The physics of fat droplets reveal DNA danger

Fat is a normal and necessary part of the body. Fat cells store and release energy, as well as play significant roles in hormonal regulation and immunity.

In recent decades, a concerning rise in metabolic illnesses -- such as cardiovascular disease, high blood pressure and diabetes -- has focused scientific attention on the biology and chemistry of fat, resulting in a wealth of information about how fat cells work.

But fat cells and their metabolic activities are only part of the story.

Fat-filled lipid droplets, tiny spheres of fat many times smaller than fat cells, are a growing subject of scientific interest. Found inside many different cell types, these lipid particles have long been little understood. Studies have begun to illuminate these droplets' participation in metabolic functions and cellular protection, but we still know next to nothing about the physical nature of fat.

Now, researchers at the University of Pennsylvania School of Engineering and Applied Science have looked beyond biochemistry to publish groundbreaking work on the physics of these droplets, revealing them to be a potential threat to a cell's nucleus. In the August issue of the Journal of Cell Biology, they are the first to discover fat-filled lipid droplets' surprising capability to indent and puncture the nucleus, the organelle which contains and regulates a cell's DNA.

The stakes of their findings are high: a ruptured nucleus can lead to elevated DNA damage that is characteristic of many diseases, including cancer.

The study was led by Dennis E. Discher, Robert D. Bent Professor in the Department of Chemical and Biomolecular Engineering, Irena Ivanovska, Ph.D. Research Associate in Penn's Molecular and Cell Biophysics Lab, and Michael Tobin, Ph.D. Candidate in the Department of Bioengineering.

"Intuitively, people think of fat as soft," says Discher. "And on a cellular level it is. But at this small size of droplet -- measuring just a few microns rather than the hundreds of microns of a mature fat cell -- it stops being soft. Its shape has a much higher curvature, bending other objects very sharply. This changes its physics in the cell. It can deform. It can damage. It can rupture."

"Imagine," adds Ivanovska, "trying to pop a balloon with your fist. Impossible. You can deform the balloon, but you won't puncture it. Now imagine trying to pop it with a pen. That's the difference between a fat cell and a cell with small fat droplets in the body. It's a fundamental physical difference, not a metabolic one."

The team's research reframes scientific inquiry into fat, underlining that fat's role in the body is much more than just a number on the scales.

"This isn't fat canonically conceived," says Tobin. "This is about how fat works at scales smaller than a cell and poses physical risks to cellular components, even at the level of DNA."

The team's work builds on a decade of foundational research, including leading contributions by Ivanovska, into the behaviors of nuclear proteins that give the nucleus its protective structural qualities. These proteins are dynamic, shifting levels to respond to their mechanical environments and provide what the nucleus needs to maintain its integrity.

"There's a constant process of repair to DNA damage that goes on in cells," says Ivanovska. "For this to happen, the nucleus needs to have enough DNA repair proteins. If a nucleus is ruptured, these proteins scatter and cannot repair damage in a timely manner. This causes DNA damage accumulation and can potentially result in a cancer cell."

A cell lives in a dynamic physical and mechanical environment where things can and do go wrong. But it also has an army of molecular helpers always working to maintain and repair it.

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Technology restores cell, organ function in pigs after death

Within minutes of the final heartbeat, a cascade of biochemical events triggered by a lack of blood flow, oxygen, and nutrients begins to destroy a body's cells and organs. But a team of Yale scientists has found that massive and permanent cellular failure doesn't have to happen so quickly.

Using a new technology they developed that delivers a specially designed cell-protective fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in pigs a full hour after their deaths, they report in the Aug. 3 edition of the journal Nature.

The findings may help extend the health of human organs during surgery and expand availability of donor organs, the authors said.

"All cells do not die immediately, there is a more protracted series of events," said David Andrijevic, associate research scientist in neuroscience at Yale School of Medicine and co-lead author of the study. "It is a process in which you can intervene, stop, and restore some cellular function."

The research builds upon an earlier Yale-led project that restored circulation and certain cellular functions in the brain of a dead pig with technology dubbed BrainEx. Published in 2019, that study and the new one were led by the lab of Yale's Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and professor of comparative medicine, genetics, and psychiatry.

"If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia [inadequate blood supply], we hypothesized that something similar could also be achieved in other vital transplantable organs," Sestan said.

In the new study -- which involved senior author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy, and Shupei Zhang, all from Yale -- the researchers applied a modified version of BrainEx called OrganEx to the whole pig. The technology consists of a perfusion device similar to heart-lung machines -- which do the work of the heart and lungs during surgery -- and an experimental fluid containing compounds that can promote cellular health and suppress inflammation throughout the pig's body. Cardiac arrest was induced in anesthetized pigs, which were treated with OrganEx an hour after death.

Six hours after treatment with OrganEx, the scientists found that certain key cellular functions were active in many areas of the pigs' bodies -- including in the heart, liver, and kidneys -- and that some organ function had been restored. For instance, they found evidence of electrical activity in the heart, which retained the ability to contract.

"We were also able to restore circulation throughout the body, which amazed us," Sestan said.

Normally when the heart stops beating, organs begin to swell, collapsing blood vessels and blocking circulation, he said. Yet circulation was restored and organs in the deceased pigs that received OrganEx treatment appeared functional at the level of cells and tissue.

"Under the microscope, it was difficult to tell the difference between a healthy organ and one which had been treated with OrganEx technology after death," Vrselja said.

As in the 2019 experiment, the researchers also found that cellular activity in some areas of the brain had been restored, though no organized electrical activity that would indicate consciousness was detected during any part of the experiment.

The team was especially surprised to observe involuntary and spontaneous muscular movements in the head and neck areas when they evaluated the treated animals, which remained anesthetized through the entire six-hour experiment. These movements indicate the preservation of some motor functions, Sestan said.

The researchers stressed that additional studies are necessary to understand the apparently restored motor functions in the animals, and that rigorous ethical review from other scientists and bioethicists is required.

The experimental protocols for the latest study were approved by Yale's Institutional Animal Care and Use Committee and guided by an external advisory and ethics committee.

The OrganEx technology could eventually have several potential applications, the authors said. For instance, it could extend the life of organs in human patients and expand the availability of donor organs for transplant. It might also be able to help treat organs or tissue damaged by ischemia during heart attacks or strokes.

"There are numerous potential applications of this exciting new technology," said Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. "However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain."

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New twist on an 80-year-old biochemical pathway

Every year, thousands of biochemistry majors and medical students around the world learn to memorize the major biochemical pathways that allow cells to function. How these 10 or so pathways are described in textbooks hasn't changed much since the early 20th century, when they were first discovered.

But with the resurgence of interest in cancer metabolism in the past decade, researchers are coming to realize that there is more to a cell's biochemistry than once thought.

The latest plot twist comes from a team of scientists at the Sloan Kettering Institute who report that they have discovered a previously unappreciated metabolic pathway -- an alternate version of the famous Krebs cycle, also known as the tricarboxylic acid (TCA) cycle.

The TCA or Krebs cycle -- named after Hans Krebs, the German-born biochemist who discovered it in 1937 -- is a central hub of cellular metabolism. It is a core part of the process by which cells "burn" sugars to make ATP, the cell's energy-carrying molecule. In its standard form, the cycle occurs entirely in a cell's mitochondria.

"We and other scientists have recognized for a while that there is variation in the degree to which cells use parts of the TCA cycle, suggesting that cells may have multiple ways to meet their fundamental metabolic needs," says Lydia Finley, a cell biologist in SKI who led the team. "Now, with this latest research, we can say there is a complete alternative to the canonical TCA cycle, and we explain how it works."

Implications for Understanding Cancer Cell Metabolism

Through several converging lines of evidence, Dr. Finley's team showed that an alternate version of the TCA cycle takes place partly in the mitochondria and partly in the cytosol. Rather than burning sugar for energy, this alternate version of the TCA cycle allows cells to use the carbons in sugar to build important molecules such as lipids for cell membranes.

Not only that, but a cell's use of one or the other version of the TCA cycle is associated with changes in its identity, the team showed.

These findings, which were reported on March 9, 2022, in Nature, have broad implications for understanding how cells adapt their metabolism to meet changing needs. They also may suggest additional avenues for cancer therapies geared at targeting a tumor's metabolism.

Putting Together the Puzzle Pieces

The new results came out of a productive collaboration in the Finley lab between Gerstner Sloan Kettering graduate student Paige Arnold and Tri-Institutional MD-PhD student Benjamin Jackson.

Arnold had been using carbon-tracing techniques to study the flow of carbons through the TCA cycle in different cell types. She had noticed, for example, that there seemed to be variation in the extent to which cells put their carbons into the TCA cycle versus skipping one part of it.

Around the same time, Jackson was using computational methods to analyze publicly available data from experiments in which the genome-editing tool CRISPR had been used to systematically knock out genes for various enzymes, one at a time, to see what effect this had on cells.

"You would hypothesize that if the TCA cycle were one functional module, then any one of those enzymes should have a relatively similar effect when you remove it," Dr. Finley points out. "What Ben noticed is that's not actually the case."

"The metabolic enzymes seemed to form two separate modules," Jackson says. "This backed up the anecdotal evidence that we were accumulating that there were different parts of the TCA cycle that cells could use or not use."

The CRISPR studies Jackson analyzed were performed in cancer cell lines -- in other words, cells that aren't "normal." Arnold wanted to know if normal also engage in this alternative or noncanonical cycle. The Finley lab often works with embryonic stem cells, so Arnold had easy access to these normal cells. Arnold traced the flow of carbons through them and found that they also engaged in the noncanonical TCA cycle.

Lessons From 80 Years Ago

These two sets of experiments seemed to confirm that there really was an alternate way to perform the TCA cycle, one that is not in textbooks. But why had Krebs missed it?

To try to answer that question, Arnold decided to review Krebs' original papers from the 1930s and 40s. She found, to her surprise, that Krebs had made his pivotal discoveries in one particular type of tissue: pigeon breast muscle.

"Nobody really talks about that," Arnold says. "But it made us wonder if maybe different cell types have distinct preferences for whether they use the traditional TCA cycle or this alternate version."

She decided to reconstruct Krebs' original experiments, only in a dish rather than in pigeon muscle. She used mouse stem-like muscle cells to grow a muscle fiber precursor called a myotube and then traced the carbons. When she did this, she saw something interesting: "When the cells were still in a more stem-like stage, they seemed to be doing a lot of this noncanonical TCA cycle, similar to embryonic stem cells and cancer cells," Arnold says. "But as soon as the cells had differentiated into myotubes, they immediately switched to the more traditional TCA cycle. This is in keeping with what Krebs saw in pigeon muscle tissue."

To the team, this result suggested a clear link between changes in cell identity and usage of particular biochemical pathways. To test whether the changes in cell fate required use of the different pathways, the team performed additional experiments in which they chemically or genetically blocked certain enzymes in the cycles and asked whether the cells could still change their fate. They could not. This finding implied that changes in cell fate required different biochemical pathways.

To Burn or To Build

Why would a cell opt for a different form of the TCA cycle at all? According to Dr. Finley, the Krebs cycle is really good at maximizing ATP production. It helps cells combust all their nutrients down to carbon dioxide.

"That's great if what you really care about is making ATP," Dr. Finley says. "But if you want to grow, ATP is actually not the limiting reagent. You actually need to retain those carbons to make new biomass. That's what the noncanonical TCA cycle does: It allows you to take carbons from glucose and export them to the cytosol, where they can be used to build other molecules. So, instead of burning the carbon, you get to keep it."

This growth-oriented cycle may have particular relevance to cancer, whose signature characteristic is unlimited growth.

Dr. Finley cautions that their laboratory experiments were all done in a dish rather than in animals. The team is keenly interested in understanding whether and when it occurs in vivo, both in normal animals and in tumors.

"That will help us know whether it might be a good cancer drug target," Dr. Finley says.

An Unexpected Opportunity due to the COVID Pandemic

Dr. Finley thinks that the more researchers begin to look for alternative biochemical pathways, the more they might find. In some ways, their discovery of a noncanonical TCA cycle was facilitated by unplanned downtime in the lab, owing to the COVID-19 pandemic.

As Jackson explains: "I was at home, and we could not come into the lab because of the pandemic. So it became a very fortuitous time to work on this project, to work out all the bugs of the code."

For Arnold, too, the pandemic-related downtime provided a chance to really delve into the historical literature and mull over other labs' data in which she thought she could see evidence of this other cycle operating.

"In the end, the computational work that I did and the model Paige was building came together, and it became a really satisfying collaboration," Jackson says.

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Scaling laws in enzymes may help predict life ‘as we don’t know it'

The only references we have for "life" are the forms we know on Earth. Astrobiologists suspect that the search for alien life, and even for the origins of life on Earth, may require a broader scope. A NASA-funded team of researchers is developing tools to predict the features of life as we don't know it. In a new study published in the Proceedings of the National Academy of Sciences, the team identifies universal patterns in the chemistry of life that do not appear to depend on specific molecules.

"We want to have new tools for identifying and even predicting features of life as we don't know it," says Santa Fe Institute External Professor Sara Imari Walker (Arizona State University), a co-author on the paper. "To do so, we are aiming to identify the universal laws that should apply to any biochemical system. This includes developing quantitative theory for the origins of life, and using theory and statistics to guide our search for life on other planets."

On Earth, life emerges from the interplay of hundreds of chemical compounds and reactions. Some of these compounds and reactions are found universally across Earth's organisms. Using the Integrated Microbial Genomes and Microbiomes database, the team investigated the enzymes -- the functional drivers of biochemistry -- found in bacteria, archaea, and eukarya to reveal a new kind of biochemical universality.

Enzymes can be categorized into a taxonomy of broad functional classes -- groups designated by what they do, from using water molecules to break chemical bonds (hydrolases) to rearranging molecular structures (isomerases) to joining large molecules together (ligases). The team compared how the abundance of enzymes in each of these functional categories changed in relation to the overall abundance of enzymes in an organism. They discovered various scaling laws -- almost algorithmic relationships -- between the number of enzymes in different enzyme classes and the size of an organism's genome. They also found that these laws don't depend on the particularenzymes in those classes.

"Here we find that you get these scaling relationships without needing to conserve exact membership. You need a certain number of transferases, but not particular transferases," says SFI Professor Chris Kempes, a co-author on the paper. "There are a lot 'synonyms,' and those synonyms scale in systematic ways."

On Earth, organisms use DNA and, through RNA, create proteins. But will the macromolecules of DNA, RNA, and proteins help us identify life across the universe, understand the origins of life on Earth, or develop synthetic biology? "As a team, we think that's not likely," says Kempes. The functions those macromolecules serve, however, and the metabolic scaling relationships observed in organic, Earth-based life, just might be. "Even if life elsewhere used really different molecules, these sort of functional categories and scaling laws might be conserved throughout the universe," says Kempes.

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How fish get their shape

The diverse colours, shapes and patterns of fish are captivating. Despite such diversity, a general feature that we can observe in fish such as salmon or tuna once they are served in a dish like sushi, is the distinct 'V' patterns in their meat. While this appears to be genetically observed in the muscle arrangement of most fish species, how such a generic 'V' pattern arises is puzzling.

A team of researchers from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) investigated the science behind the formation of the 'V' patterns -- also known as chevron patterns -- in the swimming muscles of fish. The study focused on the myotome (a group of muscles served by a spinal nerve root) that makes up most of the fish body. These fish muscles power the fish's side-to-side swimming motion and the chevron pattern is thought to increase swimming efficiency. The research team found that these patterns do not simply arise from genetic instruction or biochemical pathways but actually require physical forces to correctly develop. The findings of the study were published in the journal Proceedings of the National Academy of Sciences of the United States of America on 26 November 2019.

Friction and stress combine to shape patterns in fish muscle

The chevron pattern is not unique to salmon and tuna; it is also present in other fish species such as the zebrafish, as well as in some amphibian species like salamanders and frogs during development. The 'V' shape first appears in the somites -- the precursor building blocks of the myotome, which forms the skeletal muscles. The somites typically form during the first few days of fish development or morphogenesis.

A team of scientists led by MBI Postdoctoral Fellow Dr Sham Tlili and Principal Investigator Assistant Professor Timothy Saunders studied chevron formation in the myotome of zebrafish embryos. Initially, each future developing myotome segment is cuboidal in shape. However, over the course of five hours, it deforms into a pointed 'V' shape. To find out how this deformation actually takes place, the team adopted a combination of different techniques -- imaging of the developing zebrafish myotome at single cell resolution; quantitative analysis of the imaging data; and fitting the quantitative data into biophysical models.

Based on findings from their experimental as well as theoretical studies, the MBI scientists identified certain physical mechanisms that they thought might be guiding chevron formation during fish development.

Firstly, the developing myotomes are physically connected to other embryonic tissues such as the neural tube, notochord, skin and ventral tissues. The strength of their connection to these different tissues varies at different time points of myotome formation, and accordingly, different amounts of friction are generated across the tissue. Effectively, the side regions of the developing myotome are under greater friction than the central region. As new segments push the myotome forward, this leads to the formation of a shallow 'U' shape in the myotome tissue.

Secondly, cells within the future myotome begin to elongate as they form muscle fibres. The research team revealed that this transformation process generates an active, non-uniform force along certain directions within the somite tissue, which results in the 'U' shape sharpening into the characteristic 'V'-shaped chevron. Lastly, orientated cell rearrangements within the future myotome help to stabilise the newly acquired chevron shape.

Deciphering the patterns guiding organ formation

Asst Prof Saunders, a theoretical physicist who applies physical principles to characterise biological processes that take place during development, said, "This work reveals how a carefully balanced interplay between cell morphology and mechanical interactions can drive the emergence of complex shapes during development. We are excited to see if the principles we have revealed are also acting in the shaping of other organs."

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New fallout from 'the collision that changed the world'

Neither the continents nor the oceans have always looked the way they do now. These 'paleomaps' show how the continents and oceans appeared before (top) and during (bottom) 'the collision that changed the world,' when the landmass that is now the Indian subcontinent rammed northward into Asia, closing the Tethys Sea and building the Himalayas. Global ocean levels were higher then, creating salty shallow seas (pale blue) that covered much of North Africa and parts of each of the continents. A team of Princeton researchers, using samples gathered at the three starred locations, created an unprecedented record of ocean nitrogen and oxygen levels from 70 million years ago through 30 million years ago that shows a major shift in ocean chemistry after the India-Asia collision. Another shift came 35 million years ago, when Antarctica began accumulating ice and global sea levels fell.

When the landmass that is now the Indian subcontinent slammed into Asia about 50 million years ago, the collision changed the configuration of the continents, the landscape, global climate and more. Now a team of Princeton University scientists has identified one more effect: the oxygen in the world's oceans increased, altering the conditions for life.

"These results are different from anything people have previously seen," said Emma Kast, a graduate student in geosciences and the lead author on a paper coming out in Science on April 26. "The magnitude of the reconstructed change took us by surprise."

Kast used microscopic seashells to create a record of ocean nitrogen over a period from 70 million years ago -- shortly before the extinction of the dinosaurs -- until 30 million years ago. This record is an enormous contribution to the field of global climate studies, said John Higgins, an associate professor of geosciences at Princeton and a co-author on the paper.

"In our field, there are records that you look at as fundamental, that need to be explained by any sort of hypothesis that wants to make biogeochemical connections," Higgins said. "Those are few and far between, in part because it's very hard to create records that go far back in time. Fifty-million-year-old rocks don't willingly give up their secrets. I would certainly consider Emma's record to be one of those fundamental records. From now on, people who want to engage with how the Earth has changed over the last 70 million years will have to engage with Emma's data."

In addition to being the most abundant gas in the atmosphere, nitrogen is key to all life on Earth. "I study nitrogen so that I can study the global environment," said Daniel Sigman, Princeton's Dusenbury Professor of Geological and Geophysical Sciences and the senior author on the paper. Sigman initiated this project with Higgins and then-Princeton postdoctoral researcher Daniel Stolper, who is now an assistant professor of Earth and planetary science at the University of California-Berkeley.

Every organism on Earth requires "fixed" nitrogen -- sometimes called "biologically available nitrogen." Nitrogen makes up 78% of our planet's atmosphere, but few organisms can "fix" it by converting the gas into a biologically useful form. In the oceans, cyanobacteria in surface waters fix nitrogen for all other ocean life. As the cyanobacteria and other creatures die and sink downward, they decompose.

Nitrogen has two stable isotopes, 15N and 14N. In oxygen-poor waters, decomposition uses up "fixed" nitrogen. This occurs with a slight preference for the lighter nitrogen isotope, 14N, so the ocean's 15N-to-14N ratio reflects its oxygen levels.

That ratio is incorporated into tiny sea creatures called foraminifera during their lives, and then preserved in their shells when they die. By analyzing their fossils -- collected by the Ocean Drilling Program from the North Atlantic, North Pacific, and South Atlantic -- Kast and her colleagues were able to reconstruct the 15N-to-14N ratio of the ancient ocean, and therefore identify past changes in oxygen levels.

Oxygen controls the distribution of marine organisms, with oxygen-poor waters being bad for most ocean life. Many past climate warming events caused decreases in ocean oxygen that limited the habitats of sea creatures, from microscopic plankton to the fish and whales that feed on them. Scientists trying to predict the impact of current and future global warming have warned that low levels of ocean oxygen could decimate marine ecosystems, including important fish populations.

When the researchers assembled their unprecedented geologic record of ocean nitrogen, they found that in the 10 million years after dinosaurs went extinct, the 15N-to-14N ratio was high, suggesting that ocean oxygen levels were low. They first thought that the warm climate of the time was responsible, as oxygen is less soluble in warmer water. But the timing told another story: the change to higher ocean oxygen occurred around 55 million years ago, during a time of continuously warm climate.

"Contrary to our first expectations, global climate was not the primary cause of this change in ocean oxygen and nitrogen cycling," Kast said. The more likely culprit? Plate tectonics. The collision of India with Asia -- dubbed "the collision that changed the world" by legendary geoscientist Wally Broecker, a founder of modern climate research -- closed off an ancient sea called the Tethys, disturbing the continental shelves and their connections with the open ocean.

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Potential 'missing link' in chemistry that led to life on Earth discovered

This study is part of an ongoing effort by scientists around the world to find plausible routes for the epic journey from pre-biological chemistry to cell-based biochemistry.

Chemists at The Scripps Research Institute (TSRI) have found a compound that may have been a crucial factor in the origins of life on Earth.

Origins-of-life researchers have hypothesized that a chemical reaction called phosphorylation may have been crucial for the assembly of three key ingredients in early life forms: short strands of nucleotides to store genetic information, short chains of amino acids (peptides) to do the main work of cells, and lipids to form encapsulating structures such as cell walls. Yet, no one has ever found a phosphorylating agent that was plausibly present on early Earth and could have produced these three classes of molecules side-by-side under the same realistic conditions.

TSRI chemists have now identified just such a compound: diamidophosphate (DAP).

"We suggest a phosphorylation chemistry that could have given rise, all in the same place, to oligonucleotides, oligopeptides, and the cell-like structures to enclose them," said study senior author Ramanarayanan Krishnamurthy, associate professor of chemistry at TSRI. "That in turn would have allowed other chemistries that were not possible before, potentially leading to the first simple, cell-based living entities."

The study, reported in Nature Chemistry, is part of an ongoing effort by scientists around the world to find plausible routes for the epic journey from pre-biological chemistry to cell-based biochemistry.

Other researchers have described chemical reactions that might have enabled the phosphorylation of pre-biological molecules on the early Earth. But these scenarios have involved different phosphorylating agents for different types of molecule, as well as different and often uncommon reaction environments.

"It has been hard to imagine how these very different processes could have combined in the same place to yield the first primitive life forms," said Krishnamurthy.

He and his team, including co-first authors Clémentine Gibard, Subhendu Bhowmik, and Megha Karki, all postdoctoral research associates at TSRI, showed first that DAP could phosphorylate each of the four nucleoside building blocks of RNA in water or a paste-like state under a wide range of temperatures and other conditions.

With the addition of the catalyst imidazole, a simple organic compound that was itself plausibly present on the early Earth, DAP's activity also led to the appearance of short, RNA-like chains of these phosphorylated building blocks.

Moreover, DAP with water and imidazole efficiently phosphorylated the lipid building blocks glycerol and fatty acids, leading to the self-assembly of small phospho-lipid capsules called vesicles -- primitive versions of cells.

DAP in water at room temperature also phosphorylated the amino acids glycine, aspartic acid and glutamic acid, and then helped link these molecules into short peptide chains (peptides are smaller versions of proteins).

"With DAP and water and these mild conditions, you can get these three important classes of pre-biological molecules to come together and be transformed, creating the opportunity for them to interact together," Krishnamurthy said.

Krishnamurthy and his colleagues have shown previously that DAP can efficiently phosphorylate a variety of simple sugars and thus help construct phosphorus-containing carbohydrates that would have been involved in early life forms. Their new work suggests that DAP could have had a much more central role in the origins of life.

"It reminds me of the Fairy Godmother in Cinderella, who waves a wand and 'poof,' 'poof,' 'poof,' everything simple is transformed into something more complex and interesting," Krishnamurthy said.

DAP's importance in kick-starting life on Earth could be hard to prove several billion years after the fact. Krishnamurthy noted, though, that key aspects of the molecule's chemistry are still found in modern biology.

"DAP phosphorylates via the same phosphorus-nitrogen bond breakage and under the same conditions as protein kinases, which are ubiquitous in present-day life forms," he said. "DAP's phosphorylation chemistry also closely resembles what is seen in the reactions at the heart of every cell's metabolic cycle."

Krishnamurthy now plans to follow these leads, and he has also teamed with early-Earth geochemists to try to identify potential sources of DAP, or similarly acting phosphorus-nitrogen compounds, that were on the planet before life arose.

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