Korea Basic Science Institute

Cryptocurrency is usually 'mined' through the blockchain by asking a computer to perform a complicated mathematical problem in exchange for tokens of cryptocurrency. But now a team of chemists have repurposed this process, asking computers to instead generate the largest network ever created of chemical reactions which may have given rise to prebiotic molecules on early Earth. Cryptocurrency is usually "mined" through the blockchain by asking a computer to perform a complicated mathematical problem in exchange for tokens of cryptocurrency. But in research appearing in the journal Chem on January 24, a team of chemists have repurposed this process, asking computers to instead generate the largest network ever created of chemical reactions which may have given rise to prebiotic molecules on early Earth. This work indicates that at least some primitive forms of metabolism might have emerged without the involvement of enzymes, and it shows the potential to use blockchain to solve problems outside the financial sector that would otherwise require the use of expensive, hard to access supercomputers. "At this point we can say we exhaustively looked for every possible combination of chemical reactivity that scientists believe to had been operative on primitive Earth," says senior author Bartosz A. Grzybowski of the Korea Institute for Basic Science and the Polish Academy of Sciences. To generate this network, the researchers chose a set of starting molecules likely present on early Earth, including water, methane, and ammonia, and set rules about which reactions could occur between different types of molecules. They then translated this information into a language understandable by computers and used the blockchain to calculate which reactions would occur over multiple expansions of a giant reaction network. "The computer takes the primordial molecules and the accepted prebiotic chemistries. We coded it into the machine, and then we released it onto the world," says Grzybowski. Grzybowski's team worked with chemists and computer-specialists at Allchemy, a company that uses AI for chemical synthesis planning, to generate the network using Golem, a platform that orchestrates portions of the calculations over hundreds of computers across the world, which receive cryptocurrency in exchange for computing time. The resulting network, termed NOEL for the Network of Early Life, started off with over 11 billion reactions, which the team narrowed down to 4.9 billion plausible reactions. NOEL contains parts of well-known metabolic pathways like glycolysis, close mimics of the Krebs cycle, which organisms use to generate energy, and syntheses of 128 simple biotic molecules like sugars and amino acids. Curiously, of the 4.9 billion reactions generated, only hundreds of reaction cycles could be called "self-replicating," which means that the molecules produce additional copies of themselves. Self-replication has been postulated to be central to the emergence of life, but the vast majority of its known manifestations require complex macromolecules like enzymes. "Our results mean that with only small molecules present, self-amplification is a rare event. I don't think that this type of self-replication was operative on primitive earth, before larger molecular structures were somehow formed," says Grzybowski. "We see emergence of primitive metabolism, but we don't see self-replication, so maybe self-replication appeared later in evolution." "If you asked me two years ago, I'd be thinking we'd need years for this type of work," says Grzybowski. "But for a fraction of the cost, in two or three months, we finished a task of 10 billion reactions, 100k times bigger than we did previously." This work not only advances what we know about early prebiotic chemistry, but it also demonstrates how science can be made more accessible to researchers at smaller universities and institutions. "Our system of education is based on elite universities mostly in the western world. It's very hard for the developing world to even compete with these universities because they don't have access to supercomputers," says Grzybowski. "But if you can distribute computing in this way for a fraction of the cost, you can give other people opportunities to play." While the network generated in this work was performed on hundreds of computers around the world, Grzybowski suggests that this method can be used at institutions without having to pay out cryptocurrency tokens to the computers performing the calculations. "With a platform like Golem you can connect your institution's network and harness the entire idle power of its computers to perform calculations," says Grzybowski. "You could create this computing infrastructure without any capital expenditure." Grzybowski hopes that repurposing the blockchain in this way can revolutionize the way we perform large scale calculations across the world and change how we see the value of cryptocurrency. "I hope people in computer science can figure out how can we tokenize cryptocurrencies in some way that can benefit global science," says Grzybowski. "Maybe society could be happier about using cryptocurrencies, if you could tell people that in the process we could discover new laws of biology or some new cancer drug," says Grzybowski.

Aptamers, nucleic acids capable of selectively binding to viruses, proteins, ions, small molecules, and various other targets, are garnering attention in drug development as potential antibody substitutes for their thermal and chemical stability as well as ability to inhibit specific enzymes or target proteins through three-dimensional binding. They also hold promise for swift diagnoses of colon cancer and other challenging diseases by targeting elusive biomarkers. Despite their utility, these aptamers are susceptible to easy degradation by multiple enzymes, presenting a significant challenge. Aptamers, nucleic acids1 capable of selectively binding to viruses, proteins, ions, small molecules, and various other targets, are garnering attention in drug development as potential antibody substitutes for their thermal and chemical stability as well as ability to inhibit specific enzymes or target proteins through three-dimensional binding. They also hold promise for swift diagnoses of colon cancer and other challenging diseases by targeting elusive biomarkers.2 Despite their utility, these aptamers are susceptible to easy degradation by multiple enzymes, presenting a significant challenge. Professor Seung Soo Oh and his team from the Department of Materials Science and Engineering at Pohang University of Science and Technology (POSTECH), including Dr. Byunghwa Kang, and Dr. Soyeon V Park, have introduced a breakthrough approach using ionic liquids to address the challenges in functional nucleic acid research, paving the way for diverse applied research. Their findings have been published in Nucleic Acids Research. Functional nucleic acids are termed as such for their versatility in not only storing and transmitting genetic information in living organisms but also in performing varied functions, such as detecting target molecules or catalyzing biochemical reactions similar to aptamers. However, these nucleic acids face obstacles in research applications due to vulnerability to degradation by hydrolases.3 Conventional preservation methods such as ultra-low-temperature cryogenic storage or chemical modification of nucleic acids fail to inhibit a wide array of enzymes, resulting in significant impairment of the nucleic acids' useful functions. The team shifted away from the conventional belief that "water is essential." Although nucleic acids serve various roles and exhibit multiple functions in water, enzymes that break them down remain active in this medium. Hence, water acts as both the "home" and the "graveyard" for nucleic acids. The research team marked a significant milestone by globally validating the capability of nucleic acids to retain multiple functions in a choline dihydrogen phosphate-based ionic liquid. This ionic liquid, also present in our bodies, exhibits exceptional biocompatibility. The choline cation within the liquid effectively shields the negative charge of nucleic acids, preventing their contact with water and thereby fundamentally impeding hydrolysis. In experiments, this liquid created an environment where nucleic acids resisted degradation regardless of the enzyme type, extending their half-life up to 6.5 million times. Even in extreme environments with a mix of seven different hydrolases, the nucleic acids remained completely intact and functional. Furthermore, the team applied this innovation to enable aptamer-based biomolecular diagnostics within biological solutions for the first time. Previously, saliva containing numerous nucleic acid hydrolases made it impossible to use functional nucleic acids for biomarker detection. However, the team shielded the aptamers with an ionic liquid added to the saliva sample to achieve simple molecular diagnostics. Professor Seung Soo Oh emphasized, "By demonstrating that nucleic acids can maintain functionality even in unexplored or contaminated samples and body fluids, we've demonstrated their limitless application potential." Dr. Byunghwa Kang expressed hope, stating, "This research will significantly benefit the application of not only nucleic acids but also other molecules susceptible to hydrolysis." This research was conducted with support from various institutions, including grants from the National Research Foundation of Korea funded by the Ministry of Science and ICT, the Korea Evaluation Institute of Industrial Technology, the Institute of Civil Military Technology Cooperation funded by the Defense Acquisition Program Administration and the Ministry of Trade, Industry & Energy, the Korea Basic Science Institute, and the Brain Korea 21 FOUR project. 1. Nucleic acids Polymers composed of units called nucleotides. These are two types: DNA and RNA. 2. Biomarker An indicator that can objectively measure the normal or pathological state of an organism, the degree of response to a drug, etc., using proteins, DNA, RNA, metabolites, etc. 3. Hydrolase An enzyme that catalyzes a reaction that breaks down chemical bonds using water

A research team has identified a novel target responsible for aging-related chronic metabolic disorders. Korean researchers have unveiled a novel signaling pathway that fosters aging-related chronic metabolic disorders. A research team led by Professor Jong Kyoung Kim from the Department of Life Sciences at POSTECH along with Professor Seung-Hoi Koo from the Division of Life Sciences at Korea University and principal researcher Geum-Sook Hwang from Korea Basic Science Institute (KBSI) announced the discovery of a new mechanism where BCAA metabolic pathway becomes impaired due to aging, resulting in dysfunctions of adipose cells and chronic metabolic disorders. The research findings were published in Nature Aging (IF=16.6) on July 24. Adipocytes play a crucial role in controlling energy metabolic homeostasis. These cells along with preadipocyte cells and various immune cells comprising adipose tissues undergo cellular senescence. The release of the senescence associated secretory phenotype (SASP) from these cells accelerates aging and diminishes the functions of adipose tissues. Consequently, fat accumulation occurs in liver and muscle cells, leading to the onset of metabolic disorders and ultimately reducing health span. In their earlier research published in Nature Communications, the research team led by Professor Seung-Hoi Koo uncovered that over-activation of CRTC2 induces insulin resistance, fatty liver, and obesity. However, until now, no research findings explored the impact of CRTC2 in adipocytes on aging and its related disorders. This recent research marks the first confirmation that an increase in adipose CRTC2 due to aging accelerates cellular senescence, leading to a loss of adipocyte functions and aging-related chronic metabolic disorders. CRTC2 reduces the expression of PPAR gamma in adipocytes and impairs catabolism of branched-chain amino acid (BCAA). Consequently, the mechanistic target of rapamycin complex (mTORC1) becomes activated, as revealed by the composite analysis of metabolome-transcriptome. Increased mTORC1 activation triggers cellular senescence and controls mitochondrial hemostasis, thereby accelerating aging. The analysis of single-cell transcriptome data showed that aged mice's adipocytes had increased SASP, particularly IL-1beta and TNF-alpha. This leads to adipose tissue remodeling by inhibiting preadipocyte cell differentiation potency and immunocyte regulations. Notably, mice with CRTC2 removed from their adipocytes displayed limited activation of BCAA-mTORC1 axis, ultimately inhibiting the development of chronic metabolic disorders associated with aging. This suggests that aging can be mitigated by controlling CRTC2 or BCAA catabolism. On the significance of the study, Professor Seung-Hoi Koo explained, "This study employed the latest convergent omics technology to unveil, for the first time, that an increase of CRTC2 in adipocytes due to aging leads to impaired BCAA catabolism, which is the primary cause of cell aging and metabolic disorders. Consequently, selective inhibition of CRTC2 or activation of PPAR gamma in adipocytes may hold the potential to inhibit aging and extend health span." The study was conducted with the support from the Korea Mouse Phenotyping Center Project and the Mid-Career Researcher Project of the National Research Foundation of Korea under the Ministry of Science and ICT, and the Project for Advanced Equipment-based Multi-omics Big Data Convergence Platform Establishment of the National Research Council of Science and Technology and the Project for Establishment of Bio-research Resources Usage Foundation.