From The Swiss Federal Institute of Technology in Lausanne [EPFL-École Polytechnique Fédérale de Lausanne] (CH): “Intelligent microscopes for detecting rare biological events”

From The Swiss Federal Institute of Technology in Lausanne [EPFL-École Polytechnique Fédérale de Lausanne] (CH)

9.11.22

EPFL biophysicists have developed control software that optimizes how fluorescence microscopes collect data on living samples. Their control loop, used to image mitochondrial and bacterial sites of division in detail, is released as an open source plug-in and could inspire a new generation of intelligent microscopes.

Imagine you’re a PhD student with a fluorescent microscope and a sample of live bacteria. What’s the best way use these resources to obtain detailed observations of bacterial division from the sample?

You may be tempted to forgo food and rest, to sit at the microscope non-stop and acquire images when bacterial finally division starts. (It can take hours for one bacterium to divide!) It’s not as crazy as it sounds, since manual detection and acquisition control is widespread in many of the sciences.

Alternatively, you may want to set the microscope to take images indiscriminately and as often as possible. But excessive light depletes the fluorescence from the sample faster and can prematurely destroy living samples. Plus, you’d generate many uninteresting images, since only a few would contain images of dividing bacteria.

Another solution would be to use artificial intelligence to detect precursors to bacterial division and use these to automatically update the microscope’s control software to take more pictures of the event.

Drum roll… yes, EPFL biophysicists have indeed found a way to automate microscope control for imaging biological events in detail while limiting stress on the sample, all with the help of artificial neural networks. Their technique works for bacterial cell division, and for mitochondrial division. The details of their intelligent microscope are described in Nature Methods [below].

“An intelligent microscope is kind of like a self-driving car. It needs to process certain types of information, subtle patterns that it then responds to by changing its behavior,” explains principal investigator Suliana Manley of EPFL’s Laboratory of Experimental Biophysics. “By using a neural network, we can detect much more subtle events and use them to drive changes in acquisition speed.”

Suliana Manley in one of the labs of EPFL’s Laboratory of Experimental Biophysics. © 2022 EPFL / Hillary Sanctuary.

Manley and her colleagues first solved how to detect mitochondrial division, more difficult than for bacteria such as C. crescentus. Mitochondrial division is unpredictable, since it occurs infrequently, and can happen almost anywhere within the mitochondrial network at any moment. But the scientists solved the problem by training the neural network to look out for mitochondrial constrictions, a change in shape of mitochondria that leads to division, combined with observations of a protein known to be enriched at sites of division.

When both constrictions and protein levels are high, the microscope switches into high-speed imaging to capture many images of division events in detail. When constriction and protein levels are low, the microscope then switches to low-speed imaging to avoid exposing the sample to excessive light.

One of Manley’s fluorescence microscopes. © Hillary Sanctuary 2022/EPFL.

With this intelligent fluorescent microscope, the scientists showed that they could observe the sample for longer compared to standard fast imaging. While the sample was more stressed compared to standard slow imaging, they were able to obtain more meaningful data.

“The potential of intelligent microscopy includes measuring what standard acquisitions would miss,” Manley explains. “We capture more events, measure smaller constrictions, and can follow each division in greater detail.”

The scientists are making the control framework available as an open source plug-in for the open microscope software Micro-Manager, with the aim of allowing other scientists to integrate artificial intelligence into their own microscopes.

Artboard by Willi Stepp © 2022 EPFL.

© Hillary Sanctuary 2022/EPFL.

Science paper:
Nature Methods

See the full article here .

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EPFL campus

The Swiss Federal Institute of Technology in Lausanne [EPFL-École Polytechnique Fédérale de Lausanne] (CH) is a research institute and university in Lausanne, Switzerland, that specializes in natural sciences and engineering. It is one of the two Swiss Federal Institutes of Technology, and it has three main missions: education, research and technology transfer.

The QS World University Rankings ranks EPFL(CH) 14th in the world across all fields in their 2020/2021 ranking, whereas Times Higher Education World University Rankings ranks EPFL(CH) as the world’s 19th best school for Engineering and Technology in 2020.

EPFL(CH) is located in the French-speaking part of Switzerland; the sister institution in the German-speaking part of Switzerland is The Swiss Federal Institute of Technology ETH Zürich [Eidgenössische Technische Hochschule Zürich] (CH). Associated with several specialized research institutes, the two universities form The Domain of the Swiss Federal Institutes of Technology (ETH Domain) [ETH-Bereich; Domaine des Écoles Polytechniques Fédérales] (CH) which is directly dependent on the Federal Department of Economic Affairs, Education and Research. In connection with research and teaching activities, EPFL(CH) operates a nuclear reactor CROCUS; a Tokamak Fusion reactor; a Blue Gene/Q Supercomputer; and P3 bio-hazard facilities.

ETH Zürich, EPFL (Swiss Federal Institute of Technology in Lausanne) [École Polytechnique Fédérale de Lausanne](CH), and four associated research institutes form The Domain of the Swiss Federal Institutes of Technology (ETH Domain) [ETH-Bereich; Domaine des Écoles polytechniques fédérales] (CH) with the aim of collaborating on scientific projects.

The roots of modern-day EPFL(CH) can be traced back to the foundation of a private school under the name École Spéciale de Lausanne in 1853 at the initiative of Lois Rivier, a graduate of the École Centrale Paris (FR) and John Gay the then professor and rector of the Académie de Lausanne. At its inception it had only 11 students and the offices were located at Rue du Valentin in Lausanne. In 1869, it became the technical department of the public Académie de Lausanne. When the Académie was reorganized and acquired the status of a university in 1890, the technical faculty changed its name to École d’Ingénieurs de l’Université de Lausanne. In 1946, it was renamed the École polytechnique de l’Université de Lausanne (EPUL). In 1969, the EPUL was separated from the rest of the University of Lausanne and became a federal institute under its current name. EPFL(CH), like ETH Zürich (CH), is thus directly controlled by the Swiss federal government. In contrast, all other universities in Switzerland are controlled by their respective cantonal governments. Following the nomination of Patrick Aebischer as president in 2000, EPFL(CH) has started to develop into the field of life sciences. It absorbed the Swiss Institute for Experimental Cancer Research (ISREC) in 2008.

In 1946, there were 360 students. In 1969, EPFL(CH) had 1,400 students and 55 professors. In the past two decades the university has grown rapidly and as of 2012 roughly 14,000 people study or work on campus, about 9,300 of these being Bachelor, Master or PhD students. The environment at modern day EPFL(CH) is highly international with the school attracting students and researchers from all over the world. More than 125 countries are represented on the campus and the university has two official languages, French and English.

Organization

EPFL is organized into eight schools, themselves formed of institutes that group research units (laboratories or chairs) around common themes:

School of Basic Sciences
Institute of Mathematics
Institute of Chemical Sciences and Engineering
Institute of Physics
European Centre of Atomic and Molecular Computations
Bernoulli Center
Biomedical Imaging Research Center
Interdisciplinary Center for Electron Microscopy
MPG-EPFL Centre for Molecular Nanosciences and Technology
Swiss Plasma Center
Laboratory of Astrophysics

School of Engineering

Institute of Electrical Engineering
Institute of Mechanical Engineering
Institute of Materials
Institute of Microengineering
Institute of Bioengineering

School of Architecture, Civil and Environmental Engineering

Institute of Architecture
Civil Engineering Institute
Institute of Urban and Regional Sciences
Environmental Engineering Institute

School of Computer and Communication Sciences

Algorithms & Theoretical Computer Science
Artificial Intelligence & Machine Learning
Computational Biology
Computer Architecture & Integrated Systems
Data Management & Information Retrieval
Graphics & Vision
Human-Computer Interaction
Information & Communication Theory
Networking
Programming Languages & Formal Methods
Security & Cryptography
Signal & Image Processing
Systems

School of Life Sciences

Bachelor-Master Teaching Section in Life Sciences and Technologies
Brain Mind Institute
Institute of Bioengineering
Swiss Institute for Experimental Cancer Research
Global Health Institute
Ten Technology Platforms & Core Facilities (PTECH)
Center for Phenogenomics
NCCR Synaptic Bases of Mental Diseases

College of Management of Technology

Swiss Finance Institute at EPFL
Section of Management of Technology and Entrepreneurship
Institute of Technology and Public Policy
Institute of Management of Technology and Entrepreneurship
Section of Financial Engineering

College of Humanities

Human and social sciences teaching program

EPFL Middle East

Section of Energy Management and Sustainability

In addition to the eight schools there are seven closely related institutions

Swiss Cancer Centre
Center for Biomedical Imaging (CIBM)
Centre for Advanced Modelling Science (CADMOS)
École Cantonale d’art de Lausanne (ECAL)
Campus Biotech
Wyss Center for Bio- and Neuro-engineering
Swiss National Supercomputing Centre

From The DOE’s Pacific Northwest National Laboratory: “Exploring New Materials Through Collaboration”

From The DOE’s Pacific Northwest National Laboratory

June 13, 2022
Beth Mundy

Jim De Yoreo’s career full of insights about materials will continue at the Energy Sciences Center.

Scientists who study materials can be divided into three categories. “You have people who make things, people who make things do things, and people who try to understand why things do what they do,” said Jim De Yoreo, a Battelle fellow at Pacific Northwest National Laboratory (PNNL). He places himself into the third category.

Through advanced microscopy techniques, De Yoreo has spent his career trying to understand and predict the behavior of materials. In 2022, he was elected to the National Academy of Engineering, citing his “advances in materials synthesis from nucleation to large-scale crystal growth.” De Yoreo’s work spans materials science, geochemistry, and biophysics, often focusing on natural mineral and biological systems.

De Yoreo is particularly interested in interfaces, the place where two different materials meet. “Developing new and increasingly complicated materials requires combining existing materials,” said De Yoreo. “To effectively combine materials, we have to understand what happens at the interface.”

De Yoreo’s research team has watched tiny crystals grow and attach together in real time, solving outstanding questions about crystal formation. The team also determined the patterns that proteins form on a mineral surface, laying the groundwork for new strategies for synthesizing semiconductor and metallic nanoparticle circuits for photovoltaic or energy storage applications.

Some of De Yoreo’s most significant contributions occurred through his penchant for forging deep connections and collaborations. Since joining PNNL in 2012, he has worked with like-minded materials science researchers across Washington State.

De Yoreo approaches science through a collaborative perspective [see the blog masthead about science and collaboration]. “I know that my own view is limited,” said De Yoreo. “So if I work with people who have different skills, we can start to really understand materials.”

Many of these collaborations occur through university partnerships-particularly at the University of Washington. De Yoreo has embraced leadership roles at the Northwest Institute for Materials Physics, Chemistry, and Technology and the Center for the Science of Synthesis Across Scales, which bring together researchers from PNNL and UW.

“I think Jim has set the stage for another decade of really fruitful materials science collaborations between UW and PNNL,” said Jim Pfaendtner, PNNL joint appointee, professor, and chair of the UW Department of Chemical Engineering. “His efforts have built bridges that didn’t exist before and led to new efforts, like CSSAS.”

Pfaendtner isn’t the only one who noticed. The Department of Energy named De Yoreo a Distinguished Scientist Fellow in 2020, specifically citing his “leadership in National Laboratory-University partnerships.”

Mentoring for collaboration

A transmission electron microscopy image of an assembly of nanomaterials. (Image by Madison Monahan | University of Washington)

Through joint faculty appointments in the UW Chemistry and Materials Science and Engineering departments, De Yoreo co-mentors students like Madison Monahan. Monahan, a recent PhD graduate, helped start a collaboration among De Yoreo, PNNL materials scientist and UW joint appointee Chun-Long Chen, and UW Chemistry Professor Brandi Cossairt. Monahan’s work focuses on controlling the assembly of complex nanoscale materials.

The different material components are like toy bricks. When assembled in a precise order, a stack of different pieces can become a car or a house. While standard toy bricks require direct human assembly, it isn’t strictly necessary at the nanoscale. It’s as if putting a set of bricks into a box and shaking it the right way produces a completed model house without extra effort.

This is similar to what happens with assemblies at the nanoscale. However, creating a specific assembly isn’t as simple as adding all the components to a random box. Different conditions, including the overall temperature or type of materials, can change the final structure of the assembly. The goal of Monahan’s project, which is funded by CSSAS, is to understand design principles and key interactions between different building blocks. This will allow researchers to create predictable, functional materials, where final structure controls overall behavior, from a wide range of starting materials.

The collaboration centers on combining carbon-based (organic) and non-carbon-based (inorganic) materials.

“We want to try to fit these two different worlds together and find a place where they have complementary chemistry,” said Monahan.

The Chen group designed peptide-like molecules, called peptoids, to serve as the organic component. Monahan created inorganic nanocrystals and used microscopy to study the forming of organic-inorganic assemblies and their final structures.

The team explored whether starting assembly with either the organic or the inorganic components produced different results.

The team found that order of operations matters. When the organic base gets assembled first, it controls the overall structure. When starting with the nanocrystals, the results become less clear. It turns out the size and composition of the nanocrystal also matter. With smaller nanocrystals, the organic structure and nanocrystal both affect the final material. When the nanocrystal is larger, it primarily determines the final structure.

This work, recently published in ACS Nano, required expertise in developing biologically inspired molecules, synthesizing inorganic materials, and using advanced imaging techniques. It involved bringing together different perspectives to create and understand these complex material assemblies.

“Jim has opened my eyes to these different ways to study nanomaterials,” said Cossairt. “There are things we’d just never consider being viable for our inorganic systems. He really is the dream collaborator.”

Developing the next generation of scientific leaders

Students who work with De Yoreo have ready access to advanced microscopes and other instruments at the new Energy Sciences Center (ESC). It’s more than the instruments, though. The ESC was designed as a collaborative environment for accelerated scientific discovery and features a combination of research laboratories, flexible-use open spaces, conference rooms, and offices.

“Everyone in Jim’s group has such different backgrounds,” said Monahan. “It means that you constantly get great ideas and have access to so much knowledge. I get to hear from experienced physicists and materials scientists at PNNL as well as the chemists I work with at UW.”

Monahan is just one of De Yoreo’s UW student mentees. While some stay based at UW for their full graduate career, others spend from months to years on the PNNL campus.

“I always wanted to mentor graduate students jointly,” said De Yoreo. “Working with another mentor makes sure my students have a full lab experience no matter where they are. I also think if they can learn both synthesis and measurement, it makes their work more successful.”

Jim’s collaborators echo that sentiment. “There’s no way a student advised just by me would have been able to develop such deep microscopy skills,” said Cossairt. “The joint approach gives a student the best of both worlds.”

An adventurous approach to life and science

Collaborators note that they never know what the background of De Yoreo’s video calls will be as he often features photos of previous travels that range from savannah wildlife to snowy slopes. These backgrounds often come with an anecdote about the corresponding trip.

Once, he took instruments to explore a cave in Mexico where a unique set of crystals naturally formed. A sense of adventure permeates his personal and professional life. “You never know where he’s calling you from,” said Monahan.

“Jim has an adventurous approach to life, and you can see it in his science,” said Monahan, describing her mentor. “He has these wildly ambitious ideas, but he’s practical enough to know they might not happen now. But he’s going to break it down to where in 10 years, he’ll be able to do it.”

Others echo this sentiment. “Jim has a boundless intellectual energy and the ability to deeply think about numerous problems simultaneously,” said Pfaendtner. “It’s incredible.”

Pfaendtner collaborates with De Yoreo on multiple projects. “My group does computational modeling and he does experimental characterization,” said Pfaendtner. “Our work fits nicely together.”

Previously, a collaborative effort [Journal of the American Chemical Society] that included De Yoreo and Pfaendtner’s research groups explored how solid-binding peptides attach to a mineral surface. These biological molecules can potentially direct the formation of complex mineral-biological hybrid systems. The team used a combined approach of protein engineering, microscopy, computations, and surface bonding experiments to understand what controls peptide binding. They found that binding ability is substantially determined by a small section of the peptide structure. Using this core structure, researchers can create and identify new peptides to assemble materials.

“Every time I meet with Jim, he has new ideas about whatever we’re working on,” said Pfaendtner. “I leave most of my conversations with him feeling energized.”

See the full article here.

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Please help promote STEM in your local schools.

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The DOE’s Pacific Northwest National Laboratory is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.

From University of Exeter (UK): “Pioneering new technique could revolutionize super-resolution imaging systems”

From University of Exeter (UK)

21 January 2021

Credit: Pixabay/CC0 Public Domain

Scientists have developed a pioneering new technique that could revolutionise the accuracy, precision and clarity of super-resolution imaging systems.

A team of scientists, led by Dr Christian Soeller from the University of Exeter’s Living Systems Institute, which champions interdisciplinary research and is a hub for new high-resolution measurement techniques, has developed a new way to improve the very fine, molecular imaging of biological samples.

The new method builds upon the success of an existing super-resolution imaging technique called DNA-PAINT (Point Accumulation for Imaging in Nanoscale Topography) – where molecules in a cell are labelled with marker molecules that are attached to single DNA strands.

Matching DNA strands are then also labelled with a florescent chemical compound and introduced in solution – when they bind the marker molecules, it creates a ‘blinking effect’ that makes imaging possible.

However, DNA-PAINT has a number of drawbacks in its current form, which limit the applicability and performance of the technology when imaging biological cells and tissues.

In response, the research team have developed a new technique, called Repeat DNA-Paint, which is capable of supressing background noise and nonspecific signals, as well as decreasing the time taken for the sampling process.

Crucially, using Repeat DNA-PAINT is straightforward and does not carry any known drawbacks, it is routinely applicable, consolidating the role of DNA-PAINT as one of the most robust and versatile molecular resolution imaging methods.

The study is published in Nature Communications on 21st January 2021.

Dr Soeller, lead author of the study and who is a biophysicist at the Living Systems Institute said: “We can now see molecular detail with light microscopy in a way that a few years ago seemed out of reach. This allows us to directly see how molecules orchestrate the intricate biological functions that enable life in both health and disease”.

The research was enabled by colleagues from physics, biology, medicine, mathematics and chemistry working together across traditional discipline boundaries. Dr Lorenzo Di Michele, co-author from Imperial College London said: “This work is a clear example of how quantitative biophysical techniques and concepts can really improve our ability to study biological systems”.

See the full article here.

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The University of Exeter (UK) is a public research university in Exeter, Devon, South West England, United Kingdom. It was founded and received its royal charter in 1955, although its predecessor institutions, St Luke’s College, Exeter School of Science, Exeter School of Art, and the Camborne School of Mines were established in 1838, 1855, 1863, and 1888 respectively. In post-nominals, the University of Exeter is abbreviated as Exon. (from the Latin Exoniensis), and is the suffix given to honorary and academic degrees from the university.

The university has four campuses: Streatham and St Luke’s (both of which are in Exeter); and Truro and Penryn (both of which are in Cornwall). The university is primarily located in the city of Exeter, Devon, where it is the principal higher education institution. Streatham is the largest campus containing many of the university’s administrative buildings. The Penryn campus is maintained in conjunction with Falmouth University under the Combined Universities in Cornwall (CUC) initiative. The Exeter Streatham Campus Library holds more than 1.2 million physical library resources, including historical journals and special collections. The annual income of the institution for 2017–18 was £415.5 million of which £76.1 million was from research grants and contracts, with an expenditure of £414.2 million.

Exeter is a member of the Russell Group of research-intensive UK universities[9] and is also a member of Universities UK, the European University Association, and the Association of Commonwealth Universities and an accredited institution of the Association of MBAs (AMBA).

From Rutgers University: “Rutgers Researchers Set Out to Prove Evolution of All Life, Possibility of Extraterrestrial Life”

Our Great Seal.

From Rutgers University

November 7, 2019

Cinthia Medina
c.medina@rutgers.edu

From simple proteins to living cells, NASA-funded research at Rutgers tests theories on the origins of life.

Biophysics doctoral candidate Douglas Pike, along with postdocs Josh Mancini and Saroj Poudel, are replicating proteins from billions of years ago in an oxygen-free chamber that mimics the conditions of ancient Earth, moving one step closer to proving the origins of life.
Photo: Nick Romanenko/Rutgers University.

Using a computer and a protein synthesizer, Josh Mancini builds proteins that are supposed to resemble those that would have existed 4 billion years ago, before life arose on Earth.

He places millions of the tiny protein molecules, resembling white powder, into an oxygen-free chamber that mimics the conditions of the primordial Earth. He adds nickel – an element these pre-life proteins might have bonded with for catalysis to occur. And he tests to see if a similar reaction takes place in his chamber at Rutgers University–New Brunswick’s Department of Marine Science and at the Center for Advanced Biotechnology and Medicine Building.

If it does, that will mean Rutgers’ NASA-funded ENIGMA team has taken a step closer to understanding how life arose on earth, and the likelihood of its happening elsewhere.

ENIGMA is part of NASA’s focus on astrobiology – the study of whether extraterrestrial life exists, and whether we can find it. The Rutgers program focuses on a key astrobiological question: How did proteins emerge from the chemistry of the early Earth, and then evolve to become the basis of life itself?

Mancini, a postdoctoral researcher, serves on an ENGIMA research team along with Saroj Poudel, another postdoc, and biophysics doctoral candidate Douglas Pike. Poudel and Pike create computer models of theoretical ancient proteins by modeling the physics and chemistry of the ancient Earth and by looking at the proteins present in living things and reverse-engineering their long-lost ancestral forms. Mancini utilizes a hybrid of both approaches and together they take their computational designs and go into the lab to test them for activity in early Earth conditions.

A key function of early proteins would have been to move electrons from one place to another – usually by binding with a conductive metal like nickel or iron. That’s how they power all life, from bacteria to plants to us.

“Humans get their energy from the sugars in the foods we eat. Proteins in our cells take electrons from sugar, then bind it to the oxygen we breathe in and eventually to the carbon dioxide we breathe out,” Pike said. “Whether it is a microorganism or a plant, all creatures on Earth had to find a source of electrons and a place to put them. Present day, that place is oxygen, which we breathe in.” said Pike. “What we are trying to figure out is the alternative places electrons could go in the absence of oxygen, before ‘life’ arose billions of years ago.”

Since there was no oxygen in ancient Earth, there were only a few ways in which organisms could get energy in such hostile environment.

“It was most likely either through hydrogen from hydrothermal vents or light energy from the sun. Our goal is to take early evolving enzymes and see how they could evolve into something more complex that we know exists today. That will help us determine how we could have evolved here on Earth, and what is possible on other planets,” Poudel said.

Postdoctoral researcher Josh Mancini adds nickel to proteins inside of an oxygen-free chamber that mimics the conditions of primordial Earth.
Photo: Rutgers University.

Douglas Pike creates a computer model of an ancient protein, or nanomachine, before going to the lab to test out his theories on how it could have evolved.
Photo: Douglas Pike/Rutgers University

In addition to their lab experiments, the three researchers have also embarked on a challenging, but rewarding part of working with ENIGMA — getting kids to like astrobiology.

“We go into classrooms and help teach the fundamentals of astrobiology to kindergarten through 12th grade students in the New Brunswick area. Sometimes we’re looking at organisms via foldable paper microscopes or we’re showing them a replica of a protein. We want them to get excited about science,” Poudel said. “We predict that astrobiology is going to be one of the biggest fields of science, and we want to prepare kids for potential careers in the future.”

See the full article here .

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Please help promote STEM in your local schools.

Stem Education Coalition

Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

As a ’67 graduate of University college, second in my class, I am proud to be a member of

Alpha Sigma Lamda, National Honor Society of non-tradional students.

From Quanta: “Dividing Droplets Could Explain Life’s Origin”

Quanta Magazine

January 19, 2017
Natalie Wolchover

Researchers have discovered that simple “chemically active” droplets grow to the size of cells and spontaneously divide, suggesting they might have evolved into the first living cells.

davidope for Quanta Magazine

A collaboration of physicists and biologists in Germany has found a simple mechanism that might have enabled liquid droplets to evolve into living cells in early Earth’s primordial soup.

Origin-of-life researchers have praised the minimalism of the idea. Ramin Golestanian, a professor of theoretical physics at the University of Oxford who was not involved in the research, called it a big achievement that suggests that “the general phenomenology of life formation is a lot easier than one might think.”

The central question about the origin of life has been how the first cells arose from primitive precursors. What were those precursors, dubbed “protocells,” and how did they come alive? Proponents of the “membrane-first” hypothesis have argued that a fatty-acid membrane was needed to corral the chemicals of life and incubate biological complexity. But how could something as complex as a membrane start to self-replicate and proliferate, allowing evolution to act on it?

In 1924, Alexander Oparin, the Russian biochemist who first envisioned a hot, briny primordial soup as the source of life’s humble beginnings, proposed that the mystery protocells might have been liquid droplets — naturally forming, membrane-free containers that concentrate chemicals and thereby foster reactions. In recent years, droplets have been found to perform a range of essential functions inside modern cells, reviving Oparin’s long-forgotten speculation about their role in evolutionary history. But neither he nor anyone else could explain how droplets might have proliferated, growing and dividing and, in the process, evolving into the first cells.

Now, the new work by David Zwicker and collaborators at the Max Planck Institute for the Physics of Complex Systems and the Max Planck Institute of Molecular Cell Biology and Genetics, both in Dresden, suggests an answer. The scientists studied the physics of “chemically active” droplets, which cycle chemicals in and out of the surrounding fluid, and discovered that these droplets tend to grow to cell size and divide, just like cells. This “active droplet” behavior differs from the passive and more familiar tendencies of oil droplets in water, which glom together into bigger and bigger droplets without ever dividing.

If chemically active droplets can grow to a set size and divide of their own accord, then “it makes it more plausible that there could have been spontaneous emergence of life from nonliving soup,” said Frank Jülicher, a biophysicist in Dresden and a co-author of the new paper.

The findings, reported in Nature Physics last month, paint a possible picture of life’s start by explaining “how cells made daughters,” said Zwicker, who is now a postdoctoral researcher at Harvard University. “This is, of course, key if you want to think about evolution.”

Luca Giomi, a theoretical biophysicist at Leiden University in the Netherlands who studies the possible physical mechanisms behind the origin of life, said the new proposal is significantly simpler than other mechanisms of protocell division that have been considered, calling it “a very promising direction.”

However, David Deamer, a biochemist at the University of California, Santa Cruz, and a longtime champion of the membrane-first hypothesis, argues that while the newfound mechanism of droplet division is interesting, its relevance to the origin of life remains to be seen. The mechanism is a far cry, he noted, from the complicated, multistep process by which modern cells divide.

Could simple dividing droplets have evolved into the teeming menagerie of modern life, from amoebas to zebras? Physicists and biologists familiar with the new work say it’s plausible. As a next step, experiments are under way in Dresden to try to observe the growth and division of active droplets made of synthetic polymers that are modeled after the droplets found in living cells. After that, the scientists hope to observe biological droplets dividing in the same way.

Clifford Brangwynne, a biophysicist at Princeton University who was part of the Dresden-based team that identified the first subcellular droplets eight years ago — tiny liquid aggregates of protein and RNA in cells of the worm C. elegans — explained that it would not be surprising if these were vestiges of evolutionary history. Just as mitochondria, organelles that have their own DNA, came from ancient bacteria that infected cells and developed a symbiotic relationship with them, “the condensed liquid phases that we see in living cells might reflect, in a similar sense, a sort of fossil record of the physicochemical driving forces that helped set up cells in the first place,” he said.

When germline cells in the roundworm C. elegans divide, P granules, shown in green, condense in the daughter cell that will become a viable sperm or egg and dissolve in the other daughter cell. Courtesy of Clifford Brangwynne/Science

“This Nature Physics paper takes that to the next level,” by revealing the features that droplets would have needed “to play a role as protocells,” Brangwynne added.

Droplets in Dresden

The Dresden droplet discoveries began in 2009, when Brangwynne and collaborators demystified the nature of little dots known as “P granules” in C. elegans germline cells, which undergo division into sperm and egg cells. During this division process, the researchers observed that P granules grow, shrink and move across the cells via diffusion. The discovery that they are liquid droplets, reported in Science, prompted a wave of activity as other subcellular structures were also identified as droplets. It didn’t take long for Brangwynne and Tony Hyman, head of the Dresden biology lab where the initial experiments took place, to make the connection to Oparin’s 1924 protocell theory. In a 2012 essay about Oparin’s life and seminal book, The Origin of Life, Brangwynne and Hyman wrote that the droplets he theorized about “may still be alive and well, safe within our cells, like flies in life’s evolving amber.”

Oparin most famously hypothesized that lightning strikes or geothermal activity on early Earth could have triggered the synthesis of organic macromolecules necessary for life — a conjecture later made independently by the British scientist John Haldane and triumphantly confirmed by the Miller-Urey experiment in the 1950s. Another of Oparin’s ideas, that liquid aggregates of these macromolecules might have served as protocells, was less celebrated, in part because he had no clue as to how the droplets might have reproduced, thereby enabling evolution. The Dresden group studying P granules didn’t know either.

In the wake of their discovery, Jülicher assigned his new student, Zwicker, the task of unraveling the physics of centrosomes, organelles involved in animal cell division that also seemed to behave like droplets. Zwicker modeled the centrosomes as “out-of-equilibrium” systems that are chemically active, continuously cycling constituent proteins into and out of the surrounding liquid cytoplasm. In his model, these proteins have two chemical states. Proteins in state A dissolve in the surrounding liquid, while those in state B are insoluble, aggregating inside a droplet. Sometimes, proteins in state B spontaneously switch to state A and flow out of the droplet. An energy source can trigger the reverse reaction, causing a protein in state A to overcome a chemical barrier and transform into state B; when this insoluble protein bumps into a droplet, it slinks easily inside, like a raindrop in a puddle. Thus, as long as there’s an energy source, molecules flow in and out of an active droplet. “In the context of early Earth, sunlight would be the driving force,” Jülicher said.

Zwicker discovered that this chemical influx and efflux will exactly counterbalance each other when an active droplet reaches a certain volume, causing the droplet to stop growing. Typical droplets in Zwicker’s simulations grew to tens or hundreds of microns across depending on their properties — the scale of cells.

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The next discovery was even more unexpected. Although active droplets have a stable size, Zwicker found that they are unstable with respect to shape: When a surplus of B molecules enters a droplet on one part of its surface, causing it to bulge slightly in that direction, the extra surface area from the bulging further accelerates the droplet’s growth as more molecules can diffuse inside. The droplet elongates further and pinches in at the middle, which has low surface area. Eventually, it splits into a pair of droplets, which then grow to the characteristic size. When Jülicher saw simulations of Zwicker’s equations, “he immediately jumped on it and said, ‘That looks very much like division,’” Zwicker said. “And then this whole protocell idea emerged quickly.”

Zwicker, Jülicher and their collaborators, Rabea Seyboldt, Christoph Weber and Tony Hyman, developed their theory over the next three years, extending Oparin’s vision. “If you just think about droplets like Oparin did, then it’s not clear how evolution could act on these droplets,” Zwicker said. “For evolution, you have to make copies of yourself with slight modifications, and then natural selection decides how things get more complex.”

Globule Ancestor

Last spring, Jülicher began meeting with Dora Tang, head of a biology lab at the Max Planck Institute of Molecular Cell Biology and Genetics, to discuss plans to try to observe active-droplet division in action.

Tang’s lab synthesizes artificial cells made of polymers, lipids and proteins that resemble biochemical molecules. Over the next few months, she and her team will look for division of liquid droplets made of polymers that are physically similar to the proteins in P granules and centrosomes. The next step, which will be made in collaboration with Hyman’s lab, is to try to observe centrosomes or other biological droplets dividing, and to determine if they utilize the mechanism identified in the paper by Zwicker and colleagues. “That would be a big deal,” said Giomi, the Leiden biophysicist.

When Deamer, the membrane-first proponent, read the new paper, he recalled having once observed something like the predicted behavior in hydrocarbon droplets he had extracted from a meteorite. When he illuminated the droplets in near-ultraviolet light, they began moving and dividing. (He sent footage of the phenomenon to Jülicher.) Nonetheless, Deamer isn’t convinced of the effect’s significance. “There is no obvious way for the mechanism of division they reported to evolve into the complex process by which living cells actually divide,” he said.

Other researchers disagree, including Tang. She says that once droplets started to divide, they could easily have gained the ability to transfer genetic information, essentially divvying up a batch of protein-coding RNA or DNA into equal parcels for their daughter cells. If this genetic material coded for useful proteins that increased the rate of droplet division, natural selection would favor the behavior. Protocells, fueled by sunlight and the law of increasing entropy, would gradually have grown more complex.

Jülicher and colleagues argue that somewhere along the way, protocell droplets could have acquired membranes. Droplets naturally collect crusts of lipids that prefer to lie at the interface between the droplets and the surrounding liquid. Somehow, genes might have started coding for these membranes as a kind of protection. When this idea was put to Deamer, he said, “I can go along with that,” noting that he would define protocells as the first droplets that had membranes.

The primordial plotline hinges, of course, on the outcome of future experiments, which will determine how robust and relevant the predicted droplet division mechanism really is. Can chemicals be found with the right two states, A and B, to bear out the theory? If so, then a viable path from nonlife to life starts to come into focus.

The luckiest part of the whole process, in Jülicher’s opinion, was not that droplets turned into cells, but that the first droplet — our globule ancestor — formed to begin with. Droplets require a lot of chemical material to spontaneously arise or “nucleate,” and it’s unclear how so many of the right complex macromolecules could have accumulated in the primordial soup to make it happen. But then again, Jülicher said, there was a lot of soup, and it was stewing for eons.

“It’s a very rare event. You have to wait a long time for it to happen,” he said. “And once it happens, then the next things happen more easily, and more systematically.”

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Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.