Toward a Beautiful Amalgam: The Necessity of Heterogeneity in RNA Science and Research Culture

Abstract

RNA biology exemplifies functional heterogeneitydistinct RNA classes are expressed in tissue- and development-specific contexts, adopt dynamic conformational ensembles, and form intricate, context-dependent interactions with proteins and other molecules to regulate gene expression. These features make RNA a powerful metaphor for reimagining scientific culture. Just as RNA achieves biological complexity through versatility, feedback loops, and communication, research environments thrive when they support dynamic interactions, structural adaptability, and the intentional inclusion of divergent perspectives and experiences. However, unlike RNA, research culture is shaped by human behavior, institutional norms, and systemic barriersforces that can suppress innovation and limit who contributes to scientific discovery. Scientific excellence demands the integration of wide-ranging perspectives to challenge paradigms and push boundaries. Yet entrenched structures often reward conformity and marginalize creativity born from difference. By embracing the principles inherent to RNA biologycontextual responsiveness, structural plasticity, and cooperativitywe can transform scientific culture into one that is more inclusive, welcoming, and adaptable. This perspective argues that the biological elegance of RNA offers more than molecular insight; it provides a conceptual framework for building research environments that harness the full spectrum of talent in our richly heterogeneous society, ultimately accelerating scientific progress and broadening its societal impact.

1. Introduction

The interactions that take place among researchers, as well as the influence of their various talents, perspectives, values, and motivations, lie at the heart of science culture. Centuries of inquiry and discovery have shown that science thrives as a collective enterpriseone that welcomes a multitude of viewpoints and encourages the development, critique, and refinement of a wide range of theories. Historians and philosophers who have examined the scientific process tend to share the belief that scientific progress is more likely to occur when research communities comprise members with a variety of skill sets, different areas of expertise, and a diverse range of professional and personal experiences. , Heterogeneous scientific communities can deploy a wider range of experiences to overcome barriers to progress, including unchallenged assumptions, underappreciated areas of study, and the exclusion of qualified participants. Scientists cannot predict when or from what avenues of investigation innovative ideas will emerge. To give just one example from the realm of RNA science: studies designed to investigate bacterial immunity inadvertently led to the identification of restriction enzymes and CRISPR-Cas systems-two tools that have revolutionized the fields of molecular biology and genetics. −

Homogeneous organizational models, in contrast, tend to stifle creative potential and diminish the pool of potential scientists. These models resist accommodating varied learning styles or perspectives and can undervalue the contributions of those with less expertise. The effects of homogeneity, whether in a biological or organizational context, can lead to the enrichment of undesirable traits. , In biology, such traits may result in susceptibility to pathology or in an inability to adapt and flourish. Reliance on the use of monocultures for banana cultivation in the early 20th century, for example, had dire consequences, including the near-complete loss of a variety from a single fungal infection, a problem that persists to this day, threatening the existence of the Cavendish variety. , Likewise, homogeneous scientific teams are at greater risk of rigidity in thinking, ranging from a fear of departing from the status quo to dogmatism.

To build a robust, adaptable, and responsive team, we must bring together a wide range of viewpoints and skills. To create a team with this range, we must include members from different disciplines, training levels, technical backgrounds, and cultural contexts. Equally important is creating the space and time needed to synthesize these diverse perspectives, allowing the most resilient and high-quality outcomes to emerge. ,− When scientific challenges are tackled, we must embrace iteration, maintain healthy skepticism, and rigorously scrutinize new findings. Just as vital is establishing a common language to foster effective communication and sustain momentum throughout the research process. Ultimately, heterogeneous scientific environments not only amplify the return on research investments but also accelerate discoveries that advance the greater good of humanity.

Our lab’s exploration of RNA biochemistry and biophysics has provided us with case studies that illustrate the value of heterogeneity and in turn has provided us with useful metaphors that we believe can benefit science culture. − The lessons we have learned about the versatility of RNA interactions, the feedback loops they employ in fine-tuning biological processes, and the communication strategies they use to link diverse components of protein-RNA systems are analogous to the advantages of heterogeneity in science culture.

In the following sections, we will demonstrate in parallel how heterogeneous RNA systems rely on a core set of principles to optimize biological outcomes and how these same principles can be applied to research environments to enhance the overall scientific experience, through repeating headings in the RNA Systems and Research Culture sections. Here, we provide examples that are well-known to the scientific community as well as those from our own area of RNA research to clearly demonstrate the lessons from RNA research that can be adapted to build a better and thriving research culture. Notably, this perspective is not meant to serve as a comprehensive review of RNA biology but rather to illustrate how the principles underlying RNA function can serve as a metaphor for how the scientific community can optimize the research enterprise.

2. Heterogeneous RNA Systems

2.1. Versatility and Diversity Lead to Optimization

According to the central dogma of molecular biology, which is now understood to be an incomplete model, genetic information was initially believed to flow only in a single direction, from DNA to RNA to protein. Although this model correctly identified RNA as a central regulator of life processes, it also oversimplified RNA’s role, reducing it to that of a passive messenger that merely copies and transmits genetic instructions. Likewise, before RNA components were formally identified and classified, some noncoding regions of RNA were thought to have no purpose. The RNA revolution in contemporary research has subsequently revealed that RNA is far more than just a decoder and that both coding and noncoding regions actively participate in a wide array of biological processes. , We are now familiar with an astounding diversity of RNA biotypes and RNA regulatory mechanisms that together play a role in nearly all aspects of cellular metabolism and adaptation. RNA’s inherent diversity and versatility allow for optimization across systems and in turn enhanced organismal fitness, while defects in RNA regulation are often associated with disease. ,

The diversity and versatility of RNA molecules are reflected in their multifunctional nature and the structural changes that facilitate them. While the coding role of RNA facilitates the production of proteins from DNA, noncoding functions of diverse types of RNA regulate various aspects of cellular homeostasis including protein production. , Figure is a generalized representation of several different origins of RNA heterogeneity and a subset of their respective outcomes.

1.

Representations of the RNA heterogeneity. RNA heterogeneity helps to regulate various essential biological processes, such as cellular differentiation, tissue/organ development, and response to environmental stress. This figure illustrates several well-known sources of RNA heterogeneity: (A) alternative splicing of pre-mRNA into different mature mRNAs gives rise to different protein products; (B) RNA modifications during stress conditions alter its stability, translation, or localization in order to adapt to a stressor; (C) specific regulatory elements, such as internal ribosome entry sites (IRES), within mRNAs that code for stress response proteins, help cells to survive during environmental stress conditions that interfere with the translation of the majority of proteins. (D) Different levels of gene expression aid in cellular differentiation and are responsible for their unique functions, (E) different RNA conformations allow the binding of specific sets of proteins, depending on cellular needs, and (F) RNA mutations can inhibit existing interactions with proteins/metabolites or facilitate new interactions with proteins/metabolites, to provide a survival advantage. mRNA: mRNA, pre-mRNA: premature mRNA, IRES: internal ribosome entry site.

At the molecular level, RNA adopts dynamic conformations, forming ensembles that govern interactions with proteins and other molecules. ,, Chemical modifications on RNA bases or its ribose sugar add yet another layer of complexity by altering these structural ensembles, thereby modulating interactions with other biological ligands. , RNA, in association with proteins, also organizes itself into membraneless, phase-separated condensates, creating microenvironments for specific biochemical reactions. − Adding to its intrigue, RNA exhibits cell- and tissue-specific expression patterns to produce the proteins that are needed to carry out cell- and tissue-specific functions. − Processes such as alternative splicing, post-transcriptional modifications, changes in gene expression, and conformational dynamics between different secondary and tertiary structures play critical roles in cellular differentiation during development, immune responses, and adaptation to environmental stress. ,,−

2.1.1. Example 1: RNA Modifications in Response to Environmental Stress Leads to Optimization

RNA modifications that occur in response to environmental stress illustrate one way that RNA heterogeneity leads to optimization. In response to various stress stimuli, modified RNA mediates the assembly of translation factors, mRNAs, RNA-binding proteins (RBPs), and other proteins to form membraneless cellular compartments called stress granules (SGs). , SGs play roles in the regulation of translation, cell signaling, mRNA storage, and stabilization during stress (Figure A). SGs quickly assemble upon exposure to stress and then rapidly disperse after the stress subsides. SGs further contribute to optimization on an organismal level by playing a role in innate immune responses to viral infections. Recent studies of SG dynamics have suggested that the regulated assembly of SGs, and in turn optimization, is absent in several pathophysiological conditions, including viral infections, cancer, and neurodegenerative diseases.

2.

Versatility and diversity of RNA led to optimization. (A) RNA modifications in response to environmental stress leads to optimization. This figure illustrates an example where RNA gets m⁶A-modified in response to environmental stress, which in turn mediates the assembly of translation factors, mRNAs, RNA-binding proteins (RBPs), and other cellular proteins to form membraneless cellular compartments called stress granules (SGs). Assembly and disassembly of SGs are highly dynamic, rendering diverse roles to optimize cellular functions during environmental stress. (B) Mutations in viral RNA leads to resistance against antiviral drugs. This figure illustrates an example where Enterovirus A71 evolves to possess a pair of nucleotide mutations in stem-loop II (SLII) within its 5′-UTR to gain resistance to an antiviral small molecule drug (DMA-135). The mutated SLII retains binding affinity for the positive regulatory protein hnRNPA1; however, DMA-135 forms a ternary complex with wild-type SLII and the negative regulatory protein AUF1, thereby preventing productive interactions with hnRNPA1. In contrast, AUF1 cannot bind mutated SLII due to the loss of its binding epitope.

2.1.2. Example 2: Mutations in Viral RNA Leads to Resistance against Antiviral Drugs

Viruses often exploit the versatility of RNA structures and interactions to drive replication and pathogenicity. The IRES located at the 5′-end of Enterovirus A71 (EV-A71) RNA adopts a conserved structure with 6 stem-loops that are unique to each other in their conformations. These structures coordinate the recruitment of a set of cellular proteins, which in turn regulate viral protein synthesis and genome replication (Figure B). Our research in collaboration with other groups has discovered a small molecule (SM) that binds to and perturbs the conformation of one of these stem-loops, thereby inhibiting EV-A71 replication. This inhibition was achieved because the SM induced a change in the stem-loop structure, which selectively enhanced its binding affinity for a negative regulator protein relative to that of the positive regulator protein of IRES-driven translation. To understand the selective pressure that the SM induces, we passaged the virus in culture iteratively. The virus developed resistance to the SM through a pair of nucleotide mutations adjacent to the SM binding site. These escape mutations represent a fundamental biological strategy by which RNA virusesincluding EV-A71leverage RNA heterogeneity to enable efficient replication and long-term persistence (Figure B).

2.2. Feedback Loops Lead to Optimization

When the cost of inaccuracy would prove to be intolerable, marked heterogeneity of biological systemsoften in the form of feedback loopsexists to optimize critical processes. Thus, many RNA-dependent systems employ feedback loops that enable the up- or down-regulation of various cellular responses to ensure the smooth functioning of an organism.

2.2.1. Example 1: Heterogeneity of miRNAs Regulates Cellular Processes and Enables Adaptation via Feedback Loops

The fine-tuning of gene expression through positive and negative feedback loops employed by miRNAs illustrates one way in which RNA heterogeneity contributes to the optimization of fundamental biological processes. MicroRNAs (miRNAs) are a class of short RNAs (19–24 nucleotides) that are well-known to bind messenger RNA (mRNA) and either initiate the degradation of mRNA or otherwise prevent downstream translation, thereby reducing the level of production of a given protein product. However, some miRNAs bind to specific regions of RNA to increase the abundance of certain proteins. This class of RNAs exhibits significant heterogeneity in both their nucleotide sequences and their capabilities. Many hundreds of miRNAs have been discovered so far, and it is estimated that together they are responsible for regulating the proteins encoded by approximately 30% to 80% of human genes.

The feedback loops used by miRNAs enable adaptation to changing conditions and enact suitable responses to various stimuli. The miRNA-mediated feedback loops are involved not only in sensing metabolites and regulating metabolic pathways but also in stress signaling pathways, where miRNA acts as a signal modulator. , Disruption of these feedback loops is known to result in various pathological conditions, including cancer, diabetes, cardiovascular, neurodegenerative, and autoimmune disorders.

Consider EV-A71: to date, several miRNAs (miR-296-5p, miR-23b, and miR-16–5p) are implicated in the suppression of viral replication. Out of them, miR-16–5p was demonstrated to be involved in two feedback loop mechanisms that inhibit EV-A71 replication (Figure A). Upon infection, EV-A71 induces the level of miR-16-5p itself as well as the activation of caspase that facilitates the processing of pri-miR-16-5p. The resultant higher levels of miR-16-5p in turn activate caspase-3, leading to cell apoptosis. Hence, miR-16-5p acts as a positive feedback regulator in EV-A71-induced cell apoptosis. In addition, increased levels of miR-16-5p suppress the expression of cell cycle regulator proteins cyclin E1 and cyclin D1. This inhibits cell division, resulting in the suppression of EV-A71 replication. In the latter process, miR-16-5p acts as a negative feedback regulator in EV-A71 replication. Hence, the host cell uses its elevated levels of miR-16-5p upon EV-A71 infection in two feedback loops, against the same virus to inhibit its replication and to abort the production and release of new viral particles. This is a great example of how our cells utilize feedback loops to gain protection against viral infections, thereby maintaining health/homeostasis.

3.

Heterogeneous RNAs are involved in feedback loops that lead to optimization. (A) Heterogeneity of miRNAs regulates cellular processes and enables adaptation via feedback loops. This figure illustrates an example where increased levels of miRNA-16-5p upon EV-A71 infection are involved in positive and negative feedback loops in order to provide immunity against EV-A71 via inhibition of viral replication. (B) RNA conformational heterogeneity regulates the translation of some genes in bacteria via riboswitches. This figure illustrates the function of the cobalamin (B₁₂) riboswitch at the 5′-end of the mRNA (btuB) encoding the cobalamin transport protein. Sufficient levels of cobalamin in the cytoplasm results in the binding of cobalamin to the riboswitch (translation ON), changing its confirmation to have a kissing-loop (KL) interaction, thereby sequestering theribosome-binding site (RBS). As a result, translation of mRNA is turned OFF, preventing excess intake of Cobalamin.

2.2.2. Example 2: RNA Conformational Heterogeneity Regulates Translation of Some Messages via Riboswitches

Another example of RNA feedback loops is riboswitches. These folding elements usually occur in the mRNAs of prokaryotes, eukaryotes, and archaea and exhibit RNA folding dynamics that are related to the binding of an aptamer to a ligand. − When the ligand is abundant, the equilibrium is pushed toward the binding competent fold, which usually overlaps with some part of the mRNA’s expression platform (or, in the eukaryotic case, the pre-mRNA’s splicing platform). This can either sequester or expose the elements of the expression platform needed for translation initiation, which provides positive or negative regulation of the gene product, respectively. Many riboswitch aptamers bind ligands that are produced by the gene encoded in the message that the riboswitch regulates, tightly integrating the feedback loop in one message. A classic explicit example of this would be an “off” or negative riboswitch that sequesters the ribosome binding site upon ligand binding by having it take part in a kissing loop interaction (Figure B). For example, the cobalamin (B12) riboswitch works via this mechanism. This tunes the genes that synthesize cobalamin, which the riboswitch appears upstream of, such that the level of cobalamin in the bacterial cell is kept relatively constant and the factors that synthesize it are not wastefully overproduced.

2.2.3. Example 3: RNA Conformational Heterogeneity Permits Concentration Window Modulation of Cellular Signals

Post-transcriptional modulation of gene products can also occur via 5′ UTR conformational changes, exposing binding sites for regulatory proteins. A concrete example of this comes from the interactions carbon storage regulatory protein A (CsrA) has with one of its many targets, the uxuB mRNA. The gene product is a d-mannonate oxidoreductase that uses NAD as a cofactor and allows bacteria to grow on fructuronate. , CsrA conventionally binds to a short RNA motif that matches the Shine-Dalgarno sequence but can bind to many alternative locations on RNAs. RNAs can occupy heterogeneous conformations that can then expose or sequester these CsrA binding sites.

In the case of uxuB, a CsrA binding site in the 5′ UTR and another within the first 100 nt of the coding sequence result in a tuned interplay that serves as a band-pass filter on the amount of gene product. At low concentrations of CsrA, the ribosome binding site (RBS) is sequestered in the secondary structure. As the protein binds to higher-affinity epitopes, cooperatively causing the 5′ UTR to refold, exposing the RBS, and resulting in more translation of uxuB. Because the RBS is a lower-affinity binding site for CsrA, at higher concentrations of CsrA it is occluded, inhibiting translation of uxuB. Through cooperative RNA–protein interactions, the level of uxuB production is restricted to a range of CsrA concentrations bracketed from above and below. This level setting prevents both over and underproduction of this metabolic gene used during fructonalose-based exponential phase growth in E. coli.

2.3. Communication Leads to Optimization

Part of the strength of RNA heterogeneity can be traced to its role in an interconnected, collaborative system, where it interacts with proteins and other macromolecules and can mobilize information across a range of compartments. Although a cell cannot possibly know what new problems it is likely to encounter, through channels of communication that link diverse components, cells can stay broadly prepared, coordinate, and communicate information to solve unexpected problems when they arise. Such communication involves a network of diverse RNA molecules whose communication among themselves and with other RNA, proteins, and metabolites leads to the optimization of an RNA-dependent system. The ability of different RNAs to fold into unique conformations that allow the binding of specific protein(s) drives RNA–protein communication, while the ability to form different types of base pairing drives RNA–RNA communication.

2.3.1. Example 1: Communication among Heterogeneous RNAs Facilitates Optimized Protein Synthesis

Protein synthesis, which takes place in the ribosome, provides an illustration of one way in which communication among heterogeneous RNAs within cells leads to the optimization of a process. Ribosome contains four distinct rRNAs (rRNAs), three in the large subunit, and one in the small subunit. Each rRNA adopts unique structural features spanning the RNA that permit precise interactions with ribosomal proteins to assemble the functional eukaryotic ribosome (Figure A).

4.

Communication mediated by heterogeneous RNAs leads to optimization. (A) Communication among heterogeneous RNAs facilitates optimized protein synthesis. This figure illustrates the heterogeneous rRNAs (rRNAs) that adopt unique structural features and interact precisely with ribosomal proteins (r-proteins) to assemble the functional eukaryotic ribosome. The mRNAs are heterogeneous and communicate the unique order of amino acids for proteins by copying the information encoded in DNA. This process of protein synthesis is possible only because of the vast heterogeneity among tRNAs, which have unique anticodon sequences and can attach to only one specific amino acid. (B) Communication mediated by heterogeneous viral RNA structures facilitates viral replication. This figure illustrates how the heterogeneity within the six stem-loop structures (SLI-VI) in the EV-A71 5′-UTR results in differential regulation of viral RNA replication and translation via recruiting unique sets of host proteins onto the cloverleaf structure and internal ribosome entry site (IRES), respectively.

Ribosomes are responsible for attaching amino acids in the order specified by mRNA to form proteins. All proteins are formed by different combinations of 20 amino acids. The mRNAs themselves are heterogeneous and communicate the unique order of amino acids for proteins by copying the information encoded in DNA. This process of protein synthesis is possible only because of the vast heterogeneity among tRNAs, which can attach to only one specific amino acid. The communication between the 3-nucleotide sequence (codon) in mRNA and the corresponding complementary sequence (anticodon) in a specific tRNA molecule results in mRNA–tRNA binding, followed by the attachment of the specific amino acid that tRNA brought to the site (Figure A). Most importantly, a tRNA attached to methionine recognizes and binds to the start codon on mRNA, thereby marking the accurate starting point for the ribosome for protein synthesis. Hence, the diversity of tRNA not only facilitates the synthesis of a protein with precise sequence but also allows the synthesis of any protein that is needed by the cell. Aberrant modifications or splicing of tRNA can result in miscommunication, which in turn results in the misincorporation of amino acids and the production of inaccurate protein products. Perturbation in these critical forms of communication has been implicated in many diseases, including cancer, diabetes, and neurological and neurodevelopmental disorders. ,

2.3.2. Example 2: Communication Mediated by Heterogeneous Virus- and Host-Derived RNAs Facilitate Viral Replication

EV-A71 replication depends on coordinated interactions between various RNA elements within its genome and host cellular RNAs to support viral protein synthesis and RNA replication. Although the 5′-UTR is a single RNA segment, it adopts six distinct stem-loop structures (SLI-SLVI), each playing critical roles in these processes. The SLI structure specifically facilitates viral RNA replication by recruiting essential protein components. In contrast, stem-loop SLII-SLVI collectively form the internal ribosome entry site (IRES), with each individual structure interacting with a unique set of host proteins to differentially regulate IRES-mediated (cap-independent) translation (Figure B). Some of the recruited host proteins enhance translation, while others inhibit it, enabling fine-tuned regulation of viral protein synthesis. Additionally, both virus- and host-derived noncoding RNAs regulate various stages of viral replication through multiple mechanisms. These include binding to viral RNA to modulate protein synthesis, interacting with host proteins to suppress antiviral defense pathways, and targeting host genes or mRNAs to either promote or suppress the expression of proteins that respectively support or restrict viral replication. −

In both examples, exquisite communication of different RNAs with proteins and RNA via the language of unique binding conformations and base pairing is what allows for precise information transfer across the layers in both viral and cellular biology. Thus, RNA is written in the language of biology and will be translated to coordinate and/or communicate among different components across biological systems.

3. Heterogeneous Research Culture

3.1. Versatility and Diversity Lead to Optimization

In much the same way that the versatility and diversity of RNA optimizes the response to a given condition, such as environmental stress, a scientific team comprising members with diverse skills and perspectives enhances the versatility of the team and increases the likelihood of solving a particular problem. ,,− Even opinions and perspectives that initially may seem irrelevant sometimes lead to breakthroughs and more creative problem-solving.

In conventional research culture, for example, observations or other input by members with less experience might be politely dismissednot because their contributions lack scientific merit, but simply because such members may lack extensive expertise in RNA biology. We’ve found that such dismissals can represent missed opportunities to embrace fresh perspectives and foster innovation. Inclusive scientific environments foster divergent and creative thinking by cultivating constructive cultures that value and support the contributions of each stakeholder, regardless of hierarchy or experience. ,− Optimized teams are grounded in a shared awareness that the scientific community functions best as an interconnected ecosystem in which curiosity and creativity can thrive.

3.1.1. Example 1: Accepting the Perspectives of Nonscientists without Judgment Leads to Versatility and Successful Research Outcomes

Versatility in scientific endeavors also sometimes involves openness to acquiring valuable missing information from an unexpected source outside the team. A member of our group experienced this while preparing to perform a surgical transplant on snails during his PhD research. The goal of the downstream experiments was to develop a novel strategy for germline integration of exogenous DNA in parasitic flatworms that had no stable genetic tools available. The first step in this process was developing a surgical protocol to infect snails via a transplant of cultured flatworm tissue. Such surgery involves making a 2 mm opening in a brittle snail shell. After several unsuccessful attempts using small-diameter drills in a hand-held rotary power tool, he shared the frustration of this experiment with his father, a trained machinist without academic training or experience in biology. However, the scientist’s father was able to quickly propose a solutionthe use of a bit capable of grinding slowly, rather than cutting, which would preserve the integrity of the brittle snail shell. This new tool advanced his team’s research and reinforced the importance of remaining open to new perspectives and contributions from individuals outside the academic scientific environment.

Great scientific discoveries often come when different disciplines intersect, and some of the best insights arise when researchers step outside their own field. Just as RNA structures and modifications shift and adapt within different cellular environments to often change their binding partners, science progresses when we embrace heterogeneous perspectives, different ways of thinking, forging of new relationships, and problem-solving approaches from various backgrounds. ,,,,

3.2. Feedback Loops Lead to Optimization

Much in the same way that RNA heterogeneity provides mechanisms for optimization by means of feedback loops, science culture should employ mechanisms of self-regulation and self-correction to continually tune its performance to its context. When obstacles or problems are encountered during scientific investigations, scientists must select “among a universe of potential adjustments” that can be made. They must determine which “among a universe of threads that can be tightened or loosened” will be most likely to “sustain the fabric” of an experiment or “reweave it”. ,, A heterogeneous team can be brought together to offer new insight, increase the speed of correction, and foster greater team cohesion that allows for more feedback to provided. ,,,,

3.2.1. Example 1: Feedback Loops Involving a Heterogeneous Team Improves Troubleshooting

The troubleshooting process during scientific research, in many ways, resembles a feedback loop process. In traditional feedback loops, an irregularity in the signal that leads to suboptimal functioning triggers corrective processes within the system that adjust to improve performance in a cyclical and continuous fashion. The product of the cycle becomes the input back into the cycle until a steady state is reached. Although mediated by human input, troubleshooting a scientific procedure is similar to a feedback loop in that it is a cyclical process of identifying problems in a suboptimally functioning system, and the product of one step (correcting one variable) becomes part of the input to the next step by changing how the procedure is conducted. If the suspected error is changed but does not fix the problem, that change is incorporated into the next round of testing until a “steady state” is reached, i.e., the procedure works, and the “input” of testing ideas can stop. Such troubleshooting also leverages heterogeneity by incorporating ideas regarding adjustments from multiple sources and from consultation with colleagues who have a variety of backgrounds, experiences, and perspectives. ,,,, When scientists work together and initiate a positive feedback loop, it can create optimally functioning and thriving scientific communities and accelerate the progress of scientific discovery. Implementing positive feedback loops in daily interactions contributes to the creation of productive research teams.

3.2.2. Example 2: Heterogeneous Research Teams Foster Cultures That Create Positive Feedback Loops That Improve the Experience of Science and Scientific Outputs

Research environments that value divergent views and foster spaces for constructive feedback are more likely to produce research outputs that are rigorously vetted internally, ultimately achieving a higher standard of excellence. Such a group is more likely to generate innovative research questions that can lead to greater scientific discoveries. ,− Unique experiences and ideas will provide multiple perspectives to investigate a given research question. Exposure to divergent perspectives among the group will help to eliminate potential biases in research design or data interpretation, thereby increasing the accuracy and reliability of the research findings. The impact of scientific discovery becomes greater when it is relevant, well-communicated, and accessible to a wider range of populations/communities. This attribute in scientific research is more likely to be achieved by a group of scientists with many different backgrounds.

In an optimally functioning laboratory, peer review is not confined to the final stages but occurs throughout the lifespan of a project, serving as an iterative feedback mechanism that continually refines the quality and interpretation of the science. To enable this, every member of the research team must feel safe to contribute their perspectives, information must be shared transparently, research silos must be dismantled, and hierarchical barriers based on experience should be flattened. When these conditions are met, emerging scientific concepts are sharpened and strengthened through internal iteration before being disseminated to the broader scientific community. The positive feedback loop existing within a heterogeneous group improves the research outcomes in an iterative way during each step of the process (generation of a research question, experimental design, data analysis, and outreach). Hence, functional diversity in research groups has the potential to create positive feedback loops that gradually enhance scientific discoveries to better serve humanity.

Over the years, our research team has included individuals from every stage of their academic journey. High school students have worked alongside undergraduates, graduate students, postdoctoral fellows, and senior scientists on major scientific projects. Nontraditional students and returning community college scholars have also actively contributed to the advancement of our research. This heterogeneity has not only enriched our scientific efforts but also fostered organic, continuous feedback loops. The diversity of experiences and perspectives has strengthened the quality of our work, deepened our collective understanding, and ultimately led to more rigorous and innovative science. Moreover, many of these individuals have persisted in scientific careers, in part due to a positive feedback culture that cultivated confidence and reinforced the development of a scientific identity.

3.3. Communication Leads to Optimization

One of the challenges in scientific research, especially in biology and RNA biochemistry, is that such work often requires an in-depth study of individual components within a biological system. While a division of labor among members of a team is an essential part of the process of scientific discovery, it can be easy for individual team members to lose sight of larger project goals. It is essential to link all the individual components of any project by means of a form of communication that optimizes the process of scientific inquiry. ,

3.3.1. Example 1: Success of a Research Project is Based on Proper Communication among the Diverse Members of the Team As Well As to the Scientific Community

The path toward the preparation of a scientific manuscript is a common example of a project involving the work of diverse members of our team, whose efforts must be linked by an avenue of communication. The process of curating data from individual experiments and compiling them to draft a manuscript requires the compilation of several smaller contributions into a larger cohesive whole. This journey for us often begins with a team meeting, during which we discuss the goal of the paper we hope to produce and determine the roles that individual authors will play in collecting data and relaying information to other team members. We then share updates, raw data, and early analyses of the data asynchronously using messaging and project management tools.

Because our team comprises biochemists, NMR experts, crystallographers, biologists, and other members with diverse training and research experience, it is necessary for us to write clearly, to define and explain as we go, rather than presuming comprehension. It has also been critical that we learn enough about what our lab mates are doing to understand each othera process of meeting someone partway across the difference in scientific experience that can exist between team members in heterogeneous groups. This helps us draw better conclusions from our findings because it brings the varying expertise and viewpoints of the group members into play. Subsequently, we compile all contributions and begin to draft a manuscript. This final stage of the process requires several authors to synthesize the team’s findings and create compelling language to appropriately articulate our findings and their importance in the field of RNA research.

3.3.2. Example 2: Communication among Diverse Members of a Team Drives Innovation and Better Research Outputs

Inadvertently, we recently gained interesting insight into our communication dynamics after a series of meetings that featured discussions focused on the topic of “allostery”, a mechanism of biochemical regulation by which long-distance communication can occur within molecules. For example, a single mutation of an amino acid in an RNA-binding protein can significantly affect RNA–protein interactions, even though the mutation and RNA-binding sites are located far apart from each other. Our group has recently experienced an influx of new staff scientists and postdocs with different areas of expertise who were just beginning to establish methods of communicating with one another. Our Principal Investigator broached the topic of “allostery” in RNA-binding proteins, which led to one of our senior scientists developing a new modeling analysis to characterize communication networks within RNA–protein complexes and propose likely routes of communication from distant mutations. The senior scientist’s work helped us not only to start a new research project but also to better understand that “allostery” is cooperation and communication across many small parts, including parts that may not seem related to the function of interest. These discussions helped us gain insight into our own dynamics, and it became clear that we all have similar effects on each other, and we can gain insight by communicating and seeking input even though we are focused on a different aspect of a project and bring divergent perspectives as part of our interpretation.

4. Conclusions and Outlook

Science historians have noted that by the early twentieth century, there was a significant shift in focus from individual scientists (luminaries such as Galileo and Newton) to the collective achievements of communities of scientists. ,, Scientific facts with a high degree of accuracy were believed to emerge most efficiently by means of evolutionary processes: incremental transformations in thinking by scientists with diverse backgrounds and viewpoints. This view of scientific progress continues today, as scientists share data, evaluate evidence, respond to criticism, and adjust their opinions within a larger scientific community and frameworks provided by peer-reviewed journals, scientific conferences, and educational programs.

Just as the strength of RNA-mediated biological systems can be traced to the heterogeneity of RNA, the strength of scientific communities and their findings frequently can be traced to the diversity of their membersa form of heterogeneity that helps to optimize the processes of scientific investigation in several important ways, including those that we have outlined here (Figure ). Just as the versatility and diversity of RNA molecules allow for multifunctionality, resilience, and enhanced fitness, fostering versatility and diversity within scientific culture enhances the discovery process by increasing flexibility, adaptability, and resourcefulness of a scientific team. Just as RNA-mediated feedback loops assist in upregulating or downregulating various processes in response to stimuli and in turn help to optimize the functioning of an organism, feedback loops in scientific research provide a system for locating and correcting errors, as well as allowing for the iterative development of ideas and the optimization of procedures. RNA’s role as an accurate carrier of genetic information and therefore a source of efficient communication throughout the cell is also instructive for research teams. In the scientific community, researchers must routinely link the efforts of separate subgroups devoted to specific tasks by establishing methods for successfully communicating data, procedures, and findings to optimize the process of scientific inquiry and increase the chances of success.

5.

Heterogeneity within a system leads to optimization. The heterogeneity of RNA optimizes and increases the fitness of RNA-mediated biological systems. Similarly, heterogeneity strengthens the scientific community and optimizes the process of scientific investigation.

Homogeneous scientific communities, whose backgrounds and assumptions are more likely to be shared by all members, are more vulnerable to the weaknesses that may be inherent in shared subjectivity. , The scientific conclusions of such communities are less likely to benefit from the “transformative interrogation” characteristic of heterogeneous communities. , In contrast, a heterogeneous group of scientists is likely to minimize shared subjectivity and correct individual biases and assumptions. Interactions among members of heterogeneous teams tend to be self-correcting and therefore tend to optimize the function of the group. , In general, conclusions are more likely to be accurate when an expert consensus emerges in a scientific community that is diverse and characterized by ample opportunities for peer review and openness and responsiveness to criticism. The divergent thinking and multifunctionality of heterogeneous teams also enable them to solve complex problems more efficiently and effectively. ,,

The strengths that characterize heterogeneous scientific communities have become increasingly important in recent years, as scientific conclusions regarding a wide range of subjectsfrom climate change to vaccine safetyhave attracted heightened skepticism. Public distrust of the sciences often can be traced to suspicions of undue influence or conflicts of interestas when scientific conclusions emerge from a single, homogeneous entity that provides funding and/or is focused on the promotion of its own interests. Heterogeneous scientific communities that can demonstrate, with integrity and transparency, the incorporation of diverse skillsets and backgrounds are more likely to encourage public trust by arriving at accurate, objective, and unbiased conclusions.

We opened this perspective with the following evocative question: Can our research cultures evolve toward greater innovation by embracing the very principles of biological heterogeneity that we passionately explore in our scientific investigations? We believe that the answer is a resounding yes.

Since founding our research group in 2009, we have intentionally cultivated a team whose members represent a wide range of backgrounds, career stages, intellectual perspectives, and technical expertise, all united in the pursuit of uncovering the fundamental principles of RNA biology. Our progress has been driven by an environment where every voice is heard and ideas are sharpened through open dialogue, constructive feedback, critical thinking, and the empowerment of divergent viewpoints. We actively draw on the unique insights of each team member to foster a sense of belonging, strengthen team dynamics, and propel our science forward.

Equally essential to our human diversity is our scientific approach: we deliberately integrate complementary and orthogonal methodologies to investigate RNA mechanisms with depth and rigor. These conditions have created more than a productive laboratory: they have nurtured a culture of collaboration, mutual growth, shared understanding, and intellectual curiosity. They remind us that heterogeneity, in both people and approaches, is not merely compatible with scientific excellence; it is fundamental to achieving it.

Scientific advancement is, at its core, a human endeavor. As such, our ideological beliefs, cultural norms, and adherence to the status quo inevitably shape the enterprise, determining not only how science is conducted but also who benefits from its discoveries. It is time for us as scientists to embody the very principles of biological heterogeneity that we so passionately explore in our research. By embracing greater heterogeneityof thought, background, experience, and approachwe can transform the culture of science and cultivate a more vibrant, inclusive, and innovative scientific community. In doing so, we not only expand the boundaries of discovery but also enhance our ability to address the most pressing challenges of our time and better serve the needs of humanity.

The authors declare no competing financial interest.

Published as part of ACS Bio & Med Chem Au special issue “Juneteenth 2025”.