Molecular Life Sciences Research Articles

Novel Vibrational Proteins.

Genetically encoded green fluorescent protein (GFP) and its brighter and redder variants have tremendously revolutionized modern molecular biology and life science by enabling direct visualization of gene regulated protein functions on microscopic and nanoscopic scales. However, the current fluorescent proteins (FPs) only emit a few colors with an emission width of about 30-50 nm. Here, we engineer novel vibrational proteins (VPs) that undergo much finer vibrational transitions and emit rather narrow vibrational spectra (0.1-0.3 nm, roughly 3-10 cm-1). In response to an amber stop codon (UAG), a terminal alkyne bearing an unnatural amino acid (UAA, pEtF) is directly incorporated in place of Tyr64 in the chromophore of pr-Kaede by genetic code expansion. Essentially, the UAA64 further conjugates into a large π system with the contiguous two editable amino acid residues (His63 and Gly65), resulting in a programmable Raman resonance shift of the embedded alkyne. In the proof-of-concept experiment, we constructed a series of novel pEtF-VP mutants and observed fine Raman shifts of the alkynyl group in different chromophores. The genetically encoded novel VPs, could potentially label tens of proteins in the future.

Research highlights - The 2024 Richard Perham prize shortlist.

In this issue, we highlight the papers shortlisted for the 2024 Richard Perham prize. The papers discussed here were published in The FEBS Journal in 2023 and received prize nominations from the Editorial Board based on their scientific excellence, timeliness and broad appeal. The winning paper will be announced later this year, and authors will receive a cash prize. This batch of outstanding nominees spans original articles on a broad range of topics related to the molecular life sciences. Image created using Wordclouds.com.

Theory vs. experiment: The rise of the dynamic view of proteins

Over the past century, the scientific conception of the protein has evolved significantly. This paper focuses on the most recent stage of this evolution, namely, the origin of the dynamic view of proteins and the challenge it posed to the static view of classical molecular biology. Philosophers and scientists have offered two hypotheses to explain the origin of the dynamic view and its slow reception by structural biologists. Some have argued that the shift from the static to the dynamic view was a Kuhnian revolution, driven by the accumulation of dynamic anomalies, while others have argued that the shift was caused by new empirical findings made possible by technological advances. I analyze this scientific episode and ultimately reject both of these empiricist accounts. I argue that focusing primarily on technological advances and empirical discoveries overlooks the important role of theory in driving this scientific change. I show how the application of general thermodynamic principles to proteins gave rise to the dynamic view, and a commitment to these principles then led early adopters to seek out the empirical examples of protein dynamics, which would eventually convince their peers. My analysis of this historical case shows that empiricist accounts of modern scientific progress—at least those that aim to explain developments in the molecular life sciences—need to be tempered in order to capture the interplay between theory and experiment.

Liquid-Metal Molecular Scissors.

Molecules are the smallest units of matter that can exist independently, relatively stable, maintaining their physical and chemical activities. The key factors that dominate the structures and properties of molecules include atomic species, alignment commands, and chemical bonds. Herein, we reported a generalized effect in which liquid metals can directly cut off oxygen-containing groups in molecular matter at room temperature, allowing the remaining groups to recombine to form functional materials. Thus, we propose basic liquid-metal scissors for molecular directional clipping and functional transformations. As a proof of concept, we demonstrate the capabilities of liquid-metal scissors and reveal that the gallium on the surface of liquid metals directly extracts oxygen atoms from H2O or CH3OH molecules to form oxides. After clipping, the remaining hydrogen atoms from the H2O molecules recombine to form H2, while the remaining fragments of CH3OH produce H2, carbon materials, and carboxylates. This finding refreshes our basic understanding of chemistry and should lead to the development of straightforward molecular weaving techniques, which can help to overcome the limitations of molecular substances with single purposes. It also opens a universal route for realizing future innovations in molecular chemical engineering, life sciences, energy and environment research, and biomedicine.

The application of gene-editing technologies in plants

In recent years, we have witnessed a spurt of progress in modern molecular biology, thus enabling the perfection of genome sequencing. As a result, research into gene function has gained popularity among scientists. Since gene editing has served as an essential tool for the exploration of plant gene function, the utilization of genome editing technology contributes most to the genetic upgrading and crop breeding through modification on plant genome. Typical cases where CRISPR/Cas system has been applied to model species including Arabidopsis thaliana, Nicotiana tabacum and Oryza sativa to alleviate salinity stress and figure out the gene behind traits relative to their architecture and yield. The modified CRISPR/Cas9 system requires only simple cloning compared with the other two types of gene editing tools and the design of target sequences is easy, the construction of backbone vectors is simple, and the cost is relatively low. The CRISPR/Cas9 system, which was awarded the 2020 Nobel Prize in Chemistry, has transformed the molecular life sciences by enabling researchers to accurately modify the DNA of animals, plants, and microorganisms. This review thoroughly introduced gene editing technologies currently applied in plants, including map cloning, RNAi technology and targeted genome editing technology, containing ZFNs, TALEN, CRISPR/Cas9. The review revealed the difficulties and potential uses of genome editing technology in plants while concentrating on its theory and viability.

Molecular clips triggered on the active surface of liquid metals via oxygen capture at room temperature

Covalent bond breaking and reforming of molecules are the effective strategies to drive complex chemical reactions in clip chemistry. However, the harsh reaction conditions, complex reaction process, great energy consumption and high pollution have brought great obstacles to the previous clipping techniques. Herein, we propose a concept for molecules sustainable and directional clipping via oxygen capture at room temperature based on the special structures and interfacial properties of gallium-based liquid metals. As a proof-of-concept, we report the liquid metals of eGaIn, obtained by mixing of gallium with indium particles. The liquid phase transformation of eGaIn endowed them for an excellent active surface, which enabled spontaneously, rapidly, and directionally capturing oxygen from 1,3-butanediol molecules, and transformed into GaO(OH) semiconductor functional materials with a wide application potential. The oxygen-containing covalent bonds in 1,3-butanediol were randomly broken, including C–O and H–O, then multiple active groups were generated. After reconstruction, the active groups formed H2, carboxylates and carbon materials. These dispersed in 1,3-butanediol and endowed it with fluorescent properties under UV excitation. Particularly, liquid metals can be used as a basic tool for molecular directional clipping and obtaining specific functional materials. This finding refreshed our basic understanding of liquid metals, clip chemistry and molecules, led to easygoing practices of molecular weaving. It also has promising potential for future molecular engineering, life science, energy and environment, and biomedicine.

"Conducted Properly, Published Incorrectly": The Evolving Status of Gel Electrophoresis Images Along Instrumental Transformations in Times of Reproducibility Crisis.

For the last ten years, within molecular life sciences, the reproducibility crisis discourse has been embodied as a crisis of trust in scientific images. Beyond the contentious perception of "questionable research practices" associated with a digital turn in the production of images, this paper highlights the transformations of gel electrophoresis as a family of experimental techniques. Our aim is to analyze the evolving epistemic status of generated images and its connection with a crisis of trust in images within that field. From the 1980s to the 2000s, we identify two key innovations (precast gels and gel docs) leading to a "two-tiered" gel electrophoresis with different standardization procedures, different epistemic statuses of the produced images and different ways of generating (dis)trust in images. The first tier, exemplified by differential gel electrophoresis (DIGE), is characterized by specialized devices processing images as quantitative data. The second tier, exemplified by polyacrylamide gel electrophoresis (PAGE), is described as a routine technique making use of image as qualitative "virtual witnessing." The difference between these two tiers is particularly apparent in the ways images are processed, even though both tiers involve image digitization. Our account thus highlights different views on reproducibility within the two tiers. Comparability of images is insisted upon in the first tier while traceability is expected in the second tier. It is striking that these differences occur not only within the same scientific field, but even within the same family of experimental techniques. In the second tier, digitization entails distrust, whereas it implies a collective sentiment of trust in the first tier.

Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

Abstract Non-classically-restricted T cells have shown remarkable therapeutic activity in a variety of disease settings; most notably, CD8 T cells restricted to MHC-E (Qa-1 in mice; HLA-E in humans) have proven capable of eliminating a primate lentivirus infection. Here, we used mass spectrometry to identify a Qa-1-restricted 9-mer peptide, named M-SL9, that elicits a strong CD8 T cell response in mice infected with influenza A virus. The M-SL9 specificity accounted for roughly 5–10% of all lung CD8 T cells, approaching the frequency of classically restricted CD8 T cell responses to flu. A broad investigation of the M-SL9-specific T cells showed that they are generally similar in phenotype to classically restricted CD8 T cells, including strong co-expression of type 1-associated cytokines (polyfunctionality) and cytolytic markers; however, M-SL9-specific T cells were unique in that they were anatomically restricted to the lungs and were not present in blood and spleen like other specificities. Intriguingly, the M-SL9 epitope derives from a previously unknown translation product encoded by the +1 alternative reading frame of the matrix 1 (M1) protein-coding sequence. Presentation and immunogenicity of M-SL9 were completely dependent on ribosomal initiation at the second AUG codon of the matrix gene segment. Analysis of potential precursors suggests that M-SL9 is processed from a novel 16-mer peptide that is not required for viral replication in mice. These discoveries imply that unconventional epitopes may drive a large fraction of physiologically relevant T cell responses, and M-SL9 presents a highly tractable system in which to dissect the mechanisms governing MHC-E-restricted T cell responses and their protective effects. Supported by Cancer Research Institute Irvington Fellowship, Roy and Diana Vagelos Molecular Life Sciences Program and College Alumni Society Research Grant from the Univ. of Pennsylvania, and NIH grants R01 AI146101, R01 AI153064, R01 AI046709-18S1, R01 AI046709, R01 AI125524, and R21 AI153978.

DNA polymerase θ (POLQ): A druggable DNA polymerase for homologous recombination-deficient cancer cells

Irregularities in the DNA repair pathways are frequently observed in cancer. Dysregulated DNA repair pathways support growth advantages to tumor cells. DNA polymerase-theta (POLQ) is an error-prone DNA polymerase involved in double-strand break repair through microhomology-mediated end joining (MMEJ). POLQ also mediates translesion DNA synthesis and it is largely not expressed in normal cells. POLQ is overexpressed in a range of cancer cells, including homologous recombination (HR) deficient cancer cells. In HR deficient cells, MMEJ is crucial as a backup DNA repair pathway, indicating the indispensable role of POLQ-mediated MMEJ in HR deficient cancer cells. In addition, POLQ is synthetic lethal with a number of oncogenes. This viewpoint highlights the potential role of POLQ as a new target in the treatment of HR-deficient tumors and aims to develop enthusiasm to introduce fundamental aspects of Molecular Biology and Biochemistry to basic research related to Molecular Life Sciences, Cell Biology and Genetics in Sri Lanka as Molecular Biology and Biochemistry fundamentals can still do wonders in modern research.

Staudinger Ligation and Reactions – From Bioorthogonal Labeling to Next‐Generation Biopharmaceuticals

AbstractIn this review, we highlight groundbreaking discoveries and applications of Staudinger reactions in the molecular life sciences, starting from the engineering of the Staudinger ligation as a bioorthogonal reaction until most recent applications in modern bioconjugation methods to generate next‐generation biopharmaceuticals. Bioorthogonal reactions refer to a set of chemoselective transformations in biological environments able to take place in presence of naturally occurring functional groups. The Staudinger ligation set a new paradigm of such transformations, resulting in the development of various labeling and bioconjugation strategies for the modification of (bio‐)molecules of interest.

First Author Spotlight.

AnnouncementFirst Author SpotlightPublished Online:18 Nov 2022https://doi.org/10.1152/ajprenal.2022.323.5.AUMoreSectionsPDF (429 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat EDWIN J. BALDELOMARMallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri, United StatesFigure 1.Edwin J. BaldelomarDownload figureDownload PowerPointEdwin J. Baldelomar is an Instructor of Radiology at the Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis, MO. He earned a PhD in Physics at the University of Hawai’i at Manoa, HI, mentored by Dr. Kevin M. Bennett. Dr. Baldelomar has been a key contributor of novel imaging tools to investigate the heterogeneity of kidney microstructure and function at the scale of individual nephrons throughout the whole kidney. He is interested in applying his background in physical science to uniquely investigate biological and kidney systems. He is also interested in developing imaging tools toward clinical applications. Dr. Baldelomar was born in La Paz, Bolivia, and raised mostly in Texas. In his spare time, he enjoys watching and playing soccer with friends, spending quality time with others, and growing in his faith [Photo: Fig. 1].https://doi.org/10.1152/ajprenal.00103.2022BARNABAS P. ILENWABORDepartment of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The NetherlandsFigure 2.Barnabas IlenwaborDownload figureDownload PowerPointBarnabas Ilenwabor is a PhD candidate at the Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands. His PhD research focuses on the regulation of renal Mg2+ transport in health and rare monogenetic tubular disorders under the supervision of Prof. Dr. Joost Hoenderop and Dr. Jeroen de Baaij. In his spare time, Barnabas enjoys watching sporting activities like football, Formula 1, and tennis [Photo: Fig. 2].https://doi.org/10.1152/ajprenal.00101.2022RAM B. KHATTRIDepartment of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, United StatesFigure 3.Ram KhattriDownload figureDownload PowerPointRam Khattri is a postdoctoral associate in the Department of Applied Physiology and Kinesiology at the University of Florida, under the supervision of Dr. Terence Ryan. He completed his PhD in Chemistry from the University of Akron. At the University of Florida, he is working on studies related to the discovery of the mechanisms of muscle dysfunction in chronic kidney disease, impaired mitochondrial energetics as a driver of hemodialysis, and the roles of PFKFB3 in peripheral artery disease. Away from the laboratory bench, he enjoys outdoor activities such as bike riding and playing cricket, soccer, and badminton [Photo: Fig. 3].https://doi.org/10.1152/ajprenal.00156.2022YUJIRO MAEOKADivision of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, United StatesFigure 4.Yujiro MaeokaDownload figureDownload PowerPointYujiro Maeoka is a postdoctoral researcher in Dr. James McCormick’s laboratory at the Division of Nephrology and Hypertension, Oregon Health and Science University. He earned his MD degree and PhD degree at Hiroshima University, Hiroshima, Japan, where he studied the role of kidney-specific ubiquitin ligase, which protects cells from hypertonic stress. His current work focuses on the role of mutations in cullin 3, a key regulator of the WNK-SPAK/OSR1 kinase signaling pathway, in the pathogenesis of familial hyperkalemic hypertension. He spends his time away from the laboratory hiking with his family [Photo: Fig. 4].https://doi.org/10.1152/ajprenal.00153.2022TURUN SONGDivision of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United StatesFigure 5.Turun SongDownload figureDownload PowerPointTurun Song is a surgeon in the Organ Transplantation Center, Department of Urology, Institute of Urology of WestChina Hospitol, Sichuan University, Sichuan, China. He earned his MD degree from Sichuan University. Between 2018 and 2019, he spent more than 1 yr in Dr. Lerman's laboratory at Mayo Clinic for science training. His current research interests focus on senescence and renal ischemia-reperfusion injury and ABO-incompatible kidney transplantation. He has also specialized in robotic assisted kidney transplantation and performed more than 100 cases of it [Photo: Fig. 5].https://doi.org/10.1152/ajprenal.00064.2022This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformationRelated ArticlesMapping single-nephron filtration in the isolated, perfused rat kidney using magnetic resonance imaging 19 Oct 2022American Journal of Physiology-Renal PhysiologySLC41A1 knockout mice display normal magnesium homeostasis 19 Oct 2022American Journal of Physiology-Renal PhysiologyMetabolomic profiling reveals muscle metabolic changes following iliac arteriovenous fistula creation in mice 19 Oct 2022American Journal of Physiology-Renal PhysiologyCullin 3 mutant causing familial hyperkalemic hypertension lacks normal activity in the kidney 19 Oct 2022American Journal of Physiology-Renal PhysiologyExogenous pericyte delivery protects the mouse kidney from chronic ischemic injury 19 Oct 2022American Journal of Physiology-Renal Physiology More from this issue > Volume 323Issue 5November 2022Pages i-ii Crossmark Copyright & PermissionsPublished by the American Physiological Society.https://doi.org/10.1152/ajprenal.2022.323.5.AUPubMed36399095History Published online 18 November 2022 Published in print 1 November 2022 Metrics

Engineered helicase replaces thermocycler in DNA amplification while retaining desired PCR characteristics

Polymerase Chain Reaction (PCR) is an essential method in molecular diagnostics and life sciences. PCR requires thermal cycling for heating the DNA for strand separation and cooling it for replication. The process uses a specialized hardware and exposes biomolecules to temperatures above 95 °C. Here, we engineer a PcrA M6 helicase with enhanced speed and processivity to replace the heating step by enzymatic DNA unwinding while retaining desired PCR characteristics. We name this isothermal amplification method SHARP (SSB-Helicase Assisted Rapid PCR) because it uses the engineered helicase and single-stranded DNA binding protein (SSB) in addition to standard PCR reagents. SHARP can generate amplicons with lengths of up to 6000 base pairs. SHARP can produce functional DNA, a plasmid that imparts cells with antibiotic resistance, and can amplify specific fragments from genomic DNA of human cells. We further use SHARP to assess the outcome of CRISPR-Cas9 editing at endogenous genomic sites.

Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study.

<i>De novo</i> variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI). This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES. A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic <i>in silico</i> IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (<i>NLRP3</i> and <i>RELA</i>) and in potentially novel candidate genes, including <i>PSMB10</i>, <i>DDX1</i>, <i>KMT2C,</i> and <i>FBXW11</i>. The <i>FBXW11</i> canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease. Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for <i>FBXW11</i> loss-of-function mutations in autoinflammatory disease. This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.

Epilogue to the Gerald Maggiora Festschrift: a tribute to an exemplary mentor, colleague, collaborator, and innovator.

In May 2022, JCAMD published a Special Issue in honor of Gerald (Gerry) Maggiora, whose scientific leadership over many decades advanced the fields of computational chemistry and chemoinformatics for drug discovery. Along the way, he has impacted many researchers in both academia and the pharmaceutical industry. In this Epilogue, we explain the origins of the Festschrift and present a series of first-hand vignettes, in approximate chronological sequence, that together paint a picture of this remarkable man. Whether they highlight Gerry's endless curiosity about molecular life sciences or his willingness to challenge conventional wisdom or his generous support of junior colleagues and peers, these colleagues and collaborators are united in their appreciation of his positive influence. These tributes also reflect key trends and themes during the evolution of modern drug discovery, seen through the lens of people who worked with a visionary leader. Junior scientists will find an inspiring roadmap for creative collegiality and collaboration.

CPRiL: compound-protein relationships in literature.

Newly discovered functional relationships of (bio-)molecules are a key component in molecular biology and life science research. Especially in the drug discovery field, knowledge of how small molecules associated with proteins plays a fundamental role in understanding how drugs or metabolites can affect cells, tissues and human metabolism. Finding relevant information about these relationships among the huge number of published articles is becoming increasingly challenging and time-consuming. On average, more than 25000 new (bio-)medical articles are added to the literature database PubMed weekly. In this article, we present a new web server [compound-protein relationships in literature (CPRiL)] that provides information on functional relationships between small molecules and proteins in literature. Currently, CPRiL contains ∼465000 unique names and synonyms of small molecules, ∼100000 unique proteins and more than 9 million described functional relationships between these entities. The applied BioBERT machine learning model for the determination of functional relationships between small molecules and proteins in texts was extensively trained and tested. On a related benchmark, CPRiL yielded a high performance, with an F1 score of 84.3%, precision of 82.9% and recall of 85.7%. CPRiL is freely available at https://www.pharmbioinf.uni-freiburg.de/cpril. Supplementary data are available at Bioinformatics online.

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

Assessing the Load: Effects of Visual Representation and Task Features on Exam Performance in Undergraduate Molecular Life Sciences

Assessing the Load: Effects of Visual Representation and Task Features on Exam Performance in Undergraduate Molecular Life Sciences

The New “Normal”: Online Tools for In‐Person Learning in the Molecular Life Sciences

In the spring of 2020, the world experienced one of the worst pandemics in a century, forcing educators to almost immediately shift from on campus to online instruction. Given that most universities were largely built for teaching in person, the transition to distance learning required a rapid expansion of internet infrastructure and the mid‐semester implementation of online instructional tools. After the initial shock, confusion, and adjustment experienced in the spring of 2020, the continuation of the pandemic led many institutions to maintain a predominantly online or hybrid instruction model for the 2021 academic year. Although not as rushed as the previous semester, many faculty members were still trying to navigate the online landscape and adjust their curriculum to meet course objectives as defined during pre‐pandemic times. With universities inviting students back into the classroom and departments shifting more activities back to campus in the current academic year, we wanted to see what, if any, processes or activities implemented because of the pandemic would be retained or expanded post‐pandemic, specifically looking from the perspective of biochemists, molecular biologists, and science administrators. This feedback included information about alterations to in‐person instruction, communication with students outside of the classroom or laboratory, student assessment, additional educational opportunities that were not easily accessible previously, and enhanced research collaborations. Our conclusion is that, while few faculty members were interested in maintaining a primarily online format in future semesters, some distance learning tools were transferable to in‐person instruction and, in fact, enhanced the in‐person experience.

Connecting the Dots: Students’ Mental Organization and Storage of Biochemistry Visual Literacy Skills

Undergraduate molecular life science curricula rely on a variety of abstract visual representations to convey information. Intentional development of undergraduate students’ visual literacy skills has the potential to increase conceptual understanding while also decreasing cognitive load. There is little existing research that assesses how students interpret and store biochemical information and representations in their long‐term memory. Moreover, the number of validated instruments for measuring visual literacy is limited. Studies performed with undergraduate chemistry students measured students’ structural knowledge, or schema, of topics by asking them to rank the relatedness of words/phrases. Our study aims to develop a valid assessment tool that measures participants' schema of biochemistry visual literacy skills by asking them to rank the relatedness of biochemical representations instead of words/phrases. We created four surveys to evaluate vertical and horizontal translation visual literacy skills. With the use of Pathfinder, we analyzed the schema of undergraduate students with variable knowledge in biochemistry at four universities against an expert referentnetwork. Preliminary results also assess if pedagogical strategies and course instructional modalities impact student’s schema. The characterization of representational schema held by students and experts could aid the development of curricular materials for optimal learning and retention of information in the molecular life sciences.

Case study: Perspectives on the use of LEGO® bricks in the biochemistry classroom.

The use of LEGO® bricks in the higher education classroom has increased in the last two decades. This is no different in the STEM classroom and several disciplines, including physics, chemistry, and biology, have all made use of LEGO® bricks in some way to create models for active learning activities. Currently, the discipline to make the greatest use of LEGO® bricks is chemistry; only limited examples exist in biochemistry and the molecular life sciences. Here, we present the use of a LEGO® brick modelling activity in the introductory biochemistry classroom during the teaching of metabolism. We present student comments on the activity and the models that were generated by the students. Additionally, we focus on other instructor and project student-designed models for the teaching of ATP synthesis, gene regulation and restriction digestion. Interestingly, both the gene regulation and restriction digest activities were generated with the help of undergraduate students or recent graduates, by applying a backward design approach. This case study seeks to encourage more molecular life science educators to adopt the use of LEGO® bricks in their classrooms to engage in more active learning.