and previous smaller-scale efforts to map out parts of the fly brain. This led the researchers to conclude that there are many similarities in wiring between individual brains – that each brain isn’t a unique structure.

When comparing their brain diagram to previous diagrams of small areas of the brain, the researchers also found that about 0.5% of neurons have developmental variations that could cause connections between neurons to be mis-wired. ̽��ֱ��researchers say it will be important to understand, through future research, if these changes are linked to individuality or brain disorders.

Making the map

3D rendering of all 140,000 neurons in the fruit fly brain.

3D rendering of all ~140k neurons in the fruit fly brain. Credit: Data source FlyWire.ai; Rendering by Philipp Schlegel ( ̽��ֱ�� of Cambridge/MRC LMB).

A whole fly brain is less than one millimetre wide. ̽��ֱ��researchers started with one female brain cut into seven thousand slices, each only 40 nanometres thick, that were previously scanned using high resolution electron microscopy in the laboratory of project co-leader Davi Bock at Janelia Research Campus in the US.

Analysing over 100 terabytes of image data (equivalent to the storage in 100 typical laptops) to extract the shapes of about 140,000 neurons and 50 million connections between them is too big a challenge for humans to complete manually. ̽��ֱ��researchers built on AI developed at Princeton ̽��ֱ�� to identify and map neurons and their connections to each other.

However, the AI still makes many errors in datasets of this size. ̽��ֱ��Princeton ̽��ֱ�� researchers established the FlyWire Consortium – made up of teams in more than 76 laboratories and 287 researchers around the world, as well as volunteers from the general public – which spent an estimated 33 person-years painstakingly proofreading all the data.

Dr Sebastian Seung, from Princeton ̽��ֱ��, who was one of the co-leaders of the research, said: “Mapping the whole brain has been made possible by advances in AI computing - it would have not been possible to reconstruct the entire wiring diagram manually. This is a display of how AI can move neuroscience forward. ̽��ֱ��fly brain is a milestone on our way to reconstructing a wiring diagram of a whole mouse brain.”

̽��ֱ��researchers also annotated many details on the wiring diagram, such as classifying more than 8,000 cell types across the brain. This allows researchers to select particular systems within the brain for further study, such as the neurons involved in sight or movement.

Dr Philipp Schlegel, the first author of one of the studies, from the MRC Laboratory of Molecular Biology, said: “This dataset is a bit like Google Maps but for brains: the raw wiring diagram between neurons is like knowing which structures on satellite images of the Earth correspond to streets and buildings. Annotating neurons is like adding the names for streets and towns, business opening times, phone numbers and reviews to the map – you need both for it to be really useful.”

Simulating brain function

This is also the first whole brain wiring map – often called a connectome – to predict the function of all the connections between neurons.

Neurons use electrical signals to send messages. Each neuron can have hundreds of branches that connect it to other neurons. ̽��ֱ��points where these branches meet and transmit signals between neurons are called synapses. There are two main ways that neurons communicate across synapses: excitatory (which promotes the continuation of the electrical signal in the receiving neuron), or inhibitory (which reduces the likelihood that the next neuron will transmit signals).

Researchers from the team used AI image scanning technology to predict whether each synapse was inhibitory or excitatory.

Dr Gregory Jefferis added: “To begin to simulate the brain digitally, we need to know not only the structure of the brain, but also how the neurons function to turn each other on and off.”

“Using our data, which has been shared online as we worked, other scientists have already started trying to simulate how the fly brain responds to the outside world. This is an important start, but we will need to collect many different kinds of data to produce reliable simulations of how a brain functions.”

Associate Professor Davi Bock, one of the co-leaders of the research from the ̽��ֱ�� of Vermont, said: “ ̽��ֱ��hyper-detail of electron microscopy data creates its own challenges, especially at scale. This team wrote sophisticated software algorithms to identify patterns of cell structure and connectivity within all that detail.

“We now can make precise synaptic level maps and use these to better understand cell types and circuit structure at whole-brain scale. This will inevitably lead to a deeper understanding of how nervous systems process, store and recall information. I think this approach points the way forward for the analysis of future whole-brain connectomes, in the fly as well as in other species."

This research was conducted using a female fly brain. Since there are differences in neuronal structure between male and female fly brains, the researchers also plan to characterise a male brain in the future.

̽��ֱ��principal funders were the National Institutes of Health BRAIN Initiative, Wellcome, Medical Research Council, Princeton ̽��ֱ�� and National Science Foundation.

References

Schlegel, P. et al: Whole-brain annotation and multi-connectome cell typing of Drosophila. Nature, Oct 2024. DOI: 10.1038/s41586-024-07686-5

Dorkenwald, S. et al: Neuronal wiring diagram of an adult brain. Nature, Oct 2024. DOI: 10.1038/s41586-024-07558-y

̽��ֱ��first wiring diagram of every neuron in an adult brain and the 50 million connections between them has been produced for a fruit fly.

Brain wiring diagrams are a first step towards understanding everything we’re interested in – how we control our movement, answer the telephone, or recognise a friend.

Gregory Jefferis

̽��ֱ��first complete map of every neuron in an adult fly brain.

FlyWire.ai; Rendering by Philipp Schlegel ( ̽��ֱ�� of Cambridge/MRC LMB).

3D rendering of all 140,000 neurons in the adult fruit fly brain.

̽��ֱ��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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Nine Cambridge scientists among the new 2022 Fellows announced by the Royal Society

jg533 — Tue, 10 May 2022 11:33:12 +0000

̽��ֱ��Royal Society is a self-governing Fellowship made up of the most eminent scientists, engineers and technologists from the UK and the Commonwealth. Its Foreign Members are drawn from the rest of the world.

̽��ֱ��Society’s fundamental purpose is to recognise, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity.

This year, a total of 51 Fellows, 10 Foreign Members, and one Honorary Fellow have been selected for their outstanding contributions to science.

Sir Adrian Smith, President of the Royal Society said: “It is an honour to welcome so many outstanding researchers from around the world into the Fellowship of the Royal Society.

“Through their careers so far, these researchers have helped further our understanding of human disease, biodiversity loss and the origins of the universe. I am also pleased to see so many new Fellows working in areas likely to have a transformative impact on our society over this century, from new materials and energy technologies to synthetic biology and artificial intelligence. I look forward to seeing what great things they will achieve in the years ahead.”

̽��ֱ��Cambridge Fellows are:

Professor Graham Burton FMedSci FRS

Mary Marshall and Arthur Walton Professor Emeritus of the Physiology of Reproduction, ̽��ֱ�� of Cambridge

Burton is a reproductive biologist whose research has focused on the early stages of human pregnancy. In particular, he showed how the placenta is established in a protective low-oxygen environment, stimulating its own development through interactions with the uterus. He demonstrated that aberrations in the early stages of placental development can adversely affect the life-long health of mother and offspring. Burton was founding Director of the Centre for Trophoblast Research, and founding Chair of the Strategic Research Initiative Cambridge Reproduction.

He said: “I am delighted to receive this recognition for myself and the field of reproductive biology, and thank colleagues and collaborators for their contributions over the years.”

Professor Roberto Cipolla FREng FRS

Professor of Information Engineering, Department of Engineering, ̽��ֱ�� of Cambridge

Cipolla is distinguished for his research in computer vision and his contributions to the reconstruction, registration and recognition of three-dimensional objects from images. These include novel algorithms for the recovery of accurate 3D shape, visual localisation and semantic segmentation and their translation into commercial products.

He said: "This is the ultimate honour for any scientist and recognises the amazing contribution of my students, collaborators and mentors in my 30 years at Cambridge. I am also very fortunate to be working in the field of computer vision and machine learning at a time of revolutionary progress and ground-breaking applications.”

Professor Douglas Easton FMedSci FRS

Professor of Genetic Epidemiology, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, ̽��ֱ�� of Cambridge

Easton’s main research interests are in cancer genetics. He analyses large population studies to identify genetic variants that predispose to cancer, and to understand how they combine together with other factors to determine cancer risk. His work has characterised many important cancer genes such as BRCA1 and BRCA2, and identified of hundreds of common cancer predisposition variants in the non-coding genome. He co-developed the BOADICEA risk prediction model now used worldwide to guide genetic counselling and cancer prevention.

He said: "I am truly delighted and honoured to be elected to the Fellowship of the Royal Society. This prestigious honour is a tribute the work of many wonderful colleagues in Cambridge and worldwide, over many years, who have made the research possible."

Professor Robin Franklin FMedSci FRS

Formerly Professor of Stem Cell Medicine, Wellcome - MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge; now Principal Investigator, Altos Labs - Cambridge Institute

̽��ֱ��central question of Franklin’s career is 'how do tissues regenerate?' To address this question, he has studied the brain, an organ notorious for its poor regenerative capacity. Working with many excellent colleagues, he has described how stem cells in the adult brain regenerate oligodendrocytes - the cells responsible for making the insulating myelin sheath around nerve fibres - once they are lost in diseases such as multiple sclerosis (MS); how this process declines with age; and it can be reversed. ̽��ֱ��work has led to two regenerative medicine trials in MS.

He said: “I am absolutely delighted to have been elected a Fellow of the Royal Society - it is a huge honour.”

Professor Richard Gilbertson FMedSci FRS

Li Ka Shing Chair of Oncology and Head of Department of Oncology, ̽��ֱ�� of Cambridge, Director of Cancer Research UK Cambridge Centre and Senior Group Leader, Cancer Research UK Cambridge Institute

Gilbertson, a paediatric physician-scientist, has identified the origins of common and aggressive childhood brain tumours and many of the genetic alterations that drive these tumours. His research has helped establish a direct link between disordered development and the multiple different brain tumour types observed in children: contributing directly to their classification by the World Health Organisation (WHO); changing the way conventional treatments are used, sparing children from unnecessary side effects; and underpinning clinical trials of new therapies.

Gilbertson said: “I am truly delighted and humbled to receive this recognition that I share with all the wonderful students, trainees and colleagues I have worked with over the years.”

Professor Paul Lehner FMedSci FRS

Professor of Immunology and Medicine, Cambridge Institute for Medical Research, ̽��ֱ�� of Cambridge

Lehner studies virus-host antagonism and how our genome is defended from invasion by RNA-derived retroelements such as HIV. His discovery of the ‘HUSH’ epigenetic silencing complex explains how the genome distinguishes new genetic material from endogenous genes through recognition of intronless DNA. This work uncovered an unanticipated surveillance system that discriminates ‘self’ from ‘non-self’ genomic DNA and defends our genome against the reverse flow of genetic information (RNA to DNA), paving the way to novel applications in medicine and biotechnology.

Lehner said: “I’m absolutely delighted to be elected to the Fellowship of the Royal Society; I’ve been fortunate to work with incredibly talented people and this honour recognises the commitment of the many past and present members of my group who have contributed to our work.”

Professor Roberto Maiolino FRS

Director of the Kavli Institute for Cosmology and Professor of Experimental Astrophysics, ̽��ֱ�� of Cambridge

Maiolino studies the formation of galaxies using observations collected at some of the largest ground-based and space telescopes. He has obtained key results on the interplay between the evolution of galaxies and the supermassive black holes at their centres. He has also investigated the enrichment of chemical elements across the cosmic epochs, as well as the origin and nature of dust particles in the early Universe.

He said: “I am truly honoured by such a prestigious appointment. Being a Fellow of the Royal Society will certainly foster my research activities and will allow me to further promote exciting, cutting-edge projects.”

Professor Angelos Michaelides FRS

1968 Professor of Chemistry, Yusuf Hamied Department of Chemistry, ̽��ֱ�� of Cambridge

Michaelides’ work involves the development and application of theoretical methods to better understand contemporary problems in chemistry, physics, and materials science. His group places a particular focus on developing and applying computer simulation approaches that provide the fundamental molecular-level insight needed to help address contemporary global challenges related to water, energy, and the environment.

He said: “Holy moly! I’m delighted to have been elected an FRS and very grateful to all the outstanding students, post-docs, collaborators, and mentors I’ve had over the years without whom this would never have happened.”

Professor Jason William Chin FMedSci FRS

Head, Centre for Chemical and Synthetic Biology, and Joint Head, Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology; Professor of Chemistry and Chemical Biology, Yusuf Hamied Department of Chemistry, ̽��ֱ�� of Cambridge; Associate Faculty in Synthetic Genomics, Wellcome Sanger Institute

Chin has engineered the genetic code of living cells to synthesise modified proteins and non-canonical polymers. To accomplish this, he created new translational machinery and codons to reprogram the genetic code, going well-beyond prior work using amber suppression. He then completely synthesised a bacterial genome in which he reduced the number of sense codons in its genetic code. ̽��ֱ��codons thus unused were reassigned to encode non-canonical amino acids. Chin's fundamental advances have been widely used to drive discovery, including to define the molecular consequences of post-translational modifications, define protein interactions in cells, and provide mechanistic insight into enzymes.

̽��ֱ��nine Cambridge researchers were all selected for their exceptional contributions to science.

It is an honour to welcome so many outstanding researchers from around the world into the Fellowship of the Royal Society.

Sir Adrian Smith, President of the Royal Society

̽��ֱ��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.

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Cambridge launches new Leverhulme Centre for Life in the Universe

Anonymous — Mon, 10 Jan 2022 15:11:51 +0000

̽��ֱ��Leverhulme Centre for Life in the Universe will bring together an international team of scientists and philosophers, led by 2019 Nobel Laureate Professor Didier Queloz.

Thanks to simultaneous revolutions in exoplanet discoveries, prebiotic chemistry and solar system exploration, scientists can now investigate whether the Earth and the processes that made life possible are unique in the Universe.

̽��ֱ�� ̽��ֱ�� has recently launched the Initiative for Planetary Science and Life in the Universe (IPLU) to enable cross-disciplinary research on planetology and life in the Universe.

Building on IPLU’s activities, the new Leverhulme Centre for Life in the Universe will support fundamental cross-disciplinary research over the next 10 years to tackle one of the great interdisciplinary challenges of our time: to understand how life emerged on Earth, whether the Universe is full of life, and ask what the nature of life is.

̽��ֱ��Centre will include researchers from Cambridge’s Cavendish Laboratory, Department of Earth Sciences, Yusuf Hamied Department of Chemistry, Department of Applied Mathematics and Theoretical Physics, Institute of Astronomy, Department of Zoology, Department of History and Philosophy of Science, Faculty of Divinity, and the MRC Laboratory of Molecular Biology.

“ ̽��ֱ��Centre will act as a catalyst for the development of our vision to understanding life in the Universe through a long-term research programme that will be the driving force for international coordination of research and education,” said Queloz, Jacksonian Professor of Natural Philosophy at the Cavendish Laboratory and Director of the Centre.

Research within the Centre will focus on four themes: identifying the chemical pathways to the origins of life; characterising the environments on Earth and other planets that could act as the cradle of prebiotic chemistry and life; discovering and characterising habitable exoplanets and signatures of geological and biological evolution; and refining our understanding of life through philosophical and mathematical concepts.

̽��ֱ��Centre will collaborate with researchers at the ̽��ֱ�� of Colorado Boulder (USA), ̽��ֱ�� College London, ETH Zurich (Switzerland), Harvard ̽��ֱ�� (USA) and the Centre of Theological Inquiry in Princeton, New Jersey (USA).

“Understanding the reactions that predisposed the first cells to form on Earth is the greatest unsolved mystery in science,” said programme collaborator Matthew Powner from ̽��ֱ�� College London. “Critical challenges of increasing complexity must be addressed in this field, but these challenges represent one of the most exciting frontiers in science.”

Carol Cleland, Director of the Center for the Study of Origins and Professor of Philosophy at the ̽��ֱ�� of Colorado Boulder, also collaborator on the programme said: “ ̽��ֱ��new Centre is unique in the breadth of its interdisciplinarity, bringing together scientists and philosophers to address central questions about the nature and extent of life in the universe.

“Characteristics that scientists currently take as fundamental to life reflect our experience with a single example of life, familiar Earth life. These characteristics may represent little more than chemical and physical contingencies unique to the conditions under which life arose on Earth. If this is the case, our concepts for theorising about life will be misleading. Philosophers of science are especially well trained to help scientists 'think outside the box' by identifying and exploring the conceptual foundations of contemporary scientific theorising about life with an emphasis on developing strategies for searching for truly novel forms of life on other worlds.”

Didier Queloz is a Fellow of Trinity College, Cambridge.

With a £10 million grant awarded by the Leverhulme Trust, the ̽��ֱ�� of Cambridge is to establish a new research centre dedicated to exploring the nature and extent of life in the Universe.

̽��ֱ��Centre will act as a catalyst for the development of our vision to understanding life in the Universe through a long-term research programme that will be the driving force for international coordination of research and education

Didier Queloz

ESO/M Kornmesser

Artists’s impression of the rocky super-Earth HD 85512 b

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Could acid-neutralising life-forms make habitable pockets in Venus’ clouds?

sc604 — Mon, 20 Dec 2021 20:00:00 +0000

It’s hard to imagine a more inhospitable world than our closest planetary neighbour. With an atmosphere thick with carbon dioxide, and a surface hot enough to melt lead, Venus is a scorched and suffocating wasteland where life as we know it could not survive. ̽��ֱ��planet’s clouds are similarly hostile, blanketing the planet in droplets of sulphuric acid caustic enough to burn a hole through human skin.

And yet, a new study, published in the Proceedings of the National Academy of Sciences, supports the long-held theory that, if life exists, it might make a home in Venus’ clouds. ̽��ֱ��study’s authors, from MIT, Cardiff ̽��ֱ��, and the ̽��ֱ�� of Cambridge, have identified a chemical pathway by which life could neutralise Venus’ acidic environment, creating a self-sustaining, habitable pocket in the clouds.

Within Venus’ atmosphere, scientists have long observed puzzling anomalies — chemical signatures that are hard to explain, such as small concentrations of oxygen and nonspherical particles unlike sulphuric acid’s round droplets. Perhaps most puzzling is the presence of ammonia, a gas that was tentatively detected in the 1970s, and that by all accounts should not be produced through any chemical process known on Venus.

In their new study, the researchers modelled a set of chemical processes to show that if ammonia is indeed present, the gas would set off a cascade of chemical reactions that not only neutralises surrounding droplets of sulphuric acid, but also would explain most of the anomalies observed in Venus’ clouds. As for the source of ammonia itself, the authors propose the most plausible explanation is of biological origin, rather than an non-biological source such as lightning or volcanic eruptions.

̽��ֱ��chemistry suggests that life could be making its own environment on Venus.

This hypothesis is testable, and the researchers provide a list of chemical signatures for future missions to measure in Venus’ clouds, to either confirm or contradict their idea.

“No life that we know of could survive in the Venus droplets,” said study co-author Sara Seager, from MIT. “But the point is, maybe some life is there, and is modifying its environment so that it is livable.”

‘Life on Venus’ was a trending phrase last year, when scientists including Seager and her co-authors reported the detection of phosphine in the planet’s clouds. On Earth, phosphine is a gas that is produced mainly through biological interactions. ̽��ֱ��discovery of phosphine on Venus leaves room for the possibility of life. Since then, however, the discovery has been widely contested.

“ ̽��ֱ��phosphine detection ended up becoming incredibly controversial,” said Seager. “But phosphine was like a gateway, and there’s been this resurgence in people studying Venus.”

Inspired to look more closely, co-author Dr Paul Rimmer from Cambridge’s Department of Earth Sciences began combing through data from past missions to Venus. In these data, he identified anomalies, or chemical signatures, in the clouds that had gone unexplained for decades. In addition to the presence of oxygen and nonspherical particles, anomalies included unexpected levels of water vapor and sulphur dioxide.

Rimmer proposed the anomalies might be explained by dust. He argued that minerals, swept up from Venus’ surface and into the clouds, could interact with sulphuric acid to produce some, but not all of the observed anomalies. He showed the chemistry checked out. But the physical requirements were unfeasible: A massive amount of dust would have to loft into the clouds to produce the observed anomalies. “ ̽��ֱ��hypothesis requires either large amounts of water-rich volcanism or transport of a lot of dust rich in hydroxide salts,” he said. “So far, I have been unable to identify a plausible mineralogy for this mechanism.”

̽��ֱ��researchers wondered if the anomalies could be explained by ammonia. In the 1970s, the gas was tentatively detected in the planet’s clouds by the Venera 8 and Pioneer Venus probes. ̽��ֱ��presence of ammonia, or NH3, was an unsolved mystery.

“Ammonia shouldn’t be on Venus,” said Seager. “It has hydrogen attached to it, and there’s very little hydrogen around. Any gas that doesn’t belong in the context of its environment is automatically suspicious for being made by life.”

If the team were to assume that life was the source of ammonia, could this explain the other anomalies in Venus’ clouds? ̽��ֱ��researchers modeled a series of chemical processes in search of an answer.

They found that if life were producing ammonia in the most efficient way possible, the associated chemical reactions would naturally yield oxygen. Once present in the clouds, ammonia would dissolve in droplets of sulphuric acid, effectively neutralising the acid to make the droplets relatively habitable. ̽��ֱ��introduction of ammonia into the droplets would transform their formerly round, liquid shape into more of a nonspherical, salt-like slurry. Once ammonia dissolved in sulphuric acid, the reaction would trigger any surrounding sulphur dioxide to dissolve as well.

̽��ֱ��presence of ammonia could explain most of the major anomalies seen in Venus’ clouds. ̽��ֱ��researchers also show that sources such as lightning, volcanic eruptions, and even a meteorite strike could not chemically produce the amount of ammonia required to explain the anomalies. Life, however, might.

In fact, the team notes that there are life-forms on Earth — particuarly in our own stomachs — that produce ammonia to neutralise and make livable an otherwise highly acidic environment.

“This hypothesis predicts that the tentative detection of oxygen and ammonia in Venus’s clouds by probes will be confirmed by future missions, and that both life and ammonium sulphite and sulphate are present in the largest droplets in the lower part of the cloud,” said Rimmer, who is also affiliated with the Cavendish Laboratory and the MRC Laboratory for Molecular Biology. “There are also several remaining mysteries: if life is there, how does it propagate in an environment as dry as the clouds of Venus? If it is making water when neutralising the droplets, what happens to that water? If life is not in the clouds of Venus, what alternative abiotic chemistry is taking place to explain this depletion of sulphur dioxide and water? Future lab experiments and missions will be able to test these predictions and may shed light on these outstanding mysteries.”

Scientists may have a chance to check for the presence of ammonia, and signs of life, in the next several years with the Venus Life Finder Missions, a set of proposed privately funded missions that plan to send spacecraft to Venus to measure its clouds for ammonia and other signatures of life.

This research was supported in part by the Simons Foundation, the Change Happens Foundation, and the Breakthrough Initiatives.

Reference:
William Bains et al. ‘Production of ammonia makes Venusian clouds habitable and explains observed cloud-level chemical anomalies.’ Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2110889118

Adapted from an MIT news story.

A new study shows it’s theoretically possible. ̽��ֱ��hypothesis could be tested soon with proposed Venus-bound missions.

If life is there, how does it propagate in an environment as dry as the clouds of Venus?

Paul Rimmer

NASA/JPL-Caltech

Venus from Mariner 10

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Scientists identify exoplanets where life could develop as it did on Earth

sc604 — Wed, 01 Aug 2018 18:00:00 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge and the Medical Research Council Laboratory of Molecular Biology (MRC LMB), found that the chances for life to develop on the surface of a rocky planet like Earth are connected to the type and strength of light given off by its host star.

Their study, published in the journal Science Advances, proposes that stars which give off sufficient ultraviolet (UV) light could kick-start life on their orbiting planets in the same way it likely developed on Earth, where the UV light powers a series of chemical reactions that produce the building blocks of life.

̽��ֱ��researchers have identified a range of planets where the UV light from their host star is sufficient to allow these chemical reactions to take place, and that lie within the habitable range where liquid water can exist on the planet’s surface.

“This work allows us to narrow down the best places to search for life,” said Dr Paul Rimmer, a postdoctoral researcher with a joint affiliation at Cambridge’s Cavendish Laboratory and the MRC LMB, and the paper’s first author. “It brings us just a little bit closer to addressing the question of whether we are alone in the universe.”

̽��ֱ��new paper is the result of an ongoing collaboration between the Cavendish Laboratory and the MRC LMB, bringing together organic chemistry and exoplanet research. It builds on the work of Professor John Sutherland, a co-author on the current paper, who studies the chemical origin of life on Earth.

In a paper published in 2015, Professor Sutherland’s group at the MRC LMB proposed that cyanide, although a deadly poison, was in fact a key ingredient in the primordial soup from which all life on Earth originated.

In this hypothesis, carbon from meteorites that slammed into the young Earth interacted with nitrogen in the atmosphere to form hydrogen cyanide. ̽��ֱ��hydrogen cyanide rained to the surface, where it interacted with other elements in various ways, powered by the UV light from the sun. ̽��ֱ��chemicals produced from these interactions generated the building blocks of RNA, the close relative of DNA which most biologists believe was the first molecule of life to carry information.

In the laboratory, Sutherland’s group recreated these chemical reactions under UV lamps, and generated the precursors to lipids, amino acids and nucleotides, all of which are essential components of living cells.

“I came across these earlier experiments, and as an astronomer, my first question is always what kind of light are you using, which as chemists they hadn’t really thought about,” said Rimmer. “I started out measuring the number of photons emitted by their lamps, and then realised that comparing this light to the light of different stars was a straightforward next step.”

̽��ֱ��two groups performed a series of laboratory experiments to measure how quickly the building blocks of life can be formed from hydrogen cyanide and hydrogen sulphite ions in water when exposed to UV light. They then performed the same experiment in the absence of light.

“There is chemistry that happens in the dark: it’s slower than the chemistry that happens in the light, but it’s there,” said senior author Professor Didier Queloz, also from the Cavendish Laboratory. “We wanted to see how much light it would take for the light chemistry to win out over the dark chemistry.”

̽��ֱ��same experiment run in the dark with the hydrogen cyanide and the hydrogen sulphite resulted in an inert compound which could not be used to form the building blocks of life, while the experiment performed under the lights did result in the necessary building blocks.

̽��ֱ��researchers then compared the light chemistry to the dark chemistry against the UV light of different stars. They plotted the amount of UV light available to planets in orbit around these stars to determine where the chemistry could be activated.

They found that stars around the same temperature as our sun emitted enough light for the building blocks of life to have formed on the surfaces of their planets. Cool stars, on the other hand, do not produce enough light for these building blocks to be formed, except if they have frequent powerful solar flares to jolt the chemistry forward step by step. Planets that both receive enough light to activate the chemistry and could have liquid water on their surfaces reside in what the researchers have called the abiogenesis zone.

Among the known exoplanets which reside in the abiogenesis zone are several planets detected by the Kepler telescope, including Kepler 452b, a planet that has been nicknamed Earth’s ‘cousin’, although it is too far away to probe with current technology. Next-generation telescopes, such as NASA’s TESS and James Webb Telescopes, will hopefully be able to identify and potentially characterise many more planets that lie within the abiogenesis zone.

Of course, it is also possible that if there is life on other planets, that it has or will develop in a totally different way than it did on Earth.

“I’m not sure how contingent life is, but given that we only have one example so far, it makes sense to look for places that are most like us,” said Rimmer. “There’s an important distinction between what is necessary and what is sufficient. ̽��ֱ��building blocks are necessary, but they may not be sufficient: it’s possible you could mix them for billions of years and nothing happens. But you want to at least look at the places where the necessary things exist.”

According to recent estimates, there are as many as 700 million trillion terrestrial planets in the observable universe. “Getting some idea of what fraction have been, or might be, primed for life fascinates me,” said Sutherland. “Of course, being primed for life is not everything and we still don’t know how likely the origin of life is, even given favourable circumstances - if it’s really unlikely then we might be alone, but if not, we may have company.”

̽��ֱ��research was funded by the Kavli Foundation and the Simons Foundation.

Reference:
Paul B. Rimmer et al. ‘ ̽��ֱ��Origin of RNA Precursors on Exoplanets.’ Science Advances (2018). DOI: 10.1126/sciadv.aar3302

Inset image: Diagram of confirmed exoplanets within the liquid water habitable zone (as well as Earth). Credit: Paul Rimmer

Scientists have identified a group of planets outside our solar system where the same chemical conditions that may have led to life on Earth exist.

This work brings us just a little bit closer to addressing the question of whether we are alone in the universe.

Paul Rimmer

NASA Ames/JPL-Caltech/T. Pyle

Artist's concept depicting one possible appearance of the planet Kepler-452b

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Leprosy turns the immune system against itself, study finds

cjb250 — Wed, 23 Aug 2017 08:33:57 +0000

Leprosy is an infectious disease that affects the skin and peripheral nerves and is caused by Mycobacterium leprae and, less commonly, Mycobacterium lepromatosis. According to the World Health Organization, there has been a dramatic decrease in the global disease burden in the past few decades: from 5.2 million people with leprosy in 1985 to 176,176 at the end of 2015.

Despite the disease having been known about for thousands of years – many people will have first heard about it through references in the Bible – very little is understood about its biology. This is in part because the bacteria are difficult to grow in culture and there are no good animal models: M. leprae can grow in the footpads of mice, but do not cause nerve damage; the disease causes nerve damage in armadillos, but these animals are rarely used in research.

Now, an international team led by researchers at the ̽��ֱ�� of Cambridge, UK, and the ̽��ֱ�� of Washington, the ̽��ֱ�� of California Los Angeles and Harvard ̽��ֱ��, USA, have used a new animal model, the zebrafish, to show for the first time how M. leprae damage nerves by infiltrating the very cells that are meant to protect us. Zebrafish are already used to study another species of mycobacteria, to help understand tuberculosis (TB).

Scientists have previously shown that the nerve damage in leprosy is caused by a stripping away of the protective insulation, the myelin sheath, that protects nerve fibres, but it was thought that this process occurred because the bacteria got inside Schwann cells, specialist cells that produce myelin.

In new research published today in the journal Cell, researchers used zebrafish that had been genetically modified so that their myelin is fluorescent green; young zebrafish are themselves transparent, and so the researchers could more easily observe what was happening to the nerve cells. When they injected bacteria close to the nerve cells of the zebrafish, they observed that the bacteria settled on the nerve, developing donut-like ‘bubbles’ of myelin that had dissociated from the myelin sheath.

When they examined these bubbles more closely, they found that they were caused by M. leprae bacteria inside of macrophages – literally ‘big eaters’, immune cells that consume and destroy foreign bodies and unwanted material within the body. But, as is also often the case with TB, the M. leprae was consumed by the macrophages but not destroyed.

“These ‘Pac-Man’-like immune cells swallow the leprosy bacteria, but are not always able to destroy them,” explains Professor Lalita Ramakrishnan from the Department of Medicine at the ̽��ֱ�� of Cambridge, whose lab is within the Medical Research Council’s Laboratory of Molecular Biology. “Instead, the macrophages – which should be moving up and down the nerve fibre repairing damage – slow down and settle in place, destroying the myelin sheath.”

Professor Ramakrishnan working with Dr Cressida Madigan, Professor Alvaro Sagasti, and other colleagues confirmed that this was the case by knocking out the macrophages and showing that when the bacteria sit directly on the nerves, they do not damage the myelin sheath.

̽��ֱ��team further demonstrated how this damage occurs. A molecule known as PGL-1 that sits on the surface of M. leprae ‘reprograms’ the macrophage, causing it to overproduce a potentially destructive form of the chemical nitric oxide that damages mitochondria, the ‘batteries’ that power nerves.

“ ̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry,” says Professor Ramakrishnan. “It then starts spewing out toxic chemicals. Not only does it stop repairing damage, but it creates more damage itself.”

“We know that the immune system can lead to nerve damage – and in particular to the myelin sheath – in other diseases, such as multiple sclerosis and Guillain–Barré syndrome,” says Dr Cressida Madigan from the ̽��ֱ�� of California, Los Angeles. “Our study appears to place leprosy in the same category of these diseases.”

̽��ֱ��researchers say it is too early to say whether this study will lead to new treatments. There are several drugs being tested that inhibit the production of nitric oxide, but, says Professor Ramakrishnan, the key may be to catch the disease at an early enough stage to prevent damage to the nerve cells.

“We need to be thinking about degeneration versus regeneration,” she says. “At the moment, leprosy can be treated by a combination of drugs. While these succeed in killing the bacteria, once the nerve damage has been done, it is currently irreversible. We would like to understand how to change that. In other words, are we able to prevent damage to nerve cells in the first place and can we additionally focus on repairing damaged nerve cells?”

̽��ֱ��research was funded by the National Institutes of Health, the Wellcome Trust, and the AP Giannini Foundation.

Reference
Madigan, CA et al. A Macrophage Response To Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage In Leprosy. Cell; 24 Aug 2017; DOI: 10.1016/j.cell.2017.07.030

Leprosy hijacks our immune system, turning an important repair mechanism into one that causes potentially irreparable damage to our nerve cells, according to new research that uses zebrafish to study the disease. As such, the disease may share common characteristics with conditions such as multiple sclerosis.

̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry

Lalita Ramakrishnan

Wellcome Library, London

Hand showing leprosy

̽��ֱ��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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World’s first artificial enzymes created using synthetic biology

tdk25 — Mon, 01 Dec 2014 16:00:00 +0000

A team of researchers have created the world’s first enzymes made from artificial genetic material.

̽��ֱ��synthetic enzymes, which are made from molecules that do not occur anywhere in nature, are capable of triggering chemical reactions in the lab.

̽��ֱ��research is published in the journal Nature and promises to offer new insights into the origins of life, as well as providing a potential starting point for an entirely new generation of drugs and diagnostics. In addition, the authors speculate that the study increases the range of planets that could potentially host life.

All life on Earth depends on the chemical transformations that enable cellular function and the performance of basic tasks, from digesting food to making DNA. These are powered by naturally-occurring enzymes which operate as catalysts, kick-starting the process and enabling such reactions to happen at the necessary rate.

For the first time, however, the research shows that these natural biomolecules may not be the only option, and that artificial enzymes could also be used to power the reactions that enable life to occur.

̽��ֱ��findings build on previous work in which the scientists, from the MRC Laboratory of Molecular Biology in Cambridge and the ̽��ֱ�� of Cambridge, created synthetic molecules called “XNAs”. These are entirely artificial genetic systems that can store and pass on genetic information in a manner similar to DNA.

Using these XNAs as building blocks, the new research involved the creation of so-called “XNAzymes”. Like naturally occurring enzymes, these are capable of powering simple biochemical reactions.

Dr Alex Taylor, a Post-doctoral Researcher at St John’s College, ̽��ֱ�� of Cambridge, who is based at the MRC Laboratory and was the study’s lead author, said: “ ̽��ֱ��chemical building blocks that we used in this study are not naturally-occurring on Earth, and must be synthesised in the lab. This research shows us that our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision. ̽��ֱ��results imply that our chemistry, of DNA, RNA and proteins, may not be special and that there may be a vast range of alternative chemistries that could make life possible.”

Every one of our cells contains thousands of different enzymes, many of which are proteins. In addition, however, nucleic acids – DNA and its close chemical cousin, RNA – can also form enzymes. ̽��ֱ��ribosome, the molecular machine which manufactures proteins within all cells, is an RNA enzyme. Life itself is widely thought to have begun with the emergence of a self-copying RNA enzyme.

Dr Philipp Holliger, from the MRC Laboratory of Molecular Biology, said: “Until recently it was thought that DNA and RNA were the only molecules that could store genetic information and, together with proteins, the only biomolecules able to form enzymes.”

“Our work suggests that, in principle, there are a number of possible alternatives to nature’s molecules that will support the catalytic processes required for life. Life’s ‘choice’ of RNA and DNA may just be an accident of prehistoric chemistry.”

“ ̽��ֱ��creation of synthetic DNA, and now enzymes, from building blocks that don’t exist in nature also raises the possibility that if there is life on other planets it may have sprung up from an entirely different set of molecules, and widens the possible number of planets that might be able to host life.”

̽��ֱ��group’s previous study, carried out in 2012, showed that six alternative molecules, called XNAs, could store genetic information and evolve through natural selection. Expanding on that principle, the new research identified, for the first time, four different types of synthetic catalyst formed from these entirely unnatural building blocks.

These XNAzymes are capable of catalysing simple reactions, like cutting and joining strands of RNA in a test tube. One of the XNAzymes can even join strands together, which represents one of the first steps towards creating a living system.

Because their XNAzymes are much more stable than naturally occurring enzymes, the scientists believe that they could be particularly useful in developing new therapies for a range of diseases, including cancers and viral infections, which exploit the body’s natural processes.

Dr Holliger added: “Our XNAs are chemically extremely robust and, because they do not occur in nature, they are not recognised by the body’s natural degrading enzymes. This might make them an attractive candidate for long-lasting treatments that can disrupt disease-related RNAs.”

Professor Patrick Maxwell, Chair of the MRC’s Molecular and Cellular Medicine Board and Regius Professor of Physic at the ̽��ֱ�� of Cambridge, said: “Synthetic biology is delivering some truly amazing advances that promise to change the way we understand and treat disease. ̽��ֱ��UK excels in this field, and this latest advance offers the tantalising prospect of using designer biological parts as a starting point for an entirely new class of therapies and diagnostic tools that are more effective and have a longer shelf-life.”

Funders of the research included the MRC, European Science Foundation and the Biotechnology and Biological Sciences Research Council.

Enzymes made from artificial molecules which do not occur anywhere in nature have been shown to trigger chemical reactions in the lab, challenging existing views about the conditions that are needed to enable life to happen.

Our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision

Alex Taylor

A. Taylor

̽��ֱ��study built on previous work which created synthetic molecules known as “XNA”, then used these as the basis of creating so-called “XNAzymes”.

̽��ֱ��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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Scientists discover genetic disease which causes recurrent respiratory infections

sj387 — Fri, 18 Oct 2013 08:36:28 +0000

Cambridge scientists have discovered a rare genetic disease which predisposes patients to severe respiratory infections and lung damage. Because the scientists also identified how the genetic mutation affects the immune system, they are hopeful that new drugs that are currently undergoing clinical trials to treat leukaemia may also be effective in helping individuals with this debilitating disease.

For the study, led by the ̽��ֱ�� of Cambridge in collaboration with the Babraham Institute and the MRC Laboratory for Molecular Biology, the researchers first examined genetic information from individuals who suffer from immunodeficiency and are predisposed to infections. From this group, the scientists identified a unique genetic mutation in 17 patients that suffer from severe respiratory infections and rapidly develop lung damage.

̽��ֱ��researchers, who were primarily funded by the Wellcome Trust, MRC, BBSRC and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, found that the mutation increases activity of an enzyme called Phosphoinositide 3-Kinase δ (PI3Kδ). ̽��ֱ��enzyme is present in immune cells and regulates their function. However, constantly activated PI3Kδ impairs work of these immune cells, preventing them from responding efficiently to infection and providing long-lasting protection. Consequently, patients with this mutation have severe and recurrent infections.

“Patients with this mutation have a defect in the immune cells, so their protection from infections is weak and inefficient,” said Sergey Nejentsev, Wellcome Trust Senior Research Fellow from the ̽��ֱ�� of Cambridge who led the research. “We called this newly identified disease Activated PI3K- δ Syndrome (APDS) after the enzyme in the immune system that is affected by the genetic mutation.”

̽��ֱ��researchers believe that it may be possible to treat APDS in future. There are currently drugs in clinical trials for leukaemia that were designed specifically to inhibit the PI3Kδ enzyme. ̽��ֱ��researchers have already shown that these drugs reduce activity of the mutant protein.

Alison Condliffe, joint senior author on the paper from the ̽��ֱ�� of Cambridge, said: “We are very excited by the prospect of using these drugs to help patients with APDS. We believe that they may be able to restore functions of immune cells, thereby reducing infections and preventing lung damage.”

Although the prevalence of the disease is not yet known, the scientists believe that it is relatively frequent compared to other immunodeficiencies and may underpin immunodeficiencies and chronic lung disorders in a substantial fraction of patients.

“It is very important that doctors consider a possibility of APDS in their patients,” said Dr Nejentsev. “A simple genetic test can tell if the patient has the mutation or not. We believe that now many more APDS patients will be identified all over the world.”

̽��ֱ��research was published by Science Express (the electronic publication of selected Science papers).

Discovery could lead to new treatments for this genetic disorder.

We believe that now many more APDS patients will be identified all over the world

Sergey Nejentsev

Chikumaya

X-ray photo of a chest

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