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Scientific background: discoveries concerning nucleoside base modifications that enabled the development of effective mrna vaccines against covid-19 (pdf), scientific background, discoveries concerning nucleoside base modifications that enabled the development of effective mrna vaccines against covid-19.

When SARS-CoV-2 emerged in late 2019 and rapidly spread to all parts of the world, few thought that vaccines could be developed in time to help curb the increasing global disease burden. Yet, several vaccines were approved in record time, with two of the fastest approved and most effective vaccines produced with the new mRNA technology. The concept of using mRNA for vaccination and in vivo delivery of therapeutic proteins was first proposed over 30 years ago, but several hurdles had to be overcome to make this a clinical reality. Early experiments demonstrated that in vitro transcribed mRNA stimulates undesired inflammatory responses and inefficient protein production in cells and tissues. A turning point was the discovery by Karikó and Weissman demonstrating that mRNA produced with modified nucleoside bases evades innate immune recognition and improves protein expression. These findings, combined with the development of efficient systems for in vivo mRNA delivery, stabilization of the SARS-CoV-2 spike antigen, and unparalleled investments by industry and governments, led to the approval of two highly successful mRNA-based COVID-19 vaccines in late 2020. The discovery by Karikó and Weissman was critical for making the mRNA vaccine platform suitable for clinical use at a time when it was most needed, making this an extraordinary contribution to medicine and paving the way for future mRNA applications.form suitable for clinical use at a time when it was most needed, making this an extraordinary contribution to medicine and paving the way for future mRNA applications.

In today’s globally interconnected society the risk of new pandemics is greater than ever before. Pandemics are usually caused by zoonotic viruses that cross the species barrier into humans and spread through droplet- or aerosol-mediated transmission, causing airway infections. Developing and deploying vaccines rapidly enough to mitigate an ongoing pandemic is an enormous challenge that had never been met before the COVID-19 pandemic. The rapid sharing of the SARS-CoV-2 genome sequence, along with extensive prior developments in molecular bio-logy, vaccine research, and drug delivery over the past several decades spurred unprecedented activity among vaccine researchers during 2020. Scientists in academia and industry launched projects in record time, with financial and logistical backing from governments, industry, and non-profit organizations. The new mRNA vaccine platform represented one of the most interesting options, but how well it would work against this new virus was unknown. No mRNA-based vaccine had been approved for human use before.

Virus vaccine platforms prior to COVID-19

Most licensed anti-viral vaccines available today are produced with traditional techniques based on weakened or inactivated whole viruses ( Figure 1 ). Live attenuated virus vaccines, such as the combined rubella-mumps-measles vaccine and the yellow fever virus vaccine, induce robust and long-lived antibody and T cell-mediated immunity. For the development of the yellow fever virus vaccine, Max Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951. Vaccines based on inactivated viruses, such as the tick-borne encephalitis vaccine and the hepatitis A vaccine, induce effective but more transient immune responses, requiring repeated boosting. With the revolution of molecular biology and the development of technologies for recombinant protein production, opportunities for more targeted vaccine approaches arose. The first vaccine produced using this approach was the hepatitis B vaccine (HBV), approved in 1986, which was followed by the approval of the first human papillomavirus (HPV) vaccine in 2006. The HBV and HPV vaccines contain single protein components of the respective virus and are referred to as subunit vaccines. These vaccines protect against virus-induced cancers and are life-saving success stories [1]. Developments in molecular biology also allowed the engineering of carrier viruses encoding heterologous antigens of interest. Such viral vectors efficiently enter cells where the encoded antigens are produced by the endogenous protein synthesis machinery. The first example of a licensed viral vector vaccine was the Vesicular stomatitis virus-based vaccine against Ebola, approved in 2019, which was soon followed by an adenovirus-based Ebola vaccine [2].

Both traditional whole virus-based vaccines and viral vector-based vaccines require cell culture-based manufacturing facilities. Vaccine researchers have therefore long been interested in the development of subunit vaccines that circumvent the need for large scale cell cultures by delivering nucleic acid (DNA or mRNA) directly to vaccine recipients, exploiting the body’s own capacity to produce proteins. There was a strong sentiment that the availability of such platforms would not only increase the world’s capacity to make vaccines, but also facilitate more rapid and less costly vaccine production in response to pandemics.

Early work on nucleic acid- and viral vector-based vaccines

The first demonstrations that nucleic acid-based immunizations could work date back to the early 1990´s when DNA vaccines [3] and mRNA vaccines [4] were first tested in mice. There were several potential advantages with these approaches. Not only are nucleic acid-based vaccines easy to manufacture; they are also flexible since the sequence can be easily changed to encode different antigens. Together with the ease of production, this makes iterative testing of new candidate vaccines and the generation of updated vaccines rapid and efficient. A biological advantage is that in addition to antibody and major histocompatibility complex (MHC) class II-restricted CD4+ T cell responses, which are also induced by other vaccine types, viral vector- and nucleic acid-based vaccines have the potential to stimulate cytotoxic CD8+ T cell responses since they allow presentation of endogenously produced antigenic peptides on MHC class I molecules. Induction of CD8+ T cells is particularly interesting in the context of cancer vaccines where the aim is to kill targeted tumor cells, and also for anti-viral vaccines aimed to eliminate infected cells. However, despite the potential advantages of nucleic acid-based vaccines, whether they would be well-tolerated and stimulate sufficiently robust immune response in humans to represent a viable path forward for clinical vaccine development was unclear.

Initially, DNA vaccines were considered more promising than mRNA vaccines since DNA is more stable. However, progress was slow and early encouraging results with DNA vaccines in small animals did not translate to humans [5]. A likely reason is that injected DNA must cross two barriers, the plasma membrane and the nuclear membrane, to reach the cellular compartment where transcription takes place (DNA conversion to mRNA). In contrast, mRNA-based vaccines only need to gain access the cell cytoplasm where translation takes place (mRNA conversion to protein), making delivery easier. An additional advantage with mRNA vaccines is that the delivered nucleic acid cannot integrate into the host genome, adding an important safety aspect to this platform. Despite these advantages, skepticism about the usefulness of the approach remained high since mRNA was considered too unstable for medical applications.

Against this background, the vaccine field turned to the use of engineered viral vectors as these have their own intrinsic mechanisms to enter cells and deliver genetic cargo. Since the 1990s, many different types of viral vector-based vaccines against a variety of pathogens have been tested preclinically, demonstrating both promising results and setbacks [6]. A drawback of viral vector-based vaccines is that in addition to the desired responses elicited against the antigen of interest, antibodies against the structural proteins used to package the vector may be induced, compromising booster responses if the same vector is used again. Nevertheless, effective viral vector-based vaccines using different types of engineered adenoviruses were developed during the COVID-19 pandemic and administered at scale, demonstrating their usefulness, especially in the early phase of a pandemic [7, 8].

During the 1990s, a small community of investigators continued to explore the use of mRNA as a potential vaccine platform. Early studies had demonstrated that mRNA purified from cells was translated into protein when reintroduced into oocytes [9]. Delivery into tissue of a living organism was the next challenge. The first study to demonstrate that injection of naked mRNA into skeletal muscle resulted in protein production in vivo was published by Philip Felgner and colleagues in 1990 [10]. Soon thereafter, Martinon et al. demonstrated the induction of antigen-specific cytotoxic T lymphocyte responses in mice injected with liposome-formulated mRNA encoding the influenza virus nucleoprotein [4].

In parallel, several investigators developed alphavirus replicon vaccines, which have the added advantage that a higher copy number of antigen-encoding transcripts are produced in each cell, resulting in the induction of robust antigen-specific immune responses following in vivo delivery of naked mRNA [11, 12]. These early studies stimulated the field and led to the demonstration of promising results in animal models, but it would take more than two decades until the first mRNA-based vaccine against an infection was tested in human clinical trials.

The discovery of mRNA and systems for  in vitro  transcription

To explore the potential of mRNA-based applications, an efficient system for mRNA production and manipulation was needed. For this, the field relied on a series of fundamental research discoveries starting in the 1950s. After the landmark discoveries of DNA as the inherited genetic material, the search started for the intermediate molecule that was transcribed from nuclear DNA and transported to the ribosomes in the cytoplasm to specify protein synthesis. Experiments on cells infected with the T2 bacteriophage identified a metabolically active RNA fraction constituting approximately 1% of the total cellular RNA [13] that had proper base ratios [14]. This unstable form of RNA, or messenger RNA (mRNA), was proposed to be the missing intermediate carrier of information [15], and the hypothesis soon gained experimental support through pulse-labeling experiments in bacteria [16, 17]. Around the same time, insight into how cells produce RNA from DNA was gained through the discovery of RNA polymerase [18-20]. In the following decades, several RNA polymerases  were identified in bacteria and eukaryotic cells, including single-subunit RNA polymerases  from the T7 [21] and SP6 [22] bacteriophages.

Building on the discovery of the more versatile bacteriophage RNA polymerases , Paul Krieg and Douglas Melton demonstrated that synthetic mRNA could be produced in large quantities in vitro by using the SP6 RNA polymerase and cDNA clones containing the SP6 promoter [23, 24]. Furthermore, the in vitro produced SP6 mRNA was efficiently translated into protein when injected into frog oocytes [23]. Around this time, the T7 RNA polymerase  was cloned by William Studier’s lab [25] and developed into an efficient and inducible in vitro transcription system with a patent filed in 1984 [26]. The T7 RNA polymerase had several advantageous features, including highly specific binding to the T7 promoter (a conserved stretch of nucleotides -17 to +6 relative to the transcriptional start site) and an ability to transcribe RNA at a high speed. Similar efforts to harness the in vitro transcription capacity of T7 RNA polymerase were pursued [27]. The T7 in vitro transcription system became further optimized into a highly efficient cell-free system for large-scale production of any mRNA of interest, with major impact on science and biotechnology.

Delivering  in vitro  transcribed mRNA to cells and tissues

Another important research area focused on how to deliver nucleic acids into cells. An early strategy was to use liposomes, small cell-membrane-like vesicles composed of phospholipids and cholesterol. Already in 1978, researchers had described successful attempts at delivering purified globin mRNA into mouse lymphocytes and human epithelial cells using liposomes [28, 29] simply by trapping the mRNA inside the liposome vesicles. The field of nucleic acid de-livery improved thanks to the pioneering work by Philip Felgner while at Syntex Research. Felgner synthesized the first cationic lipid (DOTMA) and showed that it could form stable liposomes with nucleic acids [30]. The positively charged lipids improved both the entrapment of negatively charged nucleic acids (through electrostatic inter-actions) and fusion to the negatively charged cell membranes, resulting in improved delivery into cells. Cationic lipid-based liposomes (lipofectin) opened the door to the field of engineered DNA and RNA delivery into cells. Lipofectin was soon used to deliver in vitro transcribed mRNA into cultured cells to demonstrate protein production [31], encouraging future therapeutic applications. However, in vivo applications of lipofectin showed unwanted side effects and researchers continued the search for improved delivery systems.

A second major improvement was made in the lab of Pieter Cullis at the University of British Columbia with the development of ionizable cationic lipids. These lipids could be maintained in a positively charged or neutral form depending on the pH of the environment. Forming these lipid nano-particles (LNPs) at low pH had the benefits of cationic lipids in efficiently entrapping negatively charged mRNA within the vesicles. However, when delivered in vivo and exposed to physiological pH, the lipids lost their charge, which had several benefits including lower in vivo toxicity. The important discoveries by Cullis team spurred large industrial interest in the development of ionizable lipids. Notable, the delivery of nucleic acids was further optimized through the T-connector that could generate dense lipid nano-particles made of four components: an i) ionizable cationic lipid, ii) a helper lipid, iii) cholesterol and iv) polyethenylene glycol (PEG) [32]. More efficient ionizable cationic lipids were identified in large-scale screening programs in several biotech companies. Consequently, lipid nanoparticles now enable safe and efficient in vivo delivery of nucleic acids, including mRNA, into human cells. This advance is of great importance for clinical applications of nucleic acid-based technologies.

A vision to use mRNA for the delivery of therapeutic proteins

The potential of using the new molecular biology techniques to create mRNA-based vaccines or to treat human diseases by delivering mRNA to replace defective genes with functional ones, or by overexpressing a therapeutic protein, stimulated an enormous interest. In 1992, Jirikowski et al . used mRNA injection for in vivo expression of vasopressin to treat diabetes insipidus in a rodent model [33]. Around this time, a Hungarian research scientist at the University of Pennsylvania, Katalin Karikó, experimented with different forms of RNA with the ambition to optimize expression of therapeutic proteins. Karikó completed her PhD at the Biological Research Center in Szeged in 1982. Following post-doctoral work at the Hungarian Academy of Sciences and subsequent research positions at Temple University in Philadelphia and at the Uniformed Services University of the Health Sciences in Bethesda, she set up her own group at the Department of Neurosurgery at the University of Pennsylvania in 1997. Karikó had a strong drive to advance the mRNA platform and she systematically investigated different components of in vitro transcribed mRNA to identify requirements for optimal protein expression in cells and tissues [34]. Among several findings, she demonstrated that lipofectin-complexed mRNA encoding luciferase, a reporter protein, could be delivered to the rat brain and she showed that expression was improved when a longer poly(A) tail was added to the mRNA 3′ end [35]. Encouraged by these results, Karikó continued her quest to make the mRNA platform suitable for clinical use.

mRNA delivery to dendritic cells and the role of innate sensing

In the late 1990s, Karikó teamed up with Drew Weissman, a physician scientist with an interest in basic immunology and vaccine development, who had joined the University of Pennsylvania in 1997. Weissman had received his MD and PhD degrees from Boston University in immunology and microbiology in 1987. After a residency period at Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, he joined Anthony Fauci’s group at the National Institutes of Health (NIH) for a post-doctoral fellowship to investigate how the human immunodeficiency virus type 1 (HIV-1) interacts with target receptors on different types of immune cells. Having established his own group at the University of Pennsylvania, he focused increasingly on vaccine research and the use of dendritic cells to prime immune responses. Ralph Steinman was awarded a Nobel Prize in Physiology or Medicine for the discovery of dendritic cells in 2011. With Weissman’s back-ground in immunology and Karikó’s expertise in RNA biochemistry, the two scientists complemented each other well and shared a passion for exploiting the use of mRNA in medical applications.

Together, Karikó and Weissman tested whether in vitro transcribed mRNA could be delivered to dendritic cells to exploit their antigen-presentation potential. A major goal of Weissman was to develop a vaccine against HIV-1, a virus that causes chronic infections. This was an exceptional challenge given the extensive immune evasion properties of this virus, setting it apart from viruses that cause acute infections. Weissman was interested in using dendritic cells to prime antigen-specific T cells and had developed systems to culture dendritic cells and assess their activation and antigen presenting capacities. Dendritic cells have exquisite abilities to both sense pathogens and prime naïve T cells and thus they bridge the innate and adaptive immune systems [36]. Karikó and Weissman showed that dendritic cells pulsed with in vitro transcribed mRNA encoding the HIV-1 structural protein, Gag, stimulated primary CD4+ and CD8+ T cell responses in vitro [37]. The team also found that the process of mRNA loading resulted in DC activation and maturation [38], which initially was interpreted as a positive effect since activated dendritic cells are superior in T cell priming. The negative consequences of innate immune activation by in vitro transcribed mRNA were not fully appreciated at this point. Interestingly, and somewhat counterintuitively, this would turn out to be a critical factor for advancing mRNA-based vaccines.

The observation that dendritic cells were activated following uptake of in vitro transcribed mRNA led to critical questions about which signaling pathways were engaged? Dendritic cells express both surface and endosomal Toll-like receptors (TLRs), which recognize distinct molecular structures referred to as pathogen-associated molecular patterns (PAMPs) [39]. TLR binding to PAMPs results in intracellular signaling and pro-duction of anti-viral cytokines including type 1 interferons, an effective warning system to detect incoming pathogens. Studies of how TLRs distinguish different forms of nucleic acid had gained traction after Hemmi et al. showed that unmethylated CpG motifs, abundant in microbial but rare in mammalian DNA, activate TLR9 [40].

Within a few years, the ligands for most nucleic acid sensing TLRs had been identified, including TLR3 that senses double-stranded RNA (dsRNA), a viral replication intermediate, and TLR7 and TLR8 that sense single-stranded viral RNA and some forms of synthetic RNA [41, 42]. In 2004, Karikó and Weissman reported that in vitro transcribed mRNA contains dsRNA contaminants that can activate TLR3, leading to a cytokine response [43]. Another important clue was obtained when Koski, Karikó and Weissman together with Brian Czerniecki and colleagues demonstrated that transfection of dendritic cells with in vitro transcribed mRNA stimulated a cytokine response similar to that observed with prokaryotic RNA. Experimental manipulations to increase the poly(A) length of in vitro transcribed mRNA led to significantly reduced IL-12 production. However, this was not the full explanation for the observed effects. When four homopolynucleotides, polyuridylic acid (pU), polyguanylic acid (pG), polycytidylic acid (pC), polyadenylic acid (pA), were tested using IL-12 as a read-out for DC activation, only pU induced a response, suggesting that the nucleotide content also played a role [44]. A similar finding, using interferon alpha as a readout, was reported the same year from Reis e Sousa’s group in their studies of RNA recognition by TLR7 [41].

The Kariko, Weissman breakthrough

Karikó and Weissman continued their careful studies of different types of RNA and the work resulted in a breakthrough publication in 2005. The study described the influence of mRNA base modifications on the cytokine response by dendritic cells [45]. They showed that eukaryotic mRNA and tRNA, in which base modifications are abundant, did not stimulate a cytokine response while prokaryotic and in vitro -transcribed mRNA did. They further showed that the incorporation of pseudouridine (ψ), 5-methylcytidine (m5C), N6-methyladenosine (m6A), 5-methyluridine (m5U) or 2-thiouridine (s2U) into in vitro transcribed mRNA abrogated activation of inflammatory responses when these mRNAs were added to dendritic cells [45]. The incorporation of m6A and s2U almost completely abrogated recognition by TLR3, while TLR7 and TLR8 activation could be evaded using m6A, s2U, m5C, m5U and ψ. Importantly, only modifications of uridines (m5U, s2U and ψ) abolished DC activation ( Figure 2 ).

To date, researchers have uncovered more than one hundred different post-transcriptional modifications in RNA and shown that modifications are more extensive in RNA of eukaryotes than prokaryotes [46, 47]. Pseudouridine (Ψ) was discovered already in 1951 [48] and is one of the most abundant RNA modifications, initially found in tRNAs and small nuclear RNAs (snRNAs) and more recently in other types of RNA. Cells modify RNA through enzymatic reactions, for example pseudouridine is catalyzed by pseudouridine synthase enzymes, or using small ribonucleoprotein (snoRNPs) complexes. RNA modifications contribute to RNA stability, base-pairing specificity, folding and other functional properties. Of the over one hundred RNA modifications known [49], limited functional data exists on most modifications. Understanding the physiological implications of these modifications therefore remains an active research field.

The Karikó and Weissman discovery explained an observation made over 40 years earlier by Isaacs and colleagues demonstrating that delivery of deaminated RNA into cells resulted in a stronger type 1 interferon response than control RNA [50]. Deamination increases the proportion of uridines in the RNA, which Kariko and Weissman had demonstrated was critical for DC activation. Later work showed that the use of N1-methylpseudo-uridine (m1ψ), alone or in combination with m5C, further improved the mRNA platform both in terms of reducing recognition of innate immune receptors and increasing protein expression [51], the latter was in part explained by an increased ribosome occupancy on m1ψ-containing mRNA [52]. Today, m1ψ is the most common modified base used in mRNA vaccine production, including in the two COVID-19 vaccines approved in late 2020, as discussed below.

Following their breakthrough discovery that incorporation of modified bases evades undesired immune activation by in vitro transcribed mRNA, Karikó and Weissman demonstrated that pseudouridine-containing mRNA was also more efficiently translated, resulting in higher protein production in cells that have taken up the mRNA [53] ( Figure 3 ). In the same study, they showed that delivery of modified mRNA into the spleen of mice led to increased protein production and decreased immune activation, an important demonstration for future therapeutic applications. Karikó, Weissman and colleagues further demonstrated that in vitro transcribed mRNA activates protein kinase R (PKR), an anti-viral protein that protects cells from invading pathogens by recognizing dsRNA by phosphorylating the eukaryotic translation initiation factor 2 alpha (eIF2a), blocking protein translation. The team showed that the use of modified bases reduced activation of PKR and improved protein production [54]. Recognition of in vitro transcribed mRNA by the 2’5’ oligoadenylate synthetase (OAS) and degradation by the OAS-induced Rnase L enzyme were also decreased with RNA containing modified bases [55].

Furthermore, Karikó and colleagues showed that dsRNA contaminants produced during in vitro transcription could be removed through an HPLC purification step [56], or as later reported together with Uğur Şahin and colleagues at BioNTech, by using a cellulose-based purification step [57], further improving the expression of protein from in vitro transcribed mRNA.

Research leading up to the mRNA vaccines against COVID-19

By 2010, three main companies with programs focusing on the emerging mRNA technology had been established: CureVac, founded in 2000 aimed to develop vaccines against infections and cancer; BioNTech founded in 2008 had the objective to develop personalized cancer vaccines; and Moderna, founded in 2010 planned to use the mRNA platform to reprogram somatic cells to pluripotent cells and to deliver therapeutic proteins, for example to repair damaged tissue. All three companies collaborated closely with academic researchers to improve the technology and evaluate their respective platforms in disease areas of interest.

The team behind Curevac, including Ingmar Hoerr, Günter Jung, Steve Pascolo and Hans-Georg Rammensee, had realized the potential of the mRNA technology early on. They developed approaches to improve the efficiency of protein production through optimizations of the mRNA 5’ and 3′ untranslated regions and codon optimization, without using modified bases. In 2000, they reported that administration of RNA, either naked or liposome-complexed, induced antigen-specific adaptive immune responses in mice (antibody and CD8+ T cell responses) with the liposome-encapsulated RNA giving higher responses [58]. They evaluated their first mRNA vaccine in humans approximately eight years later when genetic material from tumors of melanoma patients was extracted and used to generate mRNA that was administered as an autologous vaccine with granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant. The approach was shown to be safe and to increase anti-tumor immune responses in some patients [59]. In 2012, the Curevac team reported elicitation of protective immune responses against influenza virus infection in several animal models [60] and in 2017, the first mRNA-based vaccine against an infectious disease, rabies, was tested in clinical trials.

Activities in the mRNA vaccine field now expanded rapidly. In 2017, promising pre-clinical results of mRNA-based Zika virus vaccines that used modified bases were reported by Norbert Pardi and Weissman [61] and by Michael Diamond and colleagues at Washington University School of Medicine [62]. The latter study, which described vaccination of pregnant females, demonstrated protection against viral transmission to the fetus, a major concern with Zika virus infections. In 2017, Moderna announced the start of a clinical trial with an mRNA-based vaccine against Zika virus (ClinicalTrials.gov: NCT03014089). Moderna also initiated two phase I clinical trials to evaluate the safety and immunogenicity of their mRNA vaccine candidates against influenza virus H10N8 and H7N9, two avian influenza strains with pandemic potential [63, 64] (ClinicalTrials.gov NCT03076385 and NCT03345043).

Around the time of the Zika vaccine trial, Moderna also initiated collaborations with Barney Graham and his team at the Vaccine Research Center at the NIH to develop an mRNA-based vaccine against Middle East Respiratory Syndrome coronavirus (MERS-CoV). The vaccine encoded a prefusion-stabilized form of the MERS spike where, among other modifications, prolines were introduced in the S2 domain to prevent the metastable prefusion form transitioning into the post-fusion form [65]. Early work by Qiao et al. had showed that the introduction of prolines in the influenza virus hemagglutinin 2 domain (HA2), which undergoes a loop to helix transition at low pH, interferes with the ability of the influenza virus to fuse with host membranes [66]. Based on this finding, and the knowledge that viruses from different families have evolved similar solutions for fusing with target cells, appropriately positioned prolines have been substituted into the spike glycoproteins of several viruses to stabilize them in their respective prefusion forms, including but not limited to HIV-1 [67], Respiratory syncytial virus [68] and SARS-CoV-2 [69]. The high-resolution structure of the SARS-CoV-2 spike published in record time by Jason McLellan’s group in early 2020 proved invaluable for several of the successful COVID-19 vaccines, as well as for the definition of neutralizing antibody epitopes and antibody escape mutations in later emerging SARS-CoV-2 variants, information that is of great importance for our understanding of vaccine-induced immune protection. The prefusion-stabilized form of the SARS-CoV-2 spike was used in the mRNA vaccines developed by Pfizer/BioNTech and Moderna ( Figure 4 ), as well as in the vector vaccine by Janssen and the protein-based vaccine developed by Novavax.

The moment was ripe for mRNA vaccines

When the pandemic broke in early 2020, mRNA companies acted quickly to develop COVID-19 vaccines. BioNTech and Moderna chose to use mRNA with modified bases building on the discoveries by Karikó and Weissmann. BioNTech, with Uğur Şahin and Özlem Türeci in the lead, worked in partnership with Pfizer [70, 71], while Moderna collaborated closely with the VRC/NIH where Barney Graham and an assembled team performed the vaccine evaluation [72-74]. Undoubtedly, the SARS-CoV-2 pandemic was a decisive event that led to large-scale investments in the mRNA vaccine technology, including the design of clinical trials that ran in parallel rather than sequentially, shortening the time required for clinical trials considerably while still completing all the necessary steps [75]. The collective funding and support from governments, international organizations, and industry resulted in the completion of vaccine safety and efficacy trials in record time with both the Pfizer/BioNTech’s and Moderna’s mRNA vaccinesgaining approval within a year of the SARS-CoV-2 outbreak. This development was made possible thanks to decades of basic research and optimization of the mRNA platforms, as reviewed in [76]. Both the Pfizer/BioNTech’s and Moderna’s mRNA vaccines had complete substitutions of uridine with N1-methylpseudouridine (m1ψ) to avoid unwanted inflammatory responses, to ramp up protein translation, and to enable higher mRNA amounts to be used in each vaccine dose.

The phase 3 trials, which were based on results obtained after two mRNA vaccinations, showed that the level of protection against symptomatic COVID-19 was very high, 95% efficacy for Pfizer/BioNTech’s vaccine (Polack 2020) and 94% for Moderna’s vaccine (Baden 2021). Both vaccines induced potent antibody responses, as well as memory B cell and T cell responses, providing protection against severe disease and death. Follow-up studies showed that the serological responses were relatively short-lived, and the research community soon showed that additional booster immunizations greatly improved protection, especially against the more infectious Omicron variant [77]. The spread of new SARS-CoV-2 variants is well documented and several Omicron subvariants are in circulation. The global scientific community continues to monitor the virus evolution to track the emergence of new variants and guide the design of updated vaccines. The past year has demonstrated that the mRNA platform is amenable to the production of updated vaccines at a speed that is currently not matched by other vaccine platforms.

Several COVID-19 vaccines have contributed to saving lives and reducing unsustainable pressures on health care systems since 2021. The mRNA technology represents a critical addition to the arsenal of platforms that can be used in vaccine production, not the least in response to pandemics when scalability and flexibility are essential. The wide-spread use of the two COVID-19 mRNA vaccines over the past years demonstrates the significant potential of the technology and shows that serious adverse effects to the two licensed mRNA vaccines were exceptionally rare [78], providing a strong foundation for future applications.

Are modified bases required for all clinical mRNA applications?

Several applications of the mRNA platform are now in development, including for vaccines against infections and cancer and for the delivery of therapeutic or immunomodulatory proteins. Different mRNA applications may have different requirements for modified bases. For prophylactic vaccines that are given to large numbers of healthy individuals, reactogenicity to the injection is an important consideration. A mild transient reaction may be acceptable if it is limited to the injection site, while systemic inflammatory symptoms such as fever, myalgia and headaches are undesired or, depending on the severity, unacceptable. The acceptable level of reactogenicity must be decided for each specific vaccine product, and this depends on the magnitude of the benefit of inducing a protective response. Thus, striking the right dose balance between reactogenicity and efficacy for a given vaccine can be challenging [79].

Khoury et al. reported that the protective effects of all COVID-19 vaccines for which results were available by mid-2021 correlated with the mean neutralizing antibody titers against the founder virus elicited in each of the trials [80]. This aligns with data from other licensed anti-viral vaccines for which protection against disease is known to correlate with neutralizing antibodies [81]. Once the results obtained in Curevac’s clinical trial were available [82] they were compared with the results from the other trials [83]. This analysis showed that the neutralizing antibody titers elicited by the Curevac vaccine were lower than those elicited by Pfizer/BioNTech’s and Moderna’s mRNA vaccines, suggesting that the lower mRNA dose used in the Curevac trial compromised the protective effect of this vaccine. A definitive comparison of the different mRNA vaccines is confounded by the fact that more neutralization-resistant variants were circulating by the time Curevac ran its phase 3 trial. However, the results support that the use of base-modifications in in vitro transcribed mRNA encoding the SARS-CoV-2 spike was critical for the development of mRNA-vaccines that could be given at sufficiently high doses to protect against COVID-19.

In the future, additional approaches to optimize mRNA for the development of clinically useful products, such as circular RNA [84], replicons [85] and other types of RNA that do not contain base-modifications, will likely be developed. Recent clinical studies with therapeutic mRNA vaccination combined with checkpoint inhibition using mutated or unmutated tumor antigens demonstrate successful induction of tumor-specific T cell responses in melanoma and pancreatic ductal adenocarcinoma patients [86-88]. The mRNA used in these trials used unmodified bases but included modifications to the poly(A) tail described to increase mRNA stability and translational efficiency [89]. Thus, alternative approaches to generate effective mRNA-based vaccines and therapeutics are in development. There are now numerous clinical trials using different forms of mRNA to induce prophylactic or therapeutic responses in the fields of infection [90] and cancer [91, 92], and this is predicted to increase over the coming years.

The approval of two effective and safe COVID-19 mRNA-vaccines in late 2020 propelled the mRNA vaccine field into a new era. The discovery that the use of modified bases in in vitro -transcribed mRNA circumvents undesired inflammatory responses and increases protein production following delivery to cells demonstrates the value of basic research. The results published by Karikó and Weissman in their seminal 2005 paper received little attention at the time but laid the foundation for critically important developments that have served humanity during the COVID-19 pandemic.

Gunilla Karlsson Hedestam, PhD, Professor at Karolinska Institutet ( [email protected] ), Member of the Nobel Committee

Rickard Sandberg, PhD, Professor at Karolinska Institutet ( [email protected] ), Member of the Nobel Committee

Illustrations: Mattias Karlén

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Science | December 20, 2023

The Ten Most Significant Science Stories of 2023

From an asteroid sample that was delivered to Earth to a discovery about human migration from North America, these were the biggest moments of the year

Carlyn Kranking and Joe Spring

In 2023, a whirlwind of science headlines swept across our screens, from the find that our ancestors nearly went extinct 900,000 years ago to the discovery of a brilliant green comet in the sky. In major health news, the coronavirus public health emergency expired , and the disease took up less of our attention, though it continued to have disastrous impacts . Medical experts are anticipating updated annual vaccines will be released to continue fighting the virus as it evolves.

Also evolving rapidly this year was artificial intelligence, which found uses in everything from medicine to wildlife biology. In one innovative application, it was used to help forecast when birds took to the skies. Such an ability can help officials determine when to turn off building lights to prevent bird strikes—a conservation strategy that made national news when almost 1,000 birds died in one night after hitting a single lakeside building in Chicago.

That was a grim stat, but the year was filled with amazing news as well, including the astounding images released by the James Webb Space Telescope . In major math news, researchers found a shape with a pattern that never repeats. And in France, scientists discovered that arresting patterns left in rock are the oldest known Neanderthal cave engravings .

Unfortunately, but not unexpectedly, climate change continued to generate plenty of headlines, as the year became the hottest on record . Amid intensifying natural disasters , world leaders gathered in Dubai, United Arab Emirates, for the 28th United Nations Climate Change Conference, or COP28. While the proceedings closed with a landmark deal that made the first-ever global commitment to transition away from fossil fuels , several experts criticized the text for not going far enough .

While we were riveted by all of those stories and more, only some made our list of the biggest science events and discoveries this year. Plenty of amazing new findings surely await us in 2024, but before we cover them, here’s a look back at the moments that shaped 2023 as another major year in science.

Archaeologists find ancient Native Americans crossed back over to Asia

Between 20,000 and 30,000 years ago, hunter-gatherers from eastern Eurasia likely ventured over to North America across the Bering Strait. But research this year suggests they and their descendants didn’t make a one-way trip. Several times in history, ancient Native Americans made their way back across the strait to Eurasia , according to a study published in Current Biology in January. Researchers recovered ancient DNA from ten Eurasian individuals who lived 500 to 7,500 years ago. Their analysis shows that humans with Native American lineages traveled as far away as Kamchatka and central Siberia, likely returning from North America to Asia roughly 5,000 years ago.

The find was one of many interesting discoveries related to ancient migrations and the Americas this year. In July, a study published in Proceedings of the Royal Society B described three pendants in Brazil made from sloth bones that date to between 25,000 and 27,000 years before present. That find supports the theory that humans made it to the Americas earlier than previously thought. (For many decades, researchers thought humans traveled from Russia to Alaska roughly 15,000 years ago.) And in an October study published in Science , an analysis of evidence found near fossilized footprints in New Mexico suggests that the imprints date to 23,000 years ago, which also supports the idea of an earlier migration of humans to North America. While the timeline of migrations to the Americas—and back—continues to be debated, many sites that will offer more clues await discovery and analysis. —Joe Spring

Artificial intelligence yields scientific breakthroughs as experts call for caution

2023 was a “ breakout year ” for artificial intelligence. Following the release of OpenAI’s ChatGPT at the end of 2022, machine learning has increasingly been in the public eye. A.I. made its way into courtrooms , music and art this year, raising a slew of ethical concerns . In the realm of science, the cutting-edge technology is paving the path toward new discoveries and more advanced processing of data.

Several groups of researchers experimented with having A.I. algorithms generate words , images and even music based on people’s brain scans—a technique that, down the line, could help stroke patients and paralyzed people to communicate by thinking . Machine learning has helped in conservation, such as by tracking migrating birds —the A.I.-powered tool BirdCast can alert people to an incoming wave of migrants, which may help prevent disease , inform Lights Out programs to reduce window strikes , and tip off birders about flocks in their area. Scientists are also developing A.I. tools that can identify species based only on a photograph , distinguish between similar-looking mushrooms or pinpoint a bird species from its song. And, inspired by the way ChatGPT follows patterns in language to generate words, researchers have experimented with translating whale sounds using A.I.

At the same time, experts warned this year of the need to regulate the rapidly advancing technology. Geoffrey Hinton, a machine learning pioneer widely called the “Godfather of A.I.,” quit his part-time job with Google in May so that he could speak more freely about his unease regarding A.I.’s future. Experts have raised concerns that A.I. could spread misinformation, manipulate humans and alter the job market if it isn’t controlled. But innovation continues, and it seems likely that researchers will increasingly use A.I. to attempt breakthroughs in many fields. —Carlyn Kranking

NASA retrieves asteroid bits to shine light on Earth’s origins

On September 24, 8.8 ounces of rock and dust collected from an asteroid named Bennu landed in the Utah desert . The astronomical delivery was the result of a more than seven-year NASA mission in which the agency’s OSIRIS-REx probe journeyed 1.2 billion miles to the asteroid to retrieve the sample. The 4.5-billion-year-old Bennu existed before Earth did, so it could hold clues about how our planet formed and which building blocks of life meteorites delivered here long ago.

Initial analysis revealed evidence of water and a high carbon content on Bennu. While the OSIRIS-REx spacecraft is already off to visit another asteroid, researchers on Earth will study the Bennu sample for two years and set aside some of the rock for later examination. And while much of the rock will be analyzed behind closed doors, a 0.3-inch, 0.005-ounce sample is on display at the Smithsonian’s National Museum of Natural History, so you can get a glimpse of an object that is truly far-out. —J.S.

The Titan submersible imploded while searching for a shipwreck

The world watched in June after OceanGate’s Titan submersible went quiet during a dive to the Titanic . The craft and its five passengers descended toward the famous wreck on Sunday, June 18, at 8 a.m., but it lost contact with its base ship, the Polar Prince , around 10:45 a.m. At 5:40 p.m., roughly three hours after the sub was supposed to breach the surface, officials notified the Coast Guard the craft was overdue. Airplanes and a Bahamian research vessel with remote-operated robots helped scour an area twice the size of Connecticut. Numerous television stations and news outlets covered the search as fears mounted that the crew was running out of oxygen. And on Thursday morning, the Coast Guard found debris consistent with a catastrophic implosion of the submersible.

Onboard was Stockton Rush, the CEO and co-founder of OceanGate, who considered himself a maverick and breaker of rules . He had gone forward with that dive and others despite safety concerns. Two former employees had raised issues about the craft’s hull, and more than three dozen experts warned that catastrophic problems could occur due to company’s experimental approach. Though many in the public waited to hear news about the sub after it went missing, experts expected the worst . And while the actual scientific benefits of Titan ’s dive were likely minimal , the sub’s tragic end shed a light on the value of the time and effort that goes into scientific exploration of the deep sea. Scientists who dive to the ocean’s depths for serious study go down in crafts that have undergone rigorous testing. Because of that, nearly 50 years had passed since a fatal accident on such a submersible. That all changed with a company that dove despite multiple warnings. —J.S.

Wildfires burned through Canada and Hawaii

Devastating wildfires dominated the news again in 2023. Blazes set a record in Canada, scorching more than 45 million acres by October. The country’s previous annual record, standing since 1989, was less than half that, at 19 million acres burned . As climate change causes higher temperatures, Canada’s fire season has become longer by about two weeks, and larger fires have grown more common. Hundreds of such “megafires,” covering 39 square miles (10,000 hectares) or more, incinerated our northern neighbor this year. Many had massive clouds above them, like those usually seen above volcanoes , that created lightning and high winds. And Canada’s major burns affected others around the world: During June, parts of the United States’ Midwest and Northeast regions registered the globe’s worst air quality, and pollution reached as far as Spain, Britain and Norway .

Canada’s catastrophic fires weren’t alone. On August 8 , a devastating blaze swept across the Hawaiian island of Maui and engulfed the city of Lahaina , killing at least 100 people . The death toll is the highest caused by a wildfire in the U.S. in more than a century , and thousands of residents lost their homes. On the islands, some seasons are hotter and drier due to climate change, allowing wildfires to spread at increasing speeds. Climate change is altering many other such areas around the planet, threatening to make what was once considered extreme fire become more and more the norm . —J.S.

UFOs break into government discourse and spark conspiracy theories

In 2023, alien conspiracies and UFO speculation riddled social media, but at the same time, some of the stigma around researching unidentified anomalous phenomena, or UAP, began to break down.

For starters, the U.S. Office of the Director of National Intelligence released a report in January that announced more than 350 sightings of UAPs had been logged by the government since March 2021. Nearly half of these were described as “balloon or balloon-like entities”—a subject that took center stage the following month, when the U.S. government shot down what was suspected to be a Chinese high-altitude spy balloon off the coast of South Carolina. The incident demonstrated how identifying UAPs has implications for national security.

Then, at a House of Representatives hearing in July, former U.S. intelligence officer David Grusch alleged in a testimony under oath that the federal government is covering up evidence of crashed vehicles and biological material believed to be of “non-human” origin. In September, alien discourse appeared in legislative chambers once more, when a self-proclaimed UFO expert unveiled what he claimed were the bodies of extraterrestrials in front of Mexico’s Congress. Scientists balked at the suggestion, pointing to several previous alien theories from the speaker that had been debunked. Ultimately, anyone looking for confirmation of aliens on Earth didn’t get it this year—after a 12-month study, NASA released a report on UFOs in September , stating its scientists found “no conclusive evidence” that the mysterious phenomena have an extraterrestrial origin. —C.K.

Orcas break rudders and sink ships in the Strait of Gibraltar

Maybe it’s a form of play. Maybe it’s a passing fad . Or maybe, as internet onlookers from around the world have facetiously suggested, it’s a full-fledged, female-led orca uprising, planned as retribution for humanity’s presence in the high seas. (Scientists aren’t on board with that last one.) Whatever the reason, orcas off the coasts of Portugal and Spain have been ramming into and breaking rudders off ships in the Strait of Gibraltar. Since 2020, more than 500 interactions with contact between orcas and boats have occurred, and four of these incidents—with two this year—resulted in a vessel sinking, most recently in November .

In May, a scientist suggested the curious behavior started after one orca had a negative experience with a boat, and that it spread as juveniles watched her break rudders. This led people to cheer for the orcas on social media. But in an open letter in August, a group of 35 scientists warned against attributing human traits to the animals . Doing so, they wrote, could lead mariners to take aggressive action against the orcas, which belong to a critically endangered population of fewer than 50 individuals . Indeed, some sailors have thrown firecrackers into the water in an attempt to keep orcas away.

Amid all the mystery around the behavior, one thing seems clear—the orcas do not appear to have malicious intentions. “Quite frankly, if they really wanted to take revenge, they would,” biopsychologist Lori Marino told ABC News in July. —C.K.

Covid-19 entered a new phase

Though, to many people, Covid-19 faded into the background this year, the disease remains a problem as the vaccine response has lagged. On May 11 , the Biden administration allowed the coronavirus public health emergency to expire, leading the virus to be treated like other respiratory ailments. (Insurance providers were no longer required to provide free Covid-19 tests, and some medicines, such as Paxlovid, were no longer guaranteed to be free.)

A new variant, XBB , became dominant in early 2023, and in September the Food and Drug Administration authorized an XBB booster , which also works for other Omicron variants. But by the end of October, the Department of Health and Human Services said only about 4.5 percent of the population had received the shots, despite the fact that the Centers for Disease Control and Prevention (CDC) recommended the updated dose for everyone six months or older . The reception was lower than the previous year’s booster, which more than 23 million Americans had received after a similar timespan. The lackluster uptake continued a trend of declining response to boosters. As of December , roughly 70 percent of the population had the primary series of the vaccine, while less than 20 percent had received a bivalent booster. While the virus was not spreading at the rate of previous years, as of early December , more than 5,000 people were hospitalized on an average day and more than 1,200 deaths were occurring each week. Much of the population, including people who are over 65, pregnant or immunocompromised, are still vulnerable to the disease.

And some folks continue to deal with the aftereffects of the virus: This June, roughly 6 percent of the population was suffering from long Covid, according to the CDC . And of those, more than one in four experienced significant limitations in their ability to perform normal daily activities. As the disease continues to evolve, the Biden administration says citizens should expect to have a shot available each fall , like the schedule for flu vaccines. But whether people will actually be receptive to that shot remains to be seen, following the decline in this year’s response. —J.S.

A teenage tyrannosaur fossil preserves what young dinosaurs ate

Adult tyrannosaurs—large, bipedal carnivores of the Late Cretaceous—were fearsome predators in the prehistoric landscape. With their bone-crushing bite force, the fully grown dinosaurs could bring down massive plant-eaters . Young tyrannosaurs, on the other hand, might have had more limited pickings with their slender frames, narrow skulls and blade-like teeth . At least, that’s what paleontologists suspected. But they didn’t have proof until this year, when researchers reported a fascinating discovery: a “teenage” tyrannosaur, with its final meals preserved intact .

The astounding fossil of Gorgosaurus , uncovered in 2009 and described in Science Advances in December, provides the first direct evidence of shifts in a tyrannosaur’s diet from adolescence to adulthood. Within the carnivore’s stomach were four legs—two pairs—from small, bird-like dinosaurs called Citipes elegans . Each pair of legs shows different levels of digestion, suggesting they represent the young reptile’s last two meals, consumed hours or days apart. The juvenile tyrannosaur, which was between 5 and 7 years old, likely had to chase down these fast, turkey-sized prey. The findings suggest that young, agile Gorgosaurus survived on bits of baby dinosaurs until they grew big enough to take down titans. —C.K.

2023 becomes the hottest year on record

Worldwide, 2023 started out warm . April and May ranked among the hottest months of their kind in written history. But when summer arrived in the Northern Hemisphere, records fell left and right . Heat waves gripped regions of the United States and Southern Europe. American municipalities set more than 1,000 daily temperature records in June and July, and residents of Phoenix sweltered through an unprecedented 31-day stretch of at least 110 degree Fahrenheit temperatures. Even heat-adapted saguaro cactuses fell over and died . Oceans warmed to levels unparalleled in the nearly 45-year record , with one thermometer in the Florida Keys measuring “hot tub” heat levels at 101.1 degrees Fahrenheit in July.

The life-threatening heat was wide-reaching: On one weekend day in August, more than 111 million Americans in the South and Southwest were under heat warnings. Month after month—first June, then July, August, September, October and November—clocked in as the hottest months of their kind ever documented. With both climate change and the arrival of the heat- and moisture-bringing El Niño weather pattern, 2023 is now guaranteed to become the hottest year on record. But since, historically, El Niño’s most extreme heat arrives during its second year , some scientists warn that 2024 might be even more chart-topping. —C.K.

Caption of Top Image: Illustration by Emily Lankiewicz / Clockwise from upper left: Unsplash, Mojahid Mottakin; Nadezhda F. Stepanova; Francois Gohier / VW Pics / Universal Images Group via Getty Images; NASA Johnson Space Center; Unsplash, Jarosław Kwoczała; Unsplash, Fusion Medical Animation; Ocean Gate / Handout / Anadolu Agency via Getty Images; Unsplash, Bruce Warrington; Unsplash, Benjamin Lizardo; Julius Csotonyi © Royal Tyrrell Museum of Paleontology

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Joe Spring is the associate digital science editor for Smithsonian magazine.

18 brain studies that blew our minds in 2023

From its strange "spiral signals" to a libido switch, the brain contains myriad mysteries that scientists are still working to unravel.

Perhaps the most mysterious organ in the body, the brain continues to astound scientists despite the countless hours they've spent attempting to decipher its inner workings. Each new discovery about the brain brings a thousand new questions in its wake.

Here are 18 things we learned about the brain in 2023 that blew our minds.

Related: Do we really use only 10% of our brains?

1. Newly discovered part of the brain

In January, scientists described their discovery of a kind of shield in the brain that helps clear away waste and acts as a look-out post for immune cells. The thin shield seems to help control the flow of proteins and molecules between different compartments containing cerebrospinal fluid, a colorless liquid that flows around the brain and within tubes through the organ.

2. Squid and human brains tied by evolution

Despite the 500 million years of evolution that separate squids and humans, our brains develop in a very similar way to the brains of these cephalopods. Scientists discovered this by monitoring stem cells called neural progenitor cells in developing squid embryos. To build a squid retina, where most of the animal's neural tissue is found, the cells must first form a long, densely packed structure that can also be spotted during the neural development of vertebrates like us.

3. 'Junk DNA' and big brains

The genes that enabled humans to grow notably big brains may have originally come from "junk DNA," which doesn't code for any proteins, researchers revealed early this year. At some point in human evolution, after we split from other primates, some of this junk DNA picked up the ability to encode proteins. In animal and lab-dish experiments, several of these genes appeared key for boosting brain growth.

4. Injuries plugged with minibrains

Scientists used cerebral organoids — miniature 3D models of the brain — to repair brain injuries in rats . The organoids were grown from human stem cells and transplanted into rats' visual cortices, the region of the brain where information from the eyes is initially processed. The researchers hope to eventually apply the technique in humans, but that's many years away.

5. Native language wires the brain

A person's native language may influence how their brain links up information-processing hubs within its structure, according to a study of people whose native languages were German and Arabic published in February. Differences in the study participants' brains were chalked up to linguistic differences between the languages. However, more work is needed to reveal how cultural features of conversation might shape brain structure.

6. Psychedelics invade brain cells

Psychedelics have shown promise as therapies for hard-to-treat depression, and now scientists think it may be because they invade brain cells . Psychedelics, such as LSD, DMT and psilocybin, can bind to receptors for the chemical messenger serotonin — but significantly, they can latch onto these receptors on the outside and inside of cells. Theoretically, this means psychedelics might flip switches that traditional antidepressants, which generally increase the concentration of serotonin outside the cells, can't reach. That may be why trippy drugs drive brain cells toward building new connections.

7. Never-before-seen brain wave

Octopuses generate a type of brain wave not seen in any other animal, even humans. These long-lasting, unusually slow brain waves were recorded using electrodes implanted in freely moving octopuses' brains. Scientists aren't yet sure what function these unique waves serve, or if they're tied to a specific behavior.

8. Short-circuiting chronic pain

The brains of people with chronic pain show fluctuating patterns of activity that can be tied to the subjective experience of their pain, researchers have discovered. Deciphering these patterns could someday enable doctors to disrupt them with targeted therapies, thus short-circuiting patients' pain.

9. Brain surgery in the womb

In a first-of-its-kind surgery, doctors repaired a malformed blood vessel in a fetus' brain prior to birth. The malformation occurs in an estimated 1 in 60,000 births and is usually treated after birth, when it can sometimes be too late to prevent damage or death. In March, doctors successfully treated the malformation sooner, in the womb.

10. Life flashing before your eyes?

People's brains generate a flurry of activity in their last minutes of life, scientists revealed in May, and this electrical surge may reflect conscious experiences — however, that's just a theory. It could be that this activity erupts as people "move toward the light" or see their "lives flashing before their eyes," as portrayed in many movies. Or, it could also just be "aberrant electrophysiological activity," some experts say.

11. Mystery brain spiral signals

Spiral signals uncovered in the human brain may help organize the organ's complex activity. The spirals are brain waves that pass over the surface of the brain and rotate around central points. These spirals may act as bridges of communication between different regions of the brain, scientists theorized in June.

12. Sex switch in mouse brains

Scientists discovered an "on switch" for libido in the male mouse brain — and they think a similar control center may exist in humans, although they haven't found such circuitry yet. Flipping the switch drove male mice to mate with females and with inanimate objects, and also reduced the break time needed between rounds of sex. As of now, no equivalent circuit has been found in female mice.

13. Pink Floyd in brain waves

In August, scientists revealed they were able to "read" people's brain waves and recreate Pink Floyd's famous "Another Brick in the Wall," which the volunteers had listened to during their brain recordings. Some song snippets generated by the researchers really did sound like the 1979 protest song — other snippets, however, sounded much muddier.

14. A 'tell' for false memories

Your brain's activity shifts in a distinct way when you're about to recall a false memory , or one in which the events never really happened. This "tell" specifically crops up in the hippocampus, a key brain region for memory, scientists recently discovered.

15. Brain changes across menstrual cycle 

The brain's structure goes through subtle changes throughout a person's menstrual cycle . These changes appear in the microstructure of the brain's white matter — the insulated wires that run between brain cells — as well as the thickness of its gray matter, the bodies of brain cells. For now, it's unknown whether these brain changes affect cognition or the risk of brain diseases. But the research could open the door to such discoveries in the future.

16. Complete insect brain map

The first-ever complete map of an insect's brain contains 3,016 neurons. The fruit fly brain atlas, completed over 12 years and finally revealed in June, shows all the physical connections between the thousands of cells. It could help pave the way for more-advanced artificial intelligence (AI) systems and help scientists decipher similar structures in the human brain.

17. Most-complete human brain map ever

This year, scientists unveiled the most detailed atlas of the human brain ever conceived which details the arrangement of 3,300 types of brain cells, few of which were previously known to science. The atlas is half composed of neurons — the brain cells that communicate through chemical and electrical messages — and half made up of non-neuronal cells.

18. Minibrain plugged into AI

— How many calories can the brain burn by thinking?

— Consciousness can't be explained by brain chemistry alone, one philosopher argues

— Can minds persist when they are cut off from the world?

For the first time, scientists plugged a brain organoid into the middle of an AI system and used the hybrid computer to perform tasks and computations. The experiment could help pave the way for biocomputers that borrow tricks from biology to become more energy efficient than standard computers.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun ? Send us your questions about how the human body works to [email protected] with the subject line "Health Desk Q," and you may see your question answered on the website!

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Nicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She holds a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Her work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains heavily involved in dance and performs in local choreographers' work.

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Intriguing science discoveries of 2023.

Old sperm, new mutations

As the male reproductive system ages, it becomes more and more susceptible to mutations. New research from the laboratory of Li Zhao explored this phenomenon in fruit flies, by focusing on how mutations arise during the formation of sperm. The team found that, while mutations are common in the testes of both young and old flies, the repair mechanisms that remove those mutations and maintain genomic integrity during spermatogenesis become less efficient in older individuals, leading to the accumulation and persistence of more mutations in older flies.

The findings could ultimately help researchers understand how older human dads impact the genetic health of their offspring. But the team intends to first better characterize their fly-related findings. “What genes are really driving the difference between old and young flies in terms of mutation repair?” wonders Evan Witt, a former graduate student in the lab and now a biologist at Biomarin Pharmaceuticals.

A reset button for immunity

Scientists colloquially call the body’s first encounter with a virus an “original antigenic sin” (OAS) that forever biases the immune response against newer strains. No matter how many flu vaccines or COVID boosters we receive, the theory of original antigenic sin dictates that our bodies will stubbornly churn out antibodies tailored to the first strain we encountered.

A new study from Gabriel D. Victora’s lab may have discovered a way around OAS, with findings suggesting that a booster shot containing an antigen sufficiently different from that of the original infection can reset the body’s immune response to its factory settings.

Although the work was conducted in mice, the team suspects that the same rules may apply to human booster shots—and that boosting humans against a new strain may be most effective when the new strain is sufficiently different from the one covered by the previous vaccine. “It may well be a matter of waiting to update vaccines until the virus is sufficiently divergent,” Victora says. “That would be just the right time to develop a booster.”

Pretenders to the throne

There are queen ants, and then there are “workerless social parasites”—ants living as queens, mooching off the colony while in disguise. These parasites were once thought to have evolved the characteristic wings, large eyes, and ovaries that make up their queen costume through gradual mutations, but recent work from the laboratory of Daniel Kronauer suggests that queen-like mutant ants appear in colonies spontaneously. “This mutant is like the precursor to other parasitic species,” says Waring Trible of Harvard University, who conducted the research with Kronauer. “It’s a new way of understanding how ants evolve to become socially parasitic.”

The discovery sheds light on the molecular mechanisms behind ant caste development, and some of the specific findings may inform future study of the biological processes that ensure the tissues of every animal remain proportionate to its body size as it grows.

The thalamus calls the shots

Short-term memories form in the hippocampus and, if the situation calls for it, stabilize into long-term memories in the cortex. But what happens along the winding path between short-term to long-term memory? Research from Priya Rajasethupathy’s lab now points to the anterior thalamus as the all-important brain region that determines whether a memory makes it into the archives.

“The thalamus is in continuous dialogue with the cortex over weeks, saying ‘stabilize this’,” Rajasethupathy proposes. “Less salient memories drop off because the cortex isn’t getting a constant signal from the thalamus to keep this memory.” The team suspects that this new understanding still only tells part of the story. Rajasethupathy hopes that her findings will be blended with other models, as neuroscientists continue to solve the mystery of memory.

Defeating Hep C’s ugly cousin

Although antivirals can now cure 95 percent of hepatitis C infections, its cousin hepatitis B still claims a million lives each year. A team led by Nobel laureate Charles M. Rice has now developed a platform for studying hepatitis B virus in the lab. This method sidesteps the virus’s typical replication process, providing a sharper view of its behaviors during a crucial part of its life cycle. The researchers hope that this novel approach will expose heretofore unknown weaknesses in the virus, leading to the development of new therapies, or a cure, for hepatitis B.

“Anywhere you can impinge on that life cycle and prevent this virus from replicating and spreading to new cells could be a potential target for new drugs,” says Bill Schneider, a research associate in the Rice lab.

More than skin-deep

Our skin takes a beating, continually responding to threats of injury and infection. Usually it activates the immune system upon sensing pathogens, but research from the laboratory of Elaine Fuchs has identified an alternative method by which the skin protects itself: by sensing broken blood vessels, the formation of scabs, and other signs of injury.

These telltale signs of trauma kick off an ancient wound repair response, mediated by the gene interleukin-24. “IL24 becomes an orchestrator that coordinates tissue repair,” Fuchs says. The findings also highlight an evolutionary link between IL24 and immune system proteins, suggesting a common ancestral pathway that diverged to address tissue injury.

Choline, come right this way

If we knew how metabolites entered cells, we could begin developing drugs to treat conditions linked to metabolite transport, from rheumatoid arthritis to neurological disease. But matching proteins with the nutrients that they shuttle into the cell has proven difficult—30 percent of carrier proteins and nutrients have yet to be matched up.

Kivanc Birsoy’s lab recently introduced a method for systematically identifying “orphan” transport proteins, allowing scientists to finally make those matches. As a proof of concept, the team used this method to discover the protein responsible for transporting choline into the cell. This finding may have immediate implications for people living with posterior column ataxia with retinitis pigmentosa (PCARP), a disease caused by a transporter mutation that affects vision and the nervous system. “Our findings could be easily translated into the clinic,” says Timothy Kenny, a postdoc in the Birsoy lab.

From microchips to “micro lungs”

The laboratories of Ali Brivanlou and Charles M. Rice have developed a platform that uses microchips to grow lung buds from human embryonic stem cells. These stripped down “micro lungs” have all the complexity of lung tissue without any of the molecular frills that make individual lungs different from one another, allowing scientists to drill down into how diseases impact lung tissue, free from distractions. These identical micro-lungs can also be cultured by the thousands, allowing for an unprecedented high-throughput analysis of lung tissue infection.

The researchers hope to use the micro lungs to investigate the mechanisms of COVID, influenza, RSV, pulmonary diseases, and lung cancer—and to screen new therapies to treat them. “The platform will also allow us to respond to the next pandemic with much more speed and precision,” Brivanlou says.

Bird brained? Hardly.

Only a handful of animal groups are capable of complex vocal learning, defined as learning and retaining a large number of sounds. Humans, elephants, whales, seals, bats, songbirds, parrots, and hummingbirds are among the most famous, and a recent study from Erich D. Jarvis’ lab suggests that complex vocal learning may go hand in hand with superior problem-solving skills.

“Complex vocal learners should also be better at cognitive tasks, but no one had ever demonstrated that before,” says Jean-Nicolas Audet, a research associate in the Jarvis lab.

The team spent three years catching hundreds of wild birds from 21 species in mist nets at The Rockefeller University Field Research Center, a sprawling 1,200 protected acres of land compromising many different ecosystems in New York’s Hudson Valley. They found that starlings, blue jays, and catbirds are the most advanced vocal learners and also the most adept at solving puzzles—suggesting that complex vocal learning is indeed linked to intelligence.

The MS microbe

Scientists have long suspected that multiple sclerosis is precipitated by an environmental trigger; likely some sort of microbial infection. The question is which microbe to blame.

Now, new research from Vincent Fischetti’s laboratory suggests that a toxin produced by a C. perfringens —a common microbe found in sewage, marine sediment, soil, and the GI tracts of pets and farm animals—can trigger the inflammation characteristic of MS in mice.

Whether these findings will bear out in humans remains to be seen. “If this is the environmental trigger for MS, we can now start talking about a vaccine, monoclonal antibodies, or some other therapy,” says Rashid Rumah, a physician scientist in the Fischetti lab.

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• 2023 IN REVIEW

The 11 most astonishing scientific discoveries of 2023

Space-time breakthroughs. Virgin births. A promising candidate for alien life. Science didn’t disappoint during our latest revolution around the sun.

In another stellar year for science, astronomers unveiled new discoveres about the cosmos, biologists etched out a clearer map of our planet’s creatures, and paleontologists painted a richer picture of the dinosaurs that roamed Earth millions of years ago. The latest compendium of humanity’s scientific research continues to intrigue and reveal new mysteries to solve.

Here are some of National Geographic ’s top picks for 2023’s most fascinating breakthroughs.

1. Astronomers detect immense ripples in the fabric of space-time

For the first time, scientists detected low-frequency gravitational waves moving through the galaxy. These cosmic ripples are likely the distant echoes of supermassive black holes interacting and merging many billions of light-years away. A consortium of international researchers discovered these cosmic waves by measuring tiny time variations in radio signals from pulsar stars. The findings suggest that there were far more behemoth black holes in the early universe than previously thought, and continuing to study this new type of gravitational wave could help unravel details about the origins of our universe and better explain the unseen substances and forces that power the cosmos.

2. Brain decoder translates human thoughts—providing hope for those who’ve lost speech

Though it’s not technically a “mind reading” device, University of Texas at Austin researchers reported revolutionary work with their new AI-based system—translating a person’s brain activity into a continuous stream of text in the lab. This semantic decoder doesn’t require a surgical implant, but instead it relies on functional MRI scans to pick up brain activity in response to things like podcasts or images. Rather than provide word-for-word transcripts, the brain decoding system essentially creates a dictionary of brain activity patterns based on how an individual responds to certain words or images and then uses that dictionary to cross-reference brain activity to other things that the person is thinking about. This tech, which relies on AI language generation algorithms, is currently in its early days, though it’s already raised thorny questions about mental privacy and ethics in non-voluntary situations. For the families of people with communication impairment, however, the work provides new hope.  

3. Ancient whale might be largest animal ever  

Move over blue whale—an ancient cetacean appropriately named the Perucetus colossus may have been the largest animal ever . A new analysis of fossil bones from the ancient whale that plied the waters along the coast of Peru more than 37 million years ago suggests that the animal may have weighed more than 300 tons and measured around 60 feet. If it was truly as heavy as scientists suspect, then it would have been the largest known animal to ever live. Blue whales, although still longer at around 100 feet, only weigh around 200 tons.

4.   T. rex   had lips, changing our picture of this dinosaur  

Tyrannosaurus rex and other carnivorous dinosaurs likely had a different pucker than suspected, sporting lips that covered their formidable teeth. A team of paleontologists came to this startling conclusion after studying modern analogs to the prehistoric animals , including birds and reptiles, alongside known details of the dinosaurs’ anatomy. They wrote that T. rex   and related meat-eaters likely had soft tissue that covered their sharp teeth to protect the animals’ mouths and keep their chompers in peak condition for attack.

5. 3-million-year-old stone tools reveal ingenuity of our non-human relatives

In southwestern Kenya, archaeologists dug up a surprising find: stone tools buried alongside fossils from the hominin Paranthropus,   an ancient non-human relative of our species. The discovery of the tools —which may be up to three million years old—provides evidence that non-human hominins developed stone technologies. What’s more, it suggests tool development occurred earlier than previously thought. Paranthropus had large teeth and jaws , so ideas about their possible stone tool use were largely dismissed because these items wouldn’t have been essential for food processing, Cleveland Museum of Natural History’s paleoanthropologist Emma Finestone told National Geographic . The latest findings appear to upend that assumption.

6. ‘Lost world’ may push back the origins of complex life  

Chemical clues extracted from ancient rocks in Australia and elsewhere suggest that sophisticated cells were already commonplace between about 1.6 billion and 800 million years ago , supporting theories of a surprisingly early timeline for the origins of complex life. The evolution of eukaryotes—organisms that possesses a clearly defined cellular nucleus—has proved largely elusive, so an international research team opted for a new tact: hunting for the byproducts of molecules that eukaryotes rely on to form their cell membranes. If they could find such evidence in ancient rock samples, they reasoned, that could serve as evidence of the presence of eukaryotes. Their oldest sample of these molecules, taken from Australia’s Barney Creek Formation, dates back to 1.6 billion years ago—pushing the chemical evidence for eukaryotes back in time to more closely align with genetic and microfossil evidence.

7. Number of discovered planets rises past 5,500  

In August, roughly three decades after astronomers found the first planets outside our own solar system, scientists unveiled that they’d discovered six new exoplanets , pushing our total count of known planets above 5,500. The search for exoplanets, enabled by telescopes such as the Transiting Exoplanet Survey Satellite (TESS) , continues to reveal a remarkable diversity of new worlds across the galaxy. What’s more, the James Webb Space Telescope and other powerful observatories are also providing more details about these worlds, such as K2-18 b—a planet between the sizes of Earth and Neptune that may have a global ocean beneath a thick atmosphere.  

8. Chimps, like humans, experience menopause

Biologists have long puzzled over the evolutionary benefit of animals living long past their reproductive years. Only orcas , short-finned pilot whales, narwhals, beluga whales, false killer whales, and humans are known to experience menopause. But new work that drew upon robust, long-term analysis of hormones in chimpanzee urine confirms that chimpanzees in at least one locale, Uganda’s Kibale National Park, go through menopause and continue to live on. The urine studies, which included females age 14 to 67, indicate that the chimps experienced menopause around age 50, which provides an intriguing parallel for humans that often experience menopause around that same age. Evidence suggests that in some of the whale and dolphin species, elder females contribute to raising later generations, but that doesn’t appear to be the case with chimps since the animals don’t raise related offspring. One theory, however, is that menopause helps decrease breeding competition for the primates, something that scientists will continue to study in the years ahead.

9. First known virgin birth among American crocodiles

In the latest example of an asexual reproduction technique called parthenogenesis, a lone female American crocodile at a park in Costa Rica produced offspring without a male . The phenomenon, typically seen when animals face extreme population pressures, had previously been reported in other animals including critically endangered California condors, multiple shark species , Komodo dragons, and certain snakes, but it hadn’t previously been reported in any crocodile species. The mother crocodile hadn’t had contact with other animals of its kind for about 16 years, and genetic analysis confirmed the fetus was indeed a partial clone of its mother. Though this animal lived in captivity, the finding has implications for its wild relatives since the International Union for Conservation of Nature has categorized the American crocodile as vulnerable to extinction.

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10. scientists develop a new, more representative genome  .

The U.S.   National Institutes of Health this year unveiled a new pan-genome —a much-needed update of the 20-year-old reference human genome. The new model captures a more representative slice of humanity with far more ethnic and racial diversity, which is a necessary step for improving personalized medicine. The new pan-genome currently includes the genome sequences of 47 people, though the model is slated to eventually include about 700 people. The prior reference sample largely drew from the genome of just one individual with other data points from people of mostly European descent. Though any two peoples’ genomes are typically more than 99 percent identical, teasing apart individual differences can reveal key insights about disease vulnerabilities and guide essential medical treatment decisions, according to the NIH.

11. Phosphorus discovered on Saturn’s Enceladus, a crucial sign that life is possible  

New chemical evidence suggests Saturn’s moon may be capable of supporting life. Scientists this year announced that they’d found phosphorous in the ocean on Saturn’s sixth-largest moon, Enceladus. Alongside carbon, hydrogen, nitrogen, oxygen, and sulfur, this sixth element is essential for sustaining life. Already, astronomers had found signs of the other five elements on Enceladus, so this latest find—detected in ice grains scooped up by the Cassini spacecraft’s Cosmic Dust Analyzer—makes this icy rock a promising candidate for extraterrestrial life.

Related Topics

• EXTRATERRESTRIAL LIFE
• TYRANNOSAURUS REX
• PLANETARY MOONS
• PALEONTOLOGY
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New evidence of decapitations points to this Triassic predator’s fatal flaw

How fast is the universe really expanding? The mystery deepens.

Colossal gravitational waves—trillions of miles long—found for the first time

This supermassive black hole was formed when the universe was a toddler

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Top scientific breakthroughs and emerging trends for 2023

The pace of innovation never slows, and the impact of these scientific breakthroughs will redefine the way we live, work, and connect with the world around us. From space exploration at the largest scale to diagnostics at the single-cell level, these breakthroughs will inspire innovators to push the boundaries of what is possible. To stay ahead of emerging trends, new discoveries, and unique perspectives, we invite you to subscribe to CAS Insights.

A new era of space exploration

Need to be reminded of how incredibly vast our universe is? The first ever photos from the James Webb Space Telescope are awe-inspiring. While this is the most technically advanced and powerful telescope ever created, the learnings about our universe will lead to future missions and exploration for generations ahead. Recently, the newest mission to the moon was launched as NASA’s Artemis Program which will pave the way for a future mission to Mars. This new era of space exploration will drive technological advancements in fields beyond astronautics and stimulate progress in real-world applications like materials, food science , agriculture, and even cosmetics.

A milestone in AI predictions

For decades, the scientific community has chased a greater understanding of relationships between protein functions and 3D structures. In July 2022, Deep Mind revealed that the folded 3D structure of a protein molecule can be predicted from its linear amino-acid sequence using AlphaFold2 , RoseTTAFold , and trRosettaX-Single algorithms. The algorithms’ predictions reduced the number of human proteins with unknown structural data from 4,800 to just 29. While there will always be challenges with AI, the ability to predict protein structures has implications across all life sciences. Key challenges in the future include modeling proteins with intrinsic disordered properties and those that change structures by post-translational modifications or to environmental conditions. Beyond protein modeling, AI advancements continue to reshape workflows and expand discovery capabilities across many industries and disciplines .

Developing trends in synthetic biology

Synthetic biology has the potential to redefine synthetic pathways by using engineered biological systems (i.e., microorganisms, for which a large part of the genome or the entire genome has been designed or engineered) to manufacture a range of biomolecules and materials, such as therapeutics, flavors, fabrics, food, and fuels. For example, insulin could be produced without pig pancreas, leather without cows, and spider silk without spiders. The potential in life sciences alone is unbelievable, but when applied to manufacturing industries, synthetic biology could minimize future supply chain challenges, increase efficiency, and create new opportunities for biopolymers or alternative materials with more sustainable approaches. Today, teams use AI-based metabolic modeling, CRISPR tools, and synthetic genetic circuits to control metabolism, manipulate gene expression, and build pathways for bioproduction. As this discipline begins to cross over into multiple industries, the latest developments and emerging trends for metabolic control and engineering challenges are showcased in a 2022 Journal of Biotechnology article .

Single-cell metabolomics set to soar

While much progress has been made in genetic sequencing and mapping, genomics only tells us what a cell is capable of. To have a better understanding of cellular functions, proteomic and metabolomic approaches offer different angles for revealing molecular profiles and cellular pathways. Single-cell metabolomics gives a snapshot of the cellular metabolism within a biological system. The challenge is that metabolomes change rapidly, and sample preparation is critical to understand cell function. Collectively, a series of recent advancements in single-cell metabolomics (from open-sourced techniques, advanced AI algorithms, sample preparations, and new forms of mass spectrometry) demonstrates the ability to run detailed mass spectral analyses. This allows researchers to determine the metabolite population on a cell-by-cell basis, which would unlock enormous potential for diagnostics. In the future, this could lead to the ability to detect even a single cancerous cell in an organism. Combined with new biomarker detection methods , wearable medical devices and AI- assisted data analysis, this array of technologies will improve diagnosis and lives.

New catalysts enable greener fertilizer production

Every year, billions of people depend on fertilizers for the ongoing production of food, and reducing the carbon footprint and expenses in fertilizer production would reshape the impact agriculture has on emissions. The Haber-Bosch process for fertilizer production converts nitrogen and hydrogen to ammonia. To reduce energy requirements, researchers from Tokyo Tech have developed a noble-metal-free nitride catalyst containing a catalytically active transition metal (Ni) on a lanthanum nitride support that is stable in the presence of moisture. Since the catalyst doesn't contain ruthenium, it presents an inexpensive option for reducing the carbon footprint of ammonia production. The La-Al-N support, along with the active metals, such as nickel and cobalt (Ni, Co), produced NH3 at rates similar to conventional metal nitride catalysts. Learn more about sustainable fertilizer production in our latest article .

Advancements in RNA medicine

While the application of mRNA in COVID-19 vaccines garnered lots of attention, the real revolution of RNA technology is just beginning. Recently, a new multivalent nucleoside-modified mRNA flu vaccine was developed. This vaccine has the potential to build immune protection against any of the 20 known subtypes of influenza virus and protect against future outbreaks. Many rare genetic diseases are the next target for mRNA therapies, as they are often missing a vital protein and could be cured by replacing a healthy protein through mRNA therapy. In addition to mRNA therapies, the clinical pipeline has many RNA therapeutic candidates for multiple forms of cancers, and blood and lung diseases. RNA is highly targeted, versatile, and easily customized, which makes it applicable to a wide range of diseases. Learn more about the crowded clinical pipeline and the emerging trends in RNA technologies in our latest CAS Insight Report.

Rapid skeletal transformation

Within synthetic chemistry, the challenge of safely exchanging a single atom in a molecular framework or inserting and deleting single atoms from a molecular skeleton has been formidable. While many methods have been developed to functionalize molecules with peripheral substituents (such as C-H activation), one of the first methods to perform single-atom modifications on the skeletons of organic compounds was developed by Mark Levin’s group at the University of Chicago . This enables selective cleaving of the N–N bond of pyrazole and indazole cores to afford pyrimidines and quinazolines. Further development of skeletal editing methods would enable rapid diversification of commercially available molecules, which could lead to much faster discoveries of functional molecules and ideal drug candidates.

Advancing limb regeneration

Limb loss is projected to affect over 3.6 million individuals per year by 2050. For the longest time, scientists believed the single biggest key to limb regeneration is the presence of nerves. However, work done by Dr. Muneoka and his team demonstrated the importance of mechanical load to digit regeneration in mammals and that the absence of a nerve does not inhibit regeneration. The advancement of limb regeneration was also achieved by researchers at Tufts University who have used acute multidrug delivery , via a wearable bioreactor, to successfully enable long-term limb regeneration in frogs. This early success could potentially lead to larger, more complex tissue re-engineering advances for humans, eventually benefiting military veterans, diabetics, and others impacted by amputation and trauma.

Nuclear fusion generates more net energy with ignition

Nuclear fusion is the process that powers the sun and stars. For decades, the idea of replicating nuclear fusion on earth as a source of energy, in theory, could fulfill all the planet's future energy needs. The goal is to force light atoms to collide so forcefully that they fuse and release more energy than consumed. However, overcoming the electrical repulsion between the positive nuclei requires high temperatures and pressures. Once overcome, fusion releases large amounts of energy, which should also drive the fusion of nearby nuclei. Previous attempts to initiate fusion used strong magnetic fields and powerful lasers but had been unable to generate more energy than they consumed.

Researchers at Lawrence Livermore National Laboratory’s ignition facility reported that the team was able to initiate nuclear fusion, which created 3.15 megajoules of energy from the 2.05 megajoule laser used. While this is a monumental breakthrough, the reality of a functioning nuclear fusion plant powering our grid may still be decades in the making. There are significant implementation hurdles (scalability, plant safety, energy required to generate the laser, wasted by-products, etc.) that must be addressed before this comes to fruition. However, the breakthrough of igniting nuclear fusion is a major milestone that will pave the way for future progress to be built upon this achievement.

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Science News

These are our favorite animal stories of 2023.

Even without a brain, the tiny Caribbean box jellyfish can learn to avoid obstacles, research revealed in 2023.

J. Bielecki

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By Darren Incorvaia

December 20, 2023 at 8:00 am

From birds repurposing antiavian architecture to jellyfish that can learn, here are dispatches from the animal kingdom that we went wild for in 2023.

Intelligent jellies

No brain? No problem. The fingernail-sized Caribbean box jellyfish ( Tripedalia cystophora ) uses its clusters of eyes and nerve cells to learn to avoid bumping into things, experiments in an aquatic obstacle course suggest ( SN: 9/22/23 ). In the box jelly’s natural habitat, where the creature must swerve to dodge mangrove roots in murky water, it pays to be a good pupil.

Prehistoric pout

Tyrannosaurus rex ’s menacing grin may have been less toothy than previously thought. Artistic renderings commonly depict the ravenous reptile as lipless, constantly baring its pearly whites. But T . rex may actually have had a pout that kept rows of pointy teeth covered, similar to Komodo dragons, an analysis of the skulls and teeth of dinosaurs and modern reptile suggests ( SN: 4/22/23, p. 6 ).

Revenge of the birds

City life can be hostile for birds. Municipalities across the world have put up spikes to prevent birds from roosting — and pooping — on streetlights, buildings and other structures. But some Eurasian magpies ( Pica pica ) and carrion crows ( Corvus corone ) in parts of Europe found a way to stick it to humans. The birds rip up antibird spikes and build nests with them ( SN: 9/9/23, p. 4 ). Magpies may even use the spikes as humans do, to ward off avian pests.

Swashbuckling spiders

Pirates on the high seas would be proud of their landlubbing arachnid counterparts. A species of cannibalistic pirate spider in Costa Rica tricks prey into walking the plank, right into its clutches ( SN: 10/7/23 & 10/21/23, p. 11 ). Gelanor siquirres casts a silk thread to intercept that of an unsuspecting orb weaver trying to build a web. When the eight-legged victim scuttles across its own silk thread to secure the other end, the orb weaver finds impending doom rather than harmless vegetation.

Desperate flies, desperate measures

Snow flies ( Chinoea spp.) have a macabre method to survive the frigid mountains and forests they call home. Dozens of flies that researchers subjected to below-zero temperatures self-amputated their limbs , but only when the limbs began to freeze ( SN: 7/15/23, p. 14 ). The flies probably shed the appendages to keep ice crystals from reaching the rest of the body.

Self-aware fish

When it comes to brainpower, this fish is no small fry. Not only can the bluestreak cleaner wrasse ( Labroides dimidiatus ) recognize itself in a mirror, the fish can also identify a picture of itself out of a lineup ( SN: 3/11/23, p. 13 ). The finding suggests the wrasse forms a mental image of itself — similar to what humans do — and that self-awareness may be more common in the animal kingdom than once thought.

Tight-gilled sharks

Regulating body temperature in chilly water is a challenge even for scalloped hammerhead sharks ( Sphyrna lewini ). To stay warm while hunting in the deep ocean, the sharks use a method normally seen in diving mammals: They hold their breath ( SN: 6/17/23, p. 10 ). Keeping gills closed holds in body heat, preventing the predators from becoming fish ice pops.

Big-mouthed snake

This African egg-eating snake redefines what it means to open wide. The Gans’ egg-eater ( Dasypeltis gansi ) can open its mouth wider than any other snake relative to its size, lab experiments suggest ( SN: 10/7/23 & 10/21/23, p. 36 ). An egg-eater with a 1-centimeter-wide head could fit a cylinder 5 centimeters across in its mouth. The reptile edges out the previous record holder: the Burmese python ( Python molurus bivittatus ).

Disaster dogs

The irradiated zone around Ukraine’s Chernobyl Nuclear Power Plant might be off-limits for humans, but other animals didn’t get the memo. Packs of feral dogs that for years have roamed the area abandoned since 1986 are genetically distinct from canines of similar breeds that live outside the zone ( SN: 4/8/23, p. 15 ). The differences probably aren’t due to radiation, researchers say. Whether Chernobyl’s radioactivity has had any effect on the dogs remains to be seen, but knowing their genetic makeup will help scientists spot potential radiation damage.

Landscaping ants

Many ants are expert navigators who use local landmarks to find their way around. But what’s an ant to do when the world around them is almost completely flat and featureless? Desert ants ( Cataglyphis fortis ) in Tunisia’s salt pans take matters into their own mandibles. Workers build tall mounds over their colonies’ nests so wayward foragers can find their way home ( SN: 7/1/23, p. 16 ).

More Stories from Science News on Animals

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Biological Physics Comes of Age

Once an awkward confrontation between disciplines, biological physics is having its moment — and showing that life is not just a mess..

Physics and biology were not always separate disciplines. In the 18th century, controversy about “animal electricity” proved foundational for the understanding of electricity more generally. In the 19th century, explorations of vision and hearing intermingled with the emerging understanding of optics and acoustics. In the 20th century, the chasm between physics and biology grew wider, but there were spectacular bridges. Most famously, the work that launched our modern view of life — structures of DNA and proteins, theories of base pairing and the genetic code — was done primarily in physics departments.

The revolutionary successes of (re-)connecting physics with biology in the mid-20th century completely changed how we think about life, and even changed how biologists’ work is organized. What emerged first was called molecular biology, and over the course of a generation the ideas and methods of molecular biology — grounded in physics — touched almost every part of the biological sciences. In contrast, physics itself was left relatively untouched.

Although the interaction of physics and biology did not immediately change the trajectory of physics, a small stream of physicists continued to be fascinated by the phenomena of life. I began to be (dimly) aware of all this as a student in the late 1970s. For me, the things biologists talked about were interesting, but the way they talked about them was unsatisfying. Physics was the other way: the style of thinking was attractive, and the theories elegant and powerful, but I never had an original idea about problems in the field’s traditional core. It was clear that physicists were doing all sorts of interesting things connected to the living world, but these efforts didn’t cohere into a community and certainly not into a recognizable branch of physics. We went to meetings where (mostly) we would find biologists working on the same systems, but not physicists asking the same kinds of questions.

If we asked our biology professors, they would argue that a physicist’s search for simplicity and universality was in obvious conflict with the complexity and diversity of life. If we asked our physics professors, they might talk about a colleague who had "become a biologist," and perhaps warn that experiments in biology are messy. Discussions with both groups could easily be less polite than I have rendered them here. While physicists and biologists didn’t agree on much, they did seem to agree that it was a waste of time to try doing theoretical physics in the complex context of living systems.

Forty years later, the intellectual landscape has changed radically. At the APS March Meeting, we see physicists attacking an enormous variety of problems drawn from the living world. They wrestle openly with the complexity of biological systems while searching for general principles, doing what we easily recognize as physics. More and more young people are entering the field: The number of doctoral students who write their theses in biological physics today is essentially the same as the number who wrote theses in particle physics a generation ago. Our community is no longer trapped at the interface between disciplines, and biological physics has emerged as a branch of physics. These developments are celebrated in the recent report from the National Academy of Sciences, Physics of Life — the first survey of the field as part of the broader decadal survey of physics.*

As a community, we have made progress not by ignoring the complexity of life’s mechanisms, but by taming it, revealing underlying physics problems. An important part of what drove this progress was the interaction between theory and experiment, as in other areas of physics. Theory suggested new experiments and new ways of looking at data, and new experimental techniques made once-abstract theoretical questions concrete and urgent. We have examples from the mechanics of DNA and folding/unfolding of proteins, from the control of gene expression and the development of embryos, from the mechanics of single cells and flow of tissues, from collective behaviors in bacterial communities and flocks of birds, from networks of neurons and animal behavior, from immunology and evolution, and more.

In this spirit, my colleagues and I have studied intact biological systems whose functional behaviors are reproducible in the second decimal place, and we think this precision is key to theoretical understanding. We may be wrong about the theory, but I hope these (and many other) experiments will banish forever the physicists’ old suspicion that life is just a mess.

The focus on specific systems means that we now have rather solid understanding of the physics that underlies many particular phenomena of the living world. This is wonderful. At the same time, theoretical physics is not a collection of isolated models for particular phenomena. Has the price of concrete success been the loss of once grand ambitions? I hope not.

The mechanisms of life really are complicated, and theoretical physicists are intolerant of complication. At the risk of being cartoonish, I’ve tried to classify the paths that theorists in our community are taking to cut through this complexity.

One possibility is that we should give up on the quantitative connections between theory and experiment that we expect in physics more broadly. Instead, we should explore theories that remind us loosely of the real thing, and hope that we can capture general trends. This was an especially common view when experiments were messier than they are now. We continue to learn from these simpler models, but the experimental situation today is vastly different. Better data demand better theory.

A deeper possibility is that the search for simplification misses the point. Real biological systems are described by models with a huge number of parameters, and there is no escape. The interesting theoretical problems are how experimental data allow us to infer the parameters, or how prediction might be possible even if not all parameters are known. This might once have seemed like giving up, but the revolution in machine learning has taught us that “over-parameterized” models can be powerful, even if we’re still searching for a compelling theory of how and why this works. Progress toward such a theory should change how we think about the physics of life.

If deep networks are a guide, perhaps living systems have so many ways of solving the problems essential for survival that making a predictive theory of the underlying mechanisms is hopeless. Instead, we should focus on how one generation of solutions is related to the next — the dynamics of evolution. Importantly, evolutionary dynamics can have regularities and perhaps universalities even though individual evolutionary trajectories are unique. Statistical physics has been crucial in uncovering these regularities, and in making connections to a new generation of quantitative experiments.

A different possibility draws from statistical and condensed matter physics. Successful models for macroscopic behaviors often are much simpler than the underlying microscopic dynamics, and the renormalization group (RG) gives us a framework for understanding how this is possible. Many biological physicists hope that some RG-like arguments could help us extract more universal functional behaviors from the complex microscopic mechanisms of life, but turning this into a concrete program remains challenging. A successful example is in the analysis of collective animal behaviors, such as flocking and swarming. Related ideas come from dynamical systems theory, where behaviors near bifurcations or decision boundaries take on universal forms.

The last approach rests on the fact that living organisms are not arbitrary collections of microscopic components. Rather, they have been selected by evolution to perform functions crucial to life: converting energy, sensing the environment, coordinating movements, and more. In many cases, real organisms get close to the physical limits on their performance, as with diffraction-limited imaging and photon counting in vision, molecule counting in bacterial chemotaxis, and the efficiency of neural coding. These observations suggest a variational principle, optimizing functional performance subject to physical constraints, thus determining the parameters of very complex mechanisms without fitting. There is a long tradition of taking this approach to coding and computation in the brain, and my colleagues and I are excited about progress in using this approach to understand genetic networks.

This classification is neither complete nor orthogonal, but I hope it gives some idea of what our community has been trying to do. Each approach has its advocates and detractors, as in any lively field.

The community’s experimental mastery over living systems, across scales from molecules to groups of organisms, continues to grow. One can count (almost) every messenger RNA molecule in a cell, labeled by the gene from which it was transcribed, and one can track every bird in a flock of thousands. If current trends continue, more and more of these experiments will be coupled to theory. For me, and for many of my theorist colleagues, the question is whether something unified will emerge from these efforts on specific systems — something that has the power and generality that we are used to in the rest of theoretical physics.

The emergence of biological physics is a multi-generational project. But while physics today is broader and deeper than ever before, our teaching has not kept pace. Conveying the excitement of diverse new opportunities while still transmitting the culture that unites us as physicists requires integrating new fields into the core curriculum.

The message of biological physics is that the beautiful phenomena of life connect to deep physical principles. Bacterial swimming and sensing are dominated by low Reynolds number mechanics and diffusion. Vision and photosynthesis illustrate how quantum mechanics can produce broad absorption bands rather than narrow spectral lines. DNA exemplifies the random polymer that appears in all statistical mechanics courses. These and other examples can show students that physics reaches far beyond the world of inclined planes, isolated atoms, and ideal gases, to life itself.

Beyond these now classical examples lies genuinely new physics, topics of current excitement in our field. Realizing the promise of biological physics will change how we think about life, how we think about physics, and how we think about ourselves.

*As with all Decadal Surveys of Physics, this is a “consensus report,” reflecting a large committee’s deliberations. I had the honor of chairing this committee, but I write here as an individual. I encourage you to read the report for a broader view.

William Bialek

William Bialek is the John Archibald Wheeler/Battelle Professor in Physics and a member of the multidisciplinary Lewis-Sigler Institute for Integrative Genomics, at Princeton University.

2023 BESIP Projects

The NIBIB-sponsored Biomedical Engineering Summer Internship Program (BESIP) is for undergraduate biomedical engineering students who have completed their junior year of college. The 10-week program, under the guidance of Dr. Robert Lutz, BESIP Program Director, allows rising senior bioengineering students to participate in cutting-edge biomedical research projects under the mentorship of world-class scientists in NIH laboratories in Bethesda, MD.

Adler – Sato - Choyke - 2023

Automation of radioactive cell labeling using microfluidic acoustophoresis

Intern Name: Emma Stevenson

Adler - Seidel - Green - 2023

Design and build an improved time-of-flight PET photodetector device

Basser – 2023

Use of MRI for Quantitative Imaging and Tissue Sciences

BETA Intern Name: Yem Nguimbous

Basser - Freidlin - Pohida – 2023

Augmented Reality Interactive Enhancements for Scientific Data Visualization and Manipulation

Bulea – 2023

Evaluation of Novel Approaches to Exoskeleton-Mediated Gait Training in Children

Intern Name: Elizabeth Barski

Cartegena-Rivera – 2023

Use of the Atomic Force Microscope (AFM) and mathematical modeling to understand the mechanobiology of cells and tissue

Intern Name: Adia Drayton

BETA Intern Name: Ike Keku

Damiano – Kline - 2023

Evaluating brain activity during functional tasks using noninvasive neuroimaging in healthy individuals and individuals with cerebral palsy

Ferrer – 2023

Biofabrication of engineered 3D tissues for disease modeling and drug discovery

Intern Name: Nolan Murphy-Genao

Frank – 2023

The molecular and cellular effects of Therapeutic and Focused Ultrasound on tissue microenvironment

Intern Name: Rohey Colley

Gandjbakhche - Pursley - Pohida – 2023

Self-Collection Homebased Biosensor for Monitoring and Tracking Suspected COVID-19 Patients

Intern Name: Varun Gunda

Hernandez - Kakareka - Morgan - Pohida - 2023

Optimization of Prolonged Normothermic Ex Vivo Animation of Human Tumor-bearing Liver Segments

BETA Intern Name: Joseph Editone III

Jin - Narum – 2023

Atomic Force Microscopy and Structure of Plasmodium falciparum Circumsporozoite Protein and Lipid Rafts

Intern Name: Olivia Ernst

Knepper – 2023

Application of Artificial Intelligence Methods to Predict Subcellular Locations of Proteins

Intern Name: Ryan Hsu

Knutson – 2023

Ultrafast laser microscopy to study proteins and DNA. Fluorescent Lifetime Imaging: Approaches and Applications

Intern Name: Adam Zuchowski

Larochelle – 2023

Genetic Engineering of Human Hematopoietic Stem Cells with CRISPR-Cas9: The Role of Innate Immunity

Lee – Krynitsky – Pohida – 2023

Characterizing Spontaneous Movements During Early Development of Mice

Maas-Moreno – 2023

Uncertainty characterization and propagation for emerging Nuclear Medicine targeted therapy

Nugent - 2023

Programming and advanced data analytic techniques in magnetoencephalography imaging

Platt - 2023

Magnetic Resonance Angiography to Assess Sickle Cell Disease Mediated Carotid and Cerebral Artery Damage

BETA Intern Name: Kingsley Garrett

BETA Intern Name: Jarrod Burns

Rivera - 2023

Use of the Atomic Force Microscope (AFM) and mathematical modeling to understand the mechanobiology of cells and tissues

Robey - Morgan - Gottesman - Pohida 2023

Microfabricated PDMS Vessel Mimetics for Cancer Cell Culture

Intern Name: Aasim Hawa

Sadtler – 2023

Role of innate immunity in medical device implantation and regenerative therapeutics

Intern Name: Paige Rudy

Sellers - Takagi - Billington - 2023

Deciphering the chemo-mechanical properties of myosin-6 using scattering and fluorescence single molecule techniques

Simonds – Salem – Pohida - 2023

Video Monitoring System for Automated Detection of Pain- and Itch- Related Behaviors in Mice

Summers – Liu – 2023

Deep learning to analyze anasarca in patients with major organ failure or cancer

Summers – Mathai – 2023

Project #1 – Identifying Bone Metastasis in CT scans Project #2 -  Quantification of Renal Structural Findings on CT/MRI

Summers – Mukherjee – 2023

Imaging Biomarkers for Diabetes Medications

Tanner - 2023

Measure the viscoelastic properties of zerbafish brain using frequency optical tweezers to understand how the micro -mechanical properties of tissue affect metastatic tumor outgrowth

Tanner – Krynitsky – Pohida – 2023

Cancer Studies Using a Novel 3D Printed Zebrafish Intubation Chamber for Longitudinal Imaging

Tosato – DiPrima – 2023

Targeting Eph Tyrosine Kinase Receptors in Colorectal Cancer

Intern Name: Kevin Gery

Tosato – Feng – 2023

Study of the contribution of endothelial cells to adult hematopoiesis

BETA Intern Name: Madeline Giner

Tromberg - Quang - Hill - 2023

Development of biomedical optics technologies that non-invasively characterize tissue hemodynamics and translate them to a point-of-care setting

Intern Name: Emily Yu

Valera - Romero – Ahdoot - Garmendia – Pohida – 2023

Developing an improved transurethral resection (TUR) device for bladder tumors

Intern Name: Emily Herbert

Wood - Mikhail - Negussie - 2023

Characterization of immunotherapy-loaded drug-eluting microspheres and gels for transarterial embolization of liver tumors

Intern Name: Mahid Qureshi

Wood - Mikhail - Xu – 2023

Applying artificial intelligence in medical imaging

Zaghloul – 2023

Engineering approaches involving computational and signal to develop insights into the neural code of the human brain

Intern Name: William Noll

• Chicago Cafe: California’s Oldest Chinese Restaurant
• Surprising Benefits of Using Sheep as Lawn Mowers
• California Families Project: Resilience and Community

This  In Focus  story is a part of Driven by Curiosity series.

LZ Experiment Sets New Record in Search for Dark Matter

New results leave fewer places for elusive dark matter particles to hide.

• by Lauren Biron
• August 26, 2024

Figuring out the nature of dark matter, the invisible substance that makes up most of the mass in our universe, is one of the greatest puzzles in physics. New results from the world’s most sensitive dark matter detector,  LUX-ZEPLIN (LZ), have narrowed down possibilities for one of the leading dark matter candidates: weakly interacting massive particles, or WIMPs.

LZ, led by the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), hunts for  dark matter from a cavern nearly one mile underground at the Sanford Underground Research Facility in South Dakota. Mani Tripathi, Distinguished Professor in the UC Davis Department of Physics and Astronomy, is a member of the LZ project team. 

The experiment’s new results explore weaker dark matter interactions than ever searched before and further limit what WIMPs could be.

“These are new world-leading constraints by a sizable margin on dark matter and WIMPs,” said Chamkaur Ghag, spokesperson for LZ and a professor at University College London (UCL). He noted that the detector and analysis techniques are performing even better than the collaboration expected. “If WIMPs had been within the region we searched, we’d have been able to robustly say something about them. We know we have the sensitivity and tools to see whether they’re there as we search lower energies and accrue the bulk of this experiment’s lifetime.”

Fewer places for WIMPs to hide

The collaboration found no evidence of WIMPs above a mass of 9 gigaelectronvolts/c 2 (GeV/c 2 ). (For comparison, the mass of a proton is slightly less than 1 GeV/c 2 .) The experiment's sensitivity to faint interactions helps researchers reject potential WIMP dark matter models that don't fit the data, leaving significantly fewer places for WIMPs to hide. The new results were presented at two physics conferences on August 26: TeV Particle Astrophysics 2024 in Chicago, Illinois, and LIDINE 2024 in São Paulo, Brazil. A scientific paper will be published in the coming weeks.

The results analyze 280 days’ worth of data: a new set of 220 days (collected between March 2023 and April 2024) combined with 60 earlier days from LZ’s first run. The experiment plans to collect 1,000 days’ worth of data before it ends in 2028. 

“If you think of the search for dark matter like looking for buried treasure, we’ve dug almost five times deeper than anyone else has in the past,” said Scott Kravitz, LZ’s deputy physics coordinator and a professor at the University of Texas at Austin. “That’s something you don’t do with a million shovels – you do it by inventing a new tool.”

LZ’s sensitivity comes from the myriad ways the detector can reduce backgrounds, the false signals that can impersonate or hide a dark matter interaction. Deep underground, the detector is shielded from cosmic rays coming from space. To reduce natural radiation from everyday objects, LZ was built from thousands of ultraclean, low-radiation parts. The detector is built like an onion, with each layer either blocking outside radiation or tracking particle interactions to rule out dark matter mimics. And sophisticated new analysis techniques help rule out background interactions, particularly those from the most common culprit: radon.

This result is also the first time that LZ has applied “salting”– a technique that adds fake WIMP signals during data collection. By camouflaging the real data until “unsalting” at the very end, researchers can avoid unconscious bias and keep from overly interpreting or changing their analysis.

“We’re pushing the boundary into a regime where people have not looked for dark matter before,” said Scott Haselschwardt, the LZ physics coordinator and a recent Chamberlain Fellow at Berkeley Lab who is now an assistant professor at the University of Michigan. “There’s a human tendency to want to see patterns in data, so it’s really important when you enter this new regime that no bias wanders in. If you make a discovery, you want to get it right.”

The invisible 85 percent

Dark matter, so named because it does not emit, reflect, or absorb light, is estimated to make up 85% of the mass in the universe but has never been directly detected, though it has left its fingerprints on multiple astronomical observations. We wouldn’t exist without this mysterious yet fundamental piece of the universe; dark matter’s mass contributes to the gravitational attraction that helps galaxies form and stay together.

LZ uses 10 tonnes of liquid xenon to provide a dense, transparent material for dark matter particles to potentially bump into. The hope is for a WIMP to knock into a xenon nucleus, causing it to move, much like a hit from a cue ball in a game of pool. By collecting the light and electrons emitted during interactions, LZ captures potential WIMP signals alongside other data. 

“We’ve demonstrated how strong we are as a WIMP search machine, and we’re going to keep running and getting even better – but there’s lots of other things we can do with this detector,” said Amy Cottle, lead on the WIMP search effort and an assistant professor at UCL. “The next stage is using these data to look at other interesting and rare physics processes, like rare decays of xenon atoms, neutrinoless double beta decay, boron-8 neutrinos from the sun, and other beyond-the-Standard-Model physics. And this is in addition to probing some of the most interesting and previously inaccessible dark matter models from the last 20 years.”

LZ is a collaboration of roughly 250 scientists from 38 institutions in the United States, United Kingdom, Portugal, Switzerland, South Korea, and Australia; much of the work building, operating, and analyzing the record-setting experiment is done by early career researchers. The collaboration is already looking forward to analyzing the next data set and using new analysis tricks to look for even lower-mass dark matter. Scientists are also thinking through potential upgrades to further improve LZ, and planning for a next-generation dark matter detector called XLZD.

“Our ability to search for dark matter is improving at a rate faster than Moore’s Law,” Kravitz said. “If you look at an exponential curve, everything before now is nothing. Just wait until you see what comes next.”

LZ is supported by the U.S. Department of Energy, Office of Science, Office of High Energy Physics and the National Energy Research Scientific Computing Center, a DOE Office of Science user facility. LZ is also supported by the Science & Technology Facilities Council of the United Kingdom; the Portuguese Foundation for Science and Technology; the Swiss National Science Foundation, and the Institute for Basic Science, Korea. Over 38 institutions of higher education and advanced research provided support to LZ. The LZ collaboration acknowledges the assistance of the Sanford Underground Research Facility.

Media Resources

News release from Lawrence Berkeley Lab

LUX-ZEPLIN Dark Matter Detector Starts Up (2022)

Media Contacts

• Mani Tripathi, Physics and Astronomy, [email protected]
• Andy Fell, UC Davis News and Media Relations, 530-304-8888, [email protected]

Lauren Biron is a science writer at the Lawrence Berkeley Laboratory. 

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Collection  13 June 2023

Innovations in Stem Cell Biology 2023

Stem cell models of development, regeneration, and disease are quickly advancing. New technologies and concepts are continuously combined with existing knowledge to create more realistic systems to improve our understanding of these intricate processes.

In this collection, we highlight papers published in 2022-2023 across Nature Portfolio journals on topics including embryonic development and stem cells, reproductive biology, synthetic tissues and embryo models, clinical and translational research and tissue stem cells.

Please review the editorial policies and peer review processes for each participating journal by visiting the links provided in the "Participating Journals" tab.

Robert Stephenson

Nature, Locum Senior Editor

Stylianos Lefkopoulos

Nature Cell Biology, Associate Editor

Madhura Mukhopadhyay

Nature Methods, Senior Editor

Tiago Faial

Nature Genetics, Chief Editor

Elisa Floriddia

Nature Neuroscicence, Senior Editor

Elvira Forte

Nature Cardiovascular Research, Associate Editor

Jerome Staal

Nature Medicine, Senior Editor

Evan Bardot

Nature Communications, Associate Editor

Aline Luckgen

Nature Communications, Senior Editor

Manuel Breuer

Communications Biology, Deputy Editor

Katherine Barnes

Communications Medicine, Senior Editor

• Collection content
• Participating journals

Embryoids and Organoids

Embryo model completes gastrulation to neurulation and organogenesis

Synthetic mouse embryos assembled from embryonic stem cells, trophoblast stem cells and induced extraembryonic endoderm stem cells closely recapitulate the development of wild-type and mutant natural mouse embryos up to embryonic day 8.5.

• Gianluca Amadei
• Charlotte E. Handford
• Magdalena Zernicka-Goetz

Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension

Bao et al. report that a cadherin code regulates the assembly and sorting of the first three cell lineages during mammalian development and can be manipulated to enhance the efficiency of synthetic embryogenesis.

• Jake Cornwall-Scoones

Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

Rosebrock, Arora et al. report a method to overcome limited cortical cellular diversity in human organoids, thus mirroring fundamental features of cortical development and offering a basis for organoid-based disease modelling.

• Daniel Rosebrock
• Sneha Arora
• Yechiel Elkabetz

Geometric engineering of organoid culture for enhanced organogenesis in a dish

A scalable platform with geometrical reconfiguration of culture systems for long-term growth and maturation of organoids.

• Sunghee Estelle Park
• Dan Dongeun Huh

De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids

Engraftment of human thymic organoids supports de novo development of a functional human T cell compartment in a humanized mouse model.

• Ann Zeleniak
• Connor Wiegand

Lineage recording in human cerebral organoids

A dual-channel recording system for high-resolution lineage tracing.

• Ashley Maynard
• Barbara Treutlein

Automated high-speed 3D imaging of organoid cultures with multi-scale phenotypic quantification

A method for high-content 3D imaging of organoids.

• Anne Beghin
• Gianluca Grenci
• Virgile Viasnoff

Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

Proximal nephron in pluripotent stem cell derived kidney organoids are immature with limited support for functional solute channels. Vanslambrouck et al report improved metanephric specification, generating enhanced kidney organoids with superior proximal tubules, spatially arranged nephrons, and applications for disease research, and drug screening.

• Jessica M. Vanslambrouck
• Sean B. Wilson
• Melissa H. Little

Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid

Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.

• Mariana A. Branco
• Tiago P. Dias
• Maria Margarida Diogo

Progenitors and Progeny

Progress and challenges in stem cell biology

Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self-renewal and differentiation toward diverse cell types. These abilities make stem cells an incredibly promising tool in therapeutics and have turned stem cell biology into a fast-evolving field. Here, stem cell biologists express their view on the most striking advances and current challenges in their field.

• Effie Apostolou

Molecular versatility during pluripotency progression

During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.

• Giacomo Furlan
• Aurélia Huyghe
• Fabrice Lavial

A 4D single-cell protein atlas of transcription factors delineates spatiotemporal patterning during embryogenesis

A protein expression atlas of transcription factors charted onto cell lineage maps of C aenorhabditis elegans development that uncovers mechanisms of spatiotemporal cell fate patterning and regulators of embryogenesis.

• Zhiguang Zhao

Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development

Single-cell RNA-sequencing of seven mouse developmental stages identifies lineage-specific and shared regulatory programs controlling cell-fate decisions. Cross-species analysis associates differentiation potency with ribosomal protein gene expression.

• Lijiang Fei

Bipotent transitional liver progenitor cells contribute to liver regeneration

Transitional liver progenitor cells (TLPCs), which derive from biliary epithelial cells (BECs), differentiate into hepatocytes after serious liver damage. Notch and WNT/β-catenin signaling regulate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively.

MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner

Disruption of MLL3/4 enzymatic activities prevents gastrulation and leads to early embryonic lethality in mice. This is largely due to defects in extraembryonic lineages, which compromise developmental progression.

Clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

Ratz et al. present an easy-to-use method to barcode progenitor cells, enabling profiling of cell phenotypes and clonal relations using single-cell and spatial transcriptomics, providing an integrated approach for understanding brain architecture.

• Michael Ratz
• Leonie von Berlin
• Jonas Frisén

Tmem88 confines ectodermal Wnt2bb signaling in pharyngeal arch artery progenitors for balancing cell cycle progression and cell fate decision

Using zebrafish as a model, Zhang et al. show that Tmem88a/b expression is required to balance proliferation and differentiation of pharyngeal arch artery progenitors into angioblasts by confining ectodermal Wnt2bb signaling.

• Mingming Zhang

Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth

Relatively little is known about the first hematopoietic stem and progenitor cells to arrive in the fetal bone marrow. Here they characterize the frequency, function, and molecular identity of fetal BM HSPCs and their bone marrow niche, and show that most BM HSPCs have little hematopoietic function until birth.

• Trent D. Hall
• Hyunjin Kim
• Shannon McKinney-Freeman

In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis

The lineage relationship between blood and endothelial cells has been difficult to examine due to the multiphasic timing of hematopoiesis in the embryo. Here the authors use using in vivo barcoding technology to assess cell ancestry and show that blood and endothelial cells emerge through common (haemangioblast) or separate (mesenchymoangioblasts and haematomesoblasts) progenitors in the yolk sac.

• T. S. Weber

Stem cell homeostasis regulated by hierarchy and neutral competition

A mathematical model of stem cell homeostasis is presented that comprehensively satisfies hierarchy and neutral competition is presented. The model predicts spontaneous generation of clonal bursts, which is consistent with primate hematopoietic data.

• Asahi Nakamuta
• Kana Yoshido
• Honda Naoki

Mechanical compression creates a quiescent muscle stem cell niche

Mechanical compression drives activated muscle stem cells (MuSCs) into a quiescent stem cell state providing insight into MuSC activity during injury-regeneration cycles.

• Jiaxiang Tao
• Mohammad Ikbal Choudhury
• Chen-Ming Fan

Disease Models and Therapies

Biomechanical, biophysical and biochemical modulators of cytoskeletal remodelling and emergent stem cell lineage commitment

This review highlights the biomechanical, biophysical, and biochemical modulators of cytoskeletal remodeling during tissue neogenesis in early development and postnatal healing for targeted tissue regeneration and regenerative medicine applications.

• Vina D. L. Putra
• Kristopher A. Kilian
• Melissa L. Knothe Tate

Policy for rare diseases

Professor Bobby Gaspar is a distinguished physician-scientist who is a thought leader in translating basic research from bench-to-bedside and strategic work that facilitated bringing life-saving therapies to patients with rare diseases. He has over 30 years of experience in pediatric medicine working in the NHS and the biotechnology sector, and is the founding member of Orchard Therapeutics, where he serves as Chief Executive Officer. In this Q&A, Professor Gaspar provides insight into the regulatory approval and policy considerations for bringing novel therapies for rare diseases from discovery through to clinical application.

Hijacking of transcriptional condensates by endogenous retroviruses

TRIM28 depletion in embryonic stem cells disconnects transcriptional condensates from super-enhancers, which is rescued by knockdown of endogenous retroviruses.

• Vahid Asimi
• Abhishek Sampath Kumar
• Denes Hnisz

CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states

Leng et al. establish CRISPRi screens in astrocytes to dissect pathways controlling inflammatory reactivity. They uncover two distinct inflammatory reactive signatures that are inversely regulated by STAT3 and validate that these exist in human disease.

• Indigo V. L. Rose
• Martin Kampmann

A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states

Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.

• Nina M. Dräger
• Sydney M. Sattler

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial

The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.

• Zachary D. Crees
• Michael P. Rettig
• John F. DiPersio

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study

Phase 1 trial results reveal that intrathecal transplantation of human fetal neural precursor cells in patients with progressive multiple sclerosis is feasible, safe and tolerable.

• Angela Genchi
• Elena Brambilla
• Gianvito Martino

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

• Robert H. Baloh
• J. Patrick Johnson
• Clive N. Svendsen

Hydrogel oxygen reservoirs increase functional integration of neural stem cell grafts by meeting metabolic demands

Injectable biomimetic hydrogels hold significant promise for tissue engineering applications. Here, the authors present a hybrid myoglobin:peptide hydrogel to overcome a critical oxygen shortage following neural stem cell transplantation, thus increasing cell survival and integration.

• E. R. Zoneff
• D. R. Nisbet

Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration

Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.

• Yuanxiong Cao

Msx1 + stem cells recruited by bioactive tissue engineering graft for bone regeneration

Critical-sized bone defects still present clinical challenges. Here the authors show that transplantation of neurotrophic supplement-incorporated hydrogel grafts promote full-thickness regeneration of the calvarium and perform scRNA-seq to reveal contributing stem/progenitor cells, notably a resident Msx1+ skeletal stem cell population.

• Xianzhu Zhang
• Hongwei Ouyang

An instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis

Limited stem cells and mismatched interface fusion have plagued biomaterial-mediated cranial reconstruction. Here, the authors engineer an instantly fixable and self-adaptive scaffold to promote calcium chelation and interface integration, regulate macrophage M2 polarization, and recruit endogenous stem cells.

• Gonggong Lu
• Xingdong Zhang

Infiltrating natural killer cells bind, lyse and increase chemotherapy efficacy in glioblastoma stem-like tumorospheres

“Super-charged” NK cells kill patient-derived glioblastoma stem-like cells (GSLCs) in 2D and 3D tumor models, secrete IFN-γ and upregulate the surface expression of CD54 and MHC class I in GSLCs.

• Barbara Breznik
• Meng-Wei Ko
• Anahid Jewett

PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells

Hiramoto et al. develop a base-editing approach using SpCas9-NG, an engineered Cas9 with broad PAM flexibility, to correct a causative mutation in hemophilia B. Their approach is used to repair the point mutation in patient-derived iPSCs and restore coagulation factor IX expression in HEK293 cells and knock-in mice.

• Takafumi Hiramoto
• Yuji Kashiwakura
• Tsukasa Ohmori

Intraglandular mesenchymal stem cell treatment induces changes in the salivary proteome of irradiated patients

Lynggaard et al. profile the salivary proteome and metaproteome in patients with head and neck cancer who have received radiation therapy and an intraglandular mesenchymal stem cell (MSC) treatment for radiation-induced xerostomia and in healthy controls. MSC therapy impacts the composition of the salivary proteome in the longer-term.

• Charlotte Duch Lynggaard
• Rosa Jersie-Christensen
• Christian von Buchwald

Development and Reproduction

Generation of functional oocytes from male mice in vitro

Mouse induced pluripotent stem cells derived from differentiated fibroblasts could be converted from male (XY) to female (XX), resulting in cells that could form oocytes and give rise to offspring after fertilization.

• Kenta Murakami
• Nobuhiko Hamazaki
• Katsuhiko Hayashi

Metabolic regulation of species-specific developmental rates

An in vitro system that recapitulates temporal characteristics of embryonic development demonstrates that the different rates of mouse and human embryonic development stem from differences in metabolic rates and—further downstream—the global rate of protein synthesis.

• Margarete Diaz-Cuadros
• Teemu P. Miettinen
• Olivier Pourquié

Polycomb repressive complex 2 shields naïve human pluripotent cells from trophectoderm differentiation

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naïve human pluripotent cell differentiation into alternative lineages including trophoblasts.

• Banushree Kumar
• Carmen Navarro
• Simon J. Elsässer

Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naive human pluripotent cell differentiation into alternative lineages including trophoblasts.

• Dick W. Zijlmans
• Irene Talon
• Vincent Pasque

A single-cell transcriptome atlas profiles early organogenesis in human embryos

Xu et al. provide a single-cell transcriptomic atlas of 4–6 week human embryos, thereby profiling early human organogenesis.

• Tengjiao Zhang
• Weiyang Shi

Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells

Sequencing of human induced pluripotent stem cell lines highlights pervasive mutagenesis, heterogeneity between clones derived from the same individual during a single reprogramming experiment and positive selection for acquired mutations in BCOR .

• Foad J. Rouhani
• Xueqing Zou
• Serena Nik-Zainal

Pseudodynamic analysis of heart tube formation in the mouse reveals strong regional variability and early left–right asymmetry

Using high-resolution confocal images and computational surface mapping, Esteban et al. provide a detailed pseudodynamic atlas of early heart tube development (E7.5–E8.5), develop a morphometric staging system based on landmark curves and distances in the surface of the tissues and identify parameters that can be used for precise embryo staging across different labs. This morphometric analysis reveals early signs of left–right asymmetry, before the cardiac looping stage, which is regulated by the Nodal signaling pathway.

• Isaac Esteban
• Patrick Schmidt
• Miguel Torres

Human-gained heart enhancers are associated with species-specific cardiac attributes

Destici, Zhu, et al. identify human-specific cis -regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.

• Eugin Destici
• Neil C. Chi

A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity

Knight-Schrijver et al. use single-cell and single-nuclei RNA sequencing to profile the human fetal and adult epicardium in homeostatic conditions. The analysis shows fetal-specific epicardial gene programs that could support heart regeneration.

• Vincent R. Knight-Schrijver
• Hongorzul Davaapil
• Sanjay Sinha

Healthy cloned offspring derived from freeze-dried somatic cells

The development of safe preservation methods for genetic resources is important. Here, the authors successfully produce cloned mice from freeze-dried somatic cells, demonstrating the possibility of safe and low-cost preservation of genetic resources.

• Sayaka Wakayama
• Teruhiko Wakayama

Primate-specific transposable elements shape transcriptional networks during human development

The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.

• Julien Pontis
• Cyril Pulver
• Didier Trono

Induced pluripotent stem cells of endangered avian species

iPSCs from three endangered avian species (including Okinawa rail, Japanese ptarmigan, and Blakiston’s fish owl) are developed and characterized as a potential resource for their conservation.

• Masafumi Katayama
• Tomokazu Fukuda
• Manabu Onuma

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Teach students checking vs. savings accounts!

70 Best High School Science Fair Projects in Every Subject

Fire up the Bunsen burners!

The cool thing about high school science fair projects is that kids are old enough to tackle some pretty amazing concepts. Some science experiments for high school are just advanced versions of simpler projects they did when they were younger, with detailed calculations or fewer instructions. Other projects involve fire, chemicals, or other materials they couldn’t use before.

Note: Some of these projects were written as classroom labs but can be adapted to become science fair projects too. Just consider variables that you can change up, like materials or other parameters. That changes a classroom activity into a true scientific method experiment!

To make it easier to find the right high school science fair project idea for you, we’ve rated all the projects by difficulty and the materials needed:

Difficulty:

• Easy: Low or no-prep experiments you can do pretty much anytime
• Medium: These take a little more setup or a longer time to complete
• Advanced: Experiments like these take a fairly big commitment of time or effort
• Basic: Simple items you probably already have around the house
• Medium: Items that you might not already have but are easy to get your hands on
• Advanced: These require specialized or more expensive supplies to complete
• Biology and Life Sciences High School Science Fair Projects

Chemistry High School Science Fair Projects

Physics high school science fair projects, engineering high school stem fair projects, biology and life science high school science fair projects.

Explore the living world with these biology science project ideas, learning more about plants, animals, the environment, and much more.

Extract DNA from an onion

Difficulty: Medium / Materials: Medium

You don’t need a lot of supplies to perform this experiment, but it’s impressive nonetheless. Turn this into a science fair project by trying it with other fruits and vegetables too.

Re-create Mendel’s pea plant experiment

Difficulty: Medium / Materials: Medium ADVERTISEMENT

Gregor Mendel’s pea plant experiments were some of the first to explore inherited traits and genetics. Try your own cross-pollination experiments with fast-growing plants like peas or beans.

Make plants move with light

By this age, kids know that many plants move toward sunlight, a process known as phototropism. So high school science fair projects on this topic need to introduce variables into the process, like covering seedling parts with different materials to see the effects.

Test the 5-second rule

We’d all like to know the answer to this one: Is it really safe to eat food you’ve dropped on the floor? Design and conduct an experiment to find out (although we think we might already know the answer).

Find out if color affects taste

Just how interlinked are all our senses? Does the sight of food affect how it tastes? Find out with a fun food science fair project like this one!

See the effects of antibiotics on bacteria

Difficulty: Medium / Materials: Advanced

Bacteria can be divided into two groups: gram-positive and gram-negative. In this experiment, students first determine the two groups, then try the effects of various antibiotics on them. You can get a gram stain kit , bacillus cereus and rhodospirillum rubrum cultures, and antibiotic discs from Home Science Tools.

Learn more: Antibiotics Project at Home Science Tools

Witness the carbon cycle in action

Experiment with the effects of light on the carbon cycle. Make this science fair project even more interesting by adding some small aquatic animals like snails or fish into the mix.

Learn more: Carbon Cycle at Science Lessons That Rock

Look for cell mitosis in an onion

Cell mitosis (division) is actually easy to see in action when you look at onion root tips under a microscope. Students will be amazed to see science theory become science reality right before their eyes. Adapt this lab into a high school science fair project by applying the process to other organisms too.

Test the effects of disinfectants

Grow bacteria in a petri dish along with paper disks soaked in various antiseptics and disinfectants. You’ll be able to see which ones effectively inhibit bacteria growth.

Learn more: Effectiveness of Antiseptics and Disinfectants at Amy Brown Science

Pit hydroponics against soil

Growing vegetables without soil (hydroponics) is a popular trend, allowing people to garden just about anywhere.

More Life Sciences and Biology Science Fair Projects for High School

Use these questions and ideas to design your own experiment:

• Explore ways to prevent soil erosion.
• What are the most accurate methods of predicting various weather patterns?
• Try out various fertilization methods to find the best and safest way to increase crop yield.
• What’s the best way to prevent mold growth on food for long-term storage?
• Does exposure to smoke or other air pollutants affect plant growth?
• Compare the chemical and/or bacterial content of various water sources (bottled, tap, spring, well water, etc.).
• Explore ways to clean up after an oil spill on land or water.
• Conduct a wildlife field survey in a given area and compare it to results from previous surveys.
• Find a new use for plastic bottles or bags to keep them out of landfills.
• Devise a way to desalinate seawater and make it safe to drink.

Bunsen burners, beakers and test tubes, and the possibility of (controlled) explosions? No wonder chemistry is such a popular topic for high school science fair projects!

Break apart covalent bonds

Break the covalent bond of H 2 O into H and O with this simple experiment. You only need simple supplies for this one. Turn it into a science fair project by changing up the variables—does the temperature of the water matter? What happens if you try this with other liquids?

Learn more: Covalent Bonds at Teaching Without Chairs

Measure the calories in various foods

Are the calorie counts on your favorite snacks accurate? Build your own calorimeter and find out! This kit from Home Science Tools has all the supplies you’ll need.

Detect latent fingerprints

Forensic science is engrossing and can lead to important career opportunities too. Explore the chemistry needed to detect latent (invisible) fingerprints, just like they do for crime scenes!

Learn more: Fingerprints Project at Hub Pages

Use Alka-Seltzer to explore reaction rate

Difficulty: Easy / Materials: Easy

Tweak this basic concept to create a variety of high school chemistry science fair projects. Change the temperature, surface area, pressure, and more to see how reaction rates change.

Determine whether sports drinks provide more electrolytes than OJ

Are those pricey sports drinks really worth it? Try this experiment to find out. You’ll need some special equipment for this one; buy a complete kit at Home Science Tools .

Turn flames into a rainbow

You’ll need to get your hands on a few different chemicals for this experiment, but the wow factor will make it worth the effort! Make it a science project by seeing if different materials, air temperature, or other factors change the results.

Discover the size of a mole

The mole is a key concept in chemistry, so it’s important to ensure students really understand it. This experiment uses simple materials like salt and chalk to make an abstract concept more concrete. Make it a project by applying the same procedure to a variety of substances, or determining whether outside variables have an effect on the results.

Learn more: How Big Is a Mole? at Amy Brown Science

Cook up candy to learn mole and molecule calculations

This edible experiment lets students make their own peppermint hard candy while they calculate mass, moles, molecules, and formula weights. Tweak the formulas to create different types of candy and make this into a sweet science fair project!

Learn more: Candy Chemistry at Dunigan Science on TpT

Make soap to understand saponification

Take a closer look at an everyday item: soap! Use oils and other ingredients to make your own soap, learning about esters and saponification. Tinker with the formula to find one that fits a particular set of parameters.

Learn more: Saponification at Chemistry Solutions on TpT

Uncover the secrets of evaporation

Explore the factors that affect evaporation, then come up with ways to slow them down or speed them up for a simple science fair project.

Learn more: Evaporation at Science Projects

More Chemistry Science Fair Projects for High School

These questions and ideas can spark ideas for a unique experiment:

• Compare the properties of sugar and artificial sweeteners.
• Explore the impact of temperature, concentration, and seeding on crystal growth.
• Test various antacids on the market to find the most effective product.
• What is the optimum temperature for yeast production when baking bread from scratch?
• Compare the vitamin C content of various fruits and vegetables.
• How does temperature affect enzyme-catalyzed reactions?
• Investigate the effects of pH on an acid-base chemical reaction.
• Devise a new natural way to test pH levels (such as cabbage leaves).
• What’s the best way to slow down metal oxidation (the form of rust)?
• How do changes in ingredients and method affect the results of a baking recipe?

When you think of physics science projects for high school, the first thing that comes to mind is probably the classic build-a-bridge. But there are plenty of other ways for teens to get hands-on with physics concepts. Here are some to try.

Remove the air in a DIY vacuum chamber

You can use a vacuum chamber to do lots of cool high school science fair projects, but a ready-made one can be expensive. Try this project to make your own with basic supplies.

Learn more: Vacuum Chamber at Instructables

Put together a mini Tesla coil

Looking for a simple but showy high school science fair project? Build your own mini Tesla coil and wow the crowd!

Boil water in a paper cup

Logic tells us we shouldn’t set a paper cup over a heat source, right? Yet it’s actually possible to boil water in a paper cup without burning the cup up! Learn about heat transfer and thermal conductivity with this experiment. Go deeper by trying other liquids like honey to see what happens.

Build a better light bulb

Emulate Edison and build your own simple light bulb. You can turn this into a science fair project by experimenting with different types of materials for filaments.

Measure the speed of light—with your microwave

Grab an egg and head to your microwave for this surprisingly simple experiment. By measuring the distance between cooked portions of egg whites, you’ll be able to calculate the wavelength of the microwaves in your oven and, in turn, the speed of light.

Generate a Lichtenberg figure

See electricity in action when you generate and capture a Lichtenberg figure with polyethylene sheets, wood, or even acrylic and toner. Change the electrical intensity and materials to see what types of patterns you can create.

Learn more: Lichtenberg Figure at Science Notes

Explore the power of friction with sticky note pads

Difficulty: Medium / Materials: Basic

Ever try to pull a piece of paper out of the middle of a big stack? It’s harder than you think it would be! That’s due to the power of friction. In this experiment, students interleave the sheets of two sticky note pads, then measure how much weight it takes to pull them apart. The results are astonishing!

Build a cloud chamber to prove background radiation

Ready to dip your toe into particle physics? Learn about background radiation and build a cloud chamber to prove the existence of muons.

Measure the effect of temperature on resistance

This is a popular and classic science fair experiment in physics. You’ll need a few specialized supplies, but they’re pretty easy to find.

Learn more: Temperature and Resistance at Science Project

Launch the best bottle rocket

A basic bottle rocket is pretty easy to build, but it opens the door to lots of different science fair projects. Design a powerful launcher, alter the rocket so it flies higher or farther, or use only recycled materials for your flyer.

More Physics Science Fair Projects for High School

Design your own experiment in response to these questions and prompts.

• Determine the most efficient solar panel design and placement.
• What’s the best way to eliminate friction between two objects?
• Explore the best methods of insulating an object against heat loss.
• What effect does temperature have on batteries when stored for long periods of time?
• Test the effects of magnets or electromagnetic fields on plants or other living organisms.
• Determine the best angle and speed of a bat swing in baseball.
• What’s the best way to soundproof an area or reduce noise produced by an item?
• Explore methods for reducing air resistance in automotive design.
• Use the concepts of torque and rotation to perfect a golf swing.
• Compare the strength and durability of various building materials.

Many schools are changing up their science fairs to STEM fairs, to encourage students with an interest in engineering to participate. Many great engineering science fair projects start with a STEM challenge, like those shown here. Use these ideas to spark a full-blown project to build something new and amazing!

Construct a model maglev train

Maglev trains may just be the future of mass transportation. Build a model at home, and explore ways to implement the technology on a wider basis.

Learn more: Maglev Model Train at Supermagnete

Design a more efficient wind turbine

Wind energy is renewable, making it a good solution for the fossil fuel problem. For a smart science fair project, experiment to find the most efficient wind turbine design for a given situation.

Re-create Da Vinci’s flying machine

Da Vinci sketched several models of “flying machines” and hoped to soar through the sky. Do some research into his models and try to reconstruct one of your own.

Learn more: Da Vinci Flying Machine at Student Savvy

Design a heart-rate monitor

Smartwatches are ubiquitous these days, so pretty much anyone can wear a heart-rate monitor on their wrist. But do they work any better than one you can build yourself? Get the specialized items you need like the Arduino LilyPad Board on Amazon.

Race 3D printed cars

3D printers are a marvel of the modern era, and budding engineers should definitely learn to use them. Use Tinkercad or a similar program to design and print race cars that can support a defined weight, then see which can roll the fastest! (No 3D printer in your STEM lab? Check the local library. Many of them have 3D printers available for patrons to use.)

Learn more: 3D Printed Cars at Instructables

Grow veggies in a hydroponic garden

Hydroponics is the gardening wave of the future, making it easy to grow plants anywhere with minimal soil required. For a science fair STEM engineering challenge, design and construct your own hydroponic garden capable of growing vegetables to feed a family. This model is just one possible option.

Learn more: Hydroponics at Instructables

Grab items with a mechanical claw

Delve into robotics with this engineering project. This kit includes all the materials you need, with complete video instructions. Once you’ve built the basic structure, tinker around with the design to improve its strength, accuracy, or other traits.

Learn more: Hydraulic Claw at KiwiCo

Construct a crystal radio

Return to the good old days and build a radio from scratch. This makes a cool science fair project if you experiment with different types of materials for the antenna. It takes some specialized equipment, but fortunately, Home Science Tools has an all-in-one kit for this project.

Learn more: Crystal Radio at Scitoys.com

Build a burglar alarm

The challenge? Set up a system to alert you when someone has broken into your house or classroom. This can take any form students can dream up, and you can customize this STEM high school science experiment for multiple skill levels. Keep it simple with an alarm that makes a sound that can be heard from a specified distance. Or kick it up a notch and require the alarm system to send a notification to a cell phone, like the project at the link.

Learn more: Intruder Alarm at Instructables

Walk across a plastic bottle bridge

Balsa wood bridges are OK, but this plastic bottle bridge is really impressive! In fact, students can build all sorts of structures using the concept detailed at the link. It’s the ultimate upcycled STEM challenge!

Learn more: TrussFab Structures at Instructables

Looking for more science content? Check out the Best Science Websites for Middle and High School .

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LHC Experiments at CERN Observe Quantum Entanglement at the Highest Energy Yet

The results open up a new perspective on the complex world of quantum physics.

September 18, 2024

Artist's impression of a quantum-entangled pair of top quarks. (Image: CERN)

Editor’s note: The following press release was issued today by CERN, the European Organization for Nuclear Research. The U.S. Department of Energy's Brookhaven National Laboratory serves as the U.S. host laboratory for the ATLAS experiment at CERN’s Large Hadron Collider and plays multiple roles in this international collaboration, from construction and project management to data storage, distribution, and analysis. For more details on Brookhaven’s contributions to the ATLAS experiment, visit the Lab’s ATLAS website . For more information on Brookhaven’s role in this research, contact Stephanie Kossman ( [email protected] , 631-344-8671).

Geneva, 18 September 2024. Quantum entanglement is a fascinating feature of quantum physics – the theory of the very small. If two particles are quantum-entangled, the state of one particle is tied to that of the other, no matter how far apart the particles are. This mind-bending phenomenon, which has no analogue in classical physics, has been observed in a wide variety of systems and has found several important applications, such as quantum cryptography and quantum computing. In 2022, the Nobel Prize in Physics was awarded to Alain Aspect, John F. Clauser and Anton Zeilinger for groundbreaking experiments with entangled photons. These experiments confirmed the predictions for the manifestation of entanglement made by the late CERN theorist John Bell and pioneered quantum information science.

Entanglement has remained largely unexplored at the high energies accessible at particle colliders such as the Large Hadron Collider (LHC). In an article published today in Nature , the ATLAS collaboration reports how it succeeded in observing quantum entanglement at the LHC for the first time, between fundamental particles called top quarks and at the highest energies yet. First reported by ATLAS in September 2023 and since confirmed by two observations made by the CMS collaboration, this result has opened up a new perspective on the complex world of quantum physics.

"While particle physics is deeply rooted in quantum mechanics, the observation of quantum entanglement in a new particle system and at much higher energy than previously possible is remarkable,” says ATLAS spokesperson Andreas Hoecker. “It paves the way for new investigations into this fascinating phenomenon, opening up a rich menu of exploration as our data samples continue to grow."

The ATLAS and CMS teams observed quantum entanglement between a top quark and its antimatter counterpart. The observations are based on a recently proposed method to use pairs of top quarks produced at the LHC as a new system to study entanglement.

The top quark is the heaviest known fundamental particle. It normally decays into other particles before it has time to combine with other quarks, transferring its spin and other quantum traits to its decay particles. Physicists observe and use these decay products to infer the top quark’s spin orientation.

To observe entanglement between top quarks, the ATLAS and CMS collaborations selected pairs of top quarks from data from proton–proton collisions that took place at an energy of 13 teraelectronvolts during the second run of the LHC, between 2015 and 2018. In particular, they looked for pairs in which the two quarks are simultaneously produced with low particle momentum relative to each other. This is where the spins of the two quarks are expected to be strongly entangled.

The existence and degree of spin entanglement can be inferred from the angle between the directions in which the electrically charged decay products of the two quarks are emitted. By measuring these angular separations and correcting for experimental effects that could alter the measured values, the ATLAS and CMS teams each observed spin entanglement between top quarks with a statistical significance larger than five standard deviations .

In its second study , the CMS collaboration also looked for pairs of top quarks in which the two quarks are simultaneously produced with high momentum relative to each other. In this domain, for a large fraction of top quark pairs, the relative positions and times of the two top quark decays are predicted to be such that classical exchange of information by particles traveling at no more than the speed of light is excluded, and CMS observed spin entanglement between top quarks also in this case.

“With measurements of entanglement and other quantum concepts in a new particle system and at an energy range beyond what was previously accessible, we can test the Standard Model of particle physics in new ways and look for signs of new physics that may lie beyond it,” says CMS spokesperson Patricia McBride.

2024-22088  |  INT/EXT  |   Newsroom

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2023 AWG Symposium – The Year of Open Science: Summary and Recordings

On Thursday, March 16th, Open Science hosted the 2023 Analysis Working Group (AWG) Symposium from 10 am – 2:30 pm Pacific Time. The theme focused around The Year of Open Science. This virtual event allowed the public an opportunity to view some exciting open science stemming from the AWG community and was attended by over 250 participants. The symposium was divided into morning and afternoon sessions, with the morning session containing opening remarks by GeneLab acting Project Scientist Lauren Sanders, an overview of NASA’s Transform to Open Science initiative (TOPS) by Space Biosciences Research Branch Chief Sylvain Costes, and an inspiring keynote address from AWG member, Eliah Overbey, who discussed sample analysis from the SpaceX Inspiration 4 mission. This was followed by science talks from the AWG community that included one presenter from each of the six AWGs—Animal, Plant, Microbes, Multi-Omics, Ames Life Sciences Data Archive (ALSDA), and Artificial Intelligence/Machine Learning (AI/ML). The afternoon session brought lightning science talks from AWG members with six additional speakers form each of the AWGs. Lastly, the elected leads from each of the AWGs presented an update on the status of each of the groups.

Did you miss this year’s AWG Symposium? Not to worry, a recording of the event is available below as well as on NASA GeneLab’s YouTube page. Also, learn more about how to  join the AWGs .

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North Central Climate Adaptation Science Center regional science plan—2023–28

The U.S. Geological Survey North Central Climate Adaptation Science Center (NC CASC), established in 2012, is part of a national network supporting climate-informed decisions that benefit wildlife and habitats. The NC CASC provides climate science for the U.S. Department of the Interior, State agencies, and Tribal nations to support effective resource management. Collaborating with the National and Regional Climate Adaptation Science Center network, the NC CASC addresses multiregion challenges through a partnership involving the U.S. Geological Survey and additional regional partners. Input is collected from an Advisory Committee of State, Federal, and Tribal Government representatives. The center hosts Tribal Climate Resilience Liaisons, which are funded by the Bureau of Indian Affairs Branch of Tribal Climate Resilience and aligned with a Tribal Engagement Strategy.

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