The Use of Virtual Reality in the Teaching of Challenging Concepts in Virology, Cell Culture and Molecular Biology

The rapidly expanding biotechnology sector horizon is expected to create a surge in demand for expertise underpinning cell and gene therapies, which are recognized as the next generation of medicines. New and innovative approaches to implement active and performative learning in the Molecular Life Sciences are required to support this and to address limitations associated with traditional “front of class” lectern delivery of challenging, three dimensional molecular concepts. Therefore, an immediate need exists for the development and implementation of immersive learning approaches in Virology, Cellular Sciences and Molecular Biology to underpin sustainable development of graduate students for academic and industrial research careers. The Covid-19 pandemic has led to significant changes in the delivery of education globally, with online engagement and accelerated uptake of novel teaching and assessment modalities into majority practice within institutions. This development has been driven by externally imposed necessity and it remains to be seen what form teaching and learning will take post-Covid. Irrespective of the pandemic, technologies are available which can serve intrinsically motivated, discipline specific shifts toward enhanced learner experiences and learning outcomes. Immersive virtual reality offers one such approach to open new entry points for student learning of abstract molecular concepts, which will be just as relevant upon our return to face-to-face teaching. Key to delivering this will be engagement and collaboration by disciplinary and technical experts. Here, we discuss global advances in the area of VR and Molecular Science education and assess potential paths forward for teaching and learning impact and innovative education.


INTRODUCTION
There has been a long history of anecdotal evidence for the challenges around teaching and learning in molecular biology (Tibell and Rundgren, 2010). The Teaching for Understanding (TfU) framework aims to take generative topics, knowledge that is central to a discipline, and allow teachers to better understand what students know, for example through structured tasks known as performances of understanding (Blythe and Perkins, 1998;Wiske, 1998). The content of molecular life sciences is inherently complex, highly abstract, and deeply rooted in diverse disciplines ranging from biology and math, to medicine and agriculture, through to philosophy and ethics (Tibell and Rundgren, 2010). Therefore, new approaches have been needed for some time to engage students in this important discipline, and to design new entry points for the students to explore and engage in deep learning for these challenging concepts. There is an emerging viewpoint in cognition and learning that suggests the body and the mind are intrinsically linked with respect to learning. It follows therefore that the inability of students to directly experience the molecular world may explain many of the documented learning difficulties in molecular sciences e.g. various aspects of genetics, cell structure and function, and macromolecular structure, as well as issues related to size and scale (Bell, 2001;Tibell and Rundgren, 2010).
Apart from the abstract nature of molecular biology, and the lack of a tactile spatially oriented reference point for students, there is also a large gap between what is known by practicing molecular life scientists and what is taught about the domain in secondary schools and universities (Howitt et al., 2008). This gap is closing as research-led and research-based teaching find their way into the curriculum in many Universities, and yet the technologies underpinning molecular and cellular biology continue to advance apace. Also changing is the dynamic between lecturer and student, underpinned by the realization that the centuries old practice of the professor at the lectern cannot be sustained, nor was it ever ideal. A rich tapestry of investigative studies has revealed important insights into the learning experience that have guided new approaches to knowledge construction and the facilitation of deep learning (Sanchez-Sepulveda et al., 2019).

VIRTUAL REALITY TECHNOLOGIES AND THE STUDENT EXPERIENCE
Before addressing the utility of VR in education, it is first important to define the terms used in the industry and to acknowledge the variety of means through which one can engage in a VR experience. Arriving at a concise definition of VR's key characteristics is challenging due to the rapidly evolving nature of the technology. In the broad sense, VR can be categorized as desktop (D-VR, also referred to as a 2D simulation) and immersive VR (I-VR, which is typically multimodal by nature and provides a headset experience in 360°).
While there is some evidence to suggest that the specifications of the headsets are not paramount, with low-end headsets producing comparable learning outcomes to higher-end equipment (Selzer et al., 2019), there are important considerations in matching the technology requirements with the learning goals. Essentially, the level of immersion is constrained by the physical properties of the system (Slater, 2009), and a more immersive experience can lend itself to a higher degree of implicit learning (Slater and Wilbur, 1997). The Oculus Quest offers an immersive experience, and its compact self-contained form-factor enables users to operate independent of a fixed space. The HTC Vive Pro Eye and Vive Focus Plus headsets work through a desktop computer system (as with the Oculus Rift) and as such requires a dedicated space to be developed for its use. This becomes challenging where the group dynamic is favored, with self-paced learning more difficult to deliver in this setting, and the requirement for space being a significant issue. In contrast, the HoloLens offers an Augmented Reality (AR) experience and has very clear benefits for use in the exploration of molecular constructs.
Factors that have been described to influence the user experience with VR have included age, gender, sensationseeking tendency, personal innovativeness, and geographical location (Suh and Prophet, 2018). Coxon and colleagues reported that younger users are more likely to be engaged with an AR experience than older users (Coxon et al., 2016), while Plechatá and co-workers also described how older users were more likely to engage with a non-immersive experience (Plechatá et al., 2019). In contrast, other studies have reported no age-related difference with respect to the immersive VR experience (Alelis et al., 2015). Age dependent differences in the teaching and learning experience with immersive technologies have also been reported in primary school children (Fransson et al., 2020). Research on this important aspect of the user experience is ongoing (McGlynn et al., 2018). From the perspective of gender, Tan and Waugh investigated the use of VR in molecular biology in secondary schools in Singapore and found a positive impact on male students with respect to achievement (Tan and Waugh, 2013). The issue of gender divergence with respect to learning through the VR modality will be an important research area in the development of VR immersive experiences, particularly from an academic accessibility perspective (Tan, 2014). It is important not to extrapolate this work however, merely to be aware of the potential bias that may exist in the design of the VR experiences. It is clear however that gender is a significant factor in the design and universality of VR immersive experiences. A recent study highlighted how males performed better when the avatar was a drone, rendered as a futuristic robot. On the other hand, females fared better when the avatar was a female scientist . This highlights the importance of social considerations in addition to pedagogical and technological barriers when seeking to optimize user experience and engagement. Another study reported a greater propensity to cybersickness among females (Stanney et al., 2020).
It should be noted that the virtual experience of students in their learning can occur without the need for headsets. Nonimmersive 2D virtual simulations may prove more suitable to some students. Therefore, it is important to stress that this approach does not suggest a "one size fits all" solution. Rather, the aim is to integrate the various virtual approaches into a complete package of student education that reaches all individuals within the class, rather than designing for "the average student", who simply does not exist. Consultation with students during the design phase is key to achieving flexibility in design and operation that will result in an educational experience that is as inclusive as possible. As a simple example, perhaps students could choose the gender of their avatar before they start.

IMMERSIVE LEARNING OF CHALLENGING MOLECULAR CONCEPTS THROUGH VIRTUAL REALITY
Apart from the interactive nature of VR, and the ability for the immersed learner to engage with a visual object in real time, there is also the added value of being able to interact with multiple frames of reference (Leung et al., 2018;Alalwan et al., 2020). This could be of value in the teaching of molecular and cellular biology where concepts are difficult to comprehend since they are abstract, three-dimensional, and lack real life referents to which learners can anchor their understanding. Concepts related to recombinant DNA technology and heterologous expression e.g., the functional components of plasmids and protein production/secretion, can be difficult to engage with in a 2-dimensional frame. Student paced exploration of these and other molecular aspects such as viral and cellular structures in 3D could offer new entry points to learners, providing a spatial context that cannot be achieved from a computer screen (Johnston et al., 2018). Immersive visualization may also have benefits in research led learning, with Knote and colleagues reporting the benefits of its use in the study of multi-cellular tumor spheroids (Knote et al., 2019) and crystallographic diffraction data (Knote et al., 2020). This has been recognized in other disciplines, whereby the use of VR demonstrated significant benefits to the student learning experience addressing challenging concepts in affine transformations through gamification (Oberdörfer and Latoschik, 2019a).
Early studies exploring the relationship between VR and learning reported that, on average, 66% of students in groups exposed to virtual simulations (ranging from pre-school to higher education) outperformed those in their respective control groups (Lee, 1999). Of course, the technology has advanced significantly since then and there has been an increase in studies that address the use of mixed reality and virtual systems in teaching and learning in recent years (Kamińska et al., 2018;Cook et al., 2019). In general, these studies have reported better understanding and higher motivation, among other benefits (Hernández-de-Menéndez et al.). Spatial design or otherwise dangerous environments have become a principal focus for the learning context in Higher Education Cook et al., 2019). Many of these studies focus on the enhanced engagement linked to the two profound affordances of VR: 1) the sense of presence, and 2) the embodied affordances of gesture and manipulation in the third dimension (Johnson-Glenberg, 2018). Presence [sometimes referred to as place illusion or the sense of being there (Slater 2009)], is a behavioral trait that reflects the extent to which the user considers the VR experience to be a place visited rather than a set of images seen (Slater and Wilbur, 1997). Achieving presence has been shown to impact directly on the degree to which learning is achieved (Stevens and Kincaid, 2015). It should be noted that defining presence can be a difficult task, and while there have been efforts to develop objective correlates of presence, the challenge remains to be addressed (Skarbez et al., 2017). Another illusion, that of embodiment, describes how the form of the virtual body or avatar can result in implicit changes in attitudes, perception and cognition, and changes in behavior (Slater, 2017). Embodiment and the provision of an embodied agent can facilitate implicit learning, an important trait in the educational experience (Slater, 2017). It will be fascinating to see how both presence and embodiment impact on the learner experience with respect to construction or exploration of molecular structures and how immersion in complex, dynamic, and three-dimensional structures and relationships via sensory aids such as haptics will enhance the depth of learning achieved.
Tang and colleagues reported an improved performance in spatial design in students that adopted a mixed reality approach to learning when compared to the control cohort (Tang et al., 2020). Practical guides have been presented for the use of VR in teaching of structural biology, with particular emphasis on protein modelling (Garcia-Bonete et al., 2018;Cassidy et al., 2020). An interesting feature of VR engagement is the need for, and positive outcome, of pre-training, which has been shown to increase knowledge, transfer, and self-efficacy only in VR (Meyer et al., 2019) (Table 1). Medical education in particular has been an early adopter of these technologies (Pottle, 2019), highlighted through the Medicine Meets VR (MMVR) conference series and an extensive body of research work. Zhao and colleagues reporting increased post-intervention scores in the teaching of anatomy when compared with other teaching modalities (Zhao et al., 2020). Fairén and colleagues reported similar outcomes when they presented their VR4Health platform (Fairén et al., 2020). However, there are significant limitations to the data currently available in the literature. Most of these studies only featured a single institution and data reported is typically an objective measurement of learning, i.e., test score or completion times. It is interesting to note the absence of self-assessment in these studies, perhaps a gap in the literature that can be addressed in the current proposed research project. Peer reviewed studies in the use of VR for teaching of virology, cell culture and molecular biology are rare in the literature, but some recent reports have begun to address that (Bennett and Saunders, 2019;Coan et al., 2020).
A key challenge to the implementation of VR in the study of abstract molecular concepts is understanding how it could enhance the student's capacity to achieve a deep understanding of the learning outcomes (Table 1). Indeed, research focusing on learning outcomes, intervention characteristics, and assessment measures associated with VR use has been limited thus far (Hamilton et al., 2020). It is clear from studies that a step-by-step protocol system whereby  (2019) People learn more when they obtain new material several times by using diverse methods, which require the use of different parts of their brain VR experience can be supported by other entry points such as traditional lecture to build mental models and construct knowledge, hands on active learning through approaches such as using 3D models of theory focus or concept Student-paced learning, multiple iterations allowed Accessibility issues with alternative active learning approaches Tullis and Benjamin (2011) Students can revisit material on an ongoing basis

Consistency of conceptual design
People learn when they actively examine their learning and performance In-built assessments can enable students to gauge their learning, such as getting feedback from the teacher as part of continuous assessments. VR simulations provide an underpinning deeper learning experience for students, enabling new forms of assessment and knowledge capture Measure learning and understanding, rather VR expertise How to build in feedback in realtime, linked to learning objectives Hamilton et al. (2020) Ensure intrinsic factors do not affect assessment e.g. color, light, motor skills, spatial awareness, sound, digital competency Data management, storage, and integrity People learn less by going through the material and more from being examined by others or themselves on it, as it implicates more cognitive processing and requires them to practice retrieving information Some form of peer-to-peer engagement post-simulation will be important so that students can discuss their experience and their learnings and take guidance from their peers Build and manage group dynamic to ensure level playing field with respect to assessment and peerpeer engagement People learn more when the material helps stimulate emotions and not just intellectual or physical involvement VR is experiential. An important aspect of the design will be 'just what will the student experience' from the perspective of light, interactivity, touch, sensation, spatial context, scale etc. Many factors need to be considered to provide the ultimate in universal design Interaction between student and headset Emotional elements not inherent in molecular science teaching and learning Radianti et al. (2020) Emotional stimuli need to be carefully managed and may not be universal each stage is explained and worked through with the students is key to successfully achieving long term retention of knowledge (Vergara et al., 2019) (Table 1). It is equally clear that challenges exist in the adoption of this technology with issues around safe handling and operation (Potkonjak et al., 2016) and the requirement for updating of software and content by the lecturer or design team (Vergara et al., 2020). Notwithstanding the benefits, or perhaps because of the challenges, the adoption of immersive VR learning approaches in teaching and learning in STEM remains low (Stains et al., 2018).

VIRTUAL REALITY AND LEARNING THEORY
The active learning situational experience provided by VR lends itself to several learning theory elements, principally constructivism, cognitivism, and behaviorism. Constructivist philosophy favors the learning-by-doing approach and is based on the theory that knowledge is constructed through an individual's interaction with the environment. It is not just the interaction with the environment but the integration of knowledge (new and old) via exploration of the environment, e.g., knowledge is constructed via the interaction of prior knowledge, the exploration of ideas within a contextualised environment, and that facilitates the integration of new knowledge (Piaget, 1971;Tobias and Duffy, 2009). According to the learning theory proposed by Lave (Lave and Wenger, 1991), learning is situated in a specific context or physical environment. This goes against the conventional thinking of the time where learning was equated with abstract knowledge in a classroom, a time when learning was equated with a transmission model of teaching, in which the student passively received knowledge from the 'expert' teacher. The VR experience can be designed to embed learning within the activity and context in which it occurs (Table 1). Furthermore, it can scaffold the situational learning experience in an authentic framework through which the student can grow experientially through the learning process. This can be supported by the provision of an agent which can compensate for the lack of a real person and create an illusion of perspective in the experience (Slater, 2017;Bucher et al., 2018). Embodied cognition holds that the mind alone does not construct knowledge, but rather it is mind-body axis around movement and thought in a particular environment that delivers the knowledge construct to the learner. Perhaps this can explain, in part, one of the issues faced in teaching and learning theoretical aspects of virology, cellular sciences and molecular biology. The abstract nature of the topic gives no reference point to the learner, no hands-on experiential understanding with which to engage the topic. It is thought by some that the inability of the learner to directly experience the molecular world may explain many of the documented learning difficulties in molecular sciences (Schönborn and Anderson, 2010;Tibell and Rundgren, 2010). VR can address this imbalance and enable the learner to experience visually and interactively the molecular content, in a spatial immersive context within which they can "see"' the otherwise invisible parts. Visualization has long been considered key to unlocking the complexity of molecular structures (Kozma and Russell, 2005). While the benefits of VR in embodied cognition theory might be inherently obvious, one might argue the impact on social cognitive theory might be less apparent. Social cognitive theory is based on interactive work, peer-to-peer learning, the idea that people learn from observing others. While collaborative experiences are possible in VR, the VR experience can be individualistic, based on users occupying a solitary space where they can engage with the simulation. As such, one of the challenges in VR design for academic contexts is incorporating some level of peer-to-peer engagement so that learning can be enhanced. However, VR simulations have been used to increase social awareness in users, particularly where learners might require such interventions. Didehbani and colleagues showed how VR could be used to enhance social skills, social cognition, and social functioning in young adults with autism spectrum disorder (Didehbani et al., 2016). Often, lecturers can be unaware of the personal histories of their students and designing accessible and compatible VR simulations is an important consideration.
While the VR experience is primarily best represented by constructivist and cognitive theories, the educational requirements for VR design also lend to situations of behaviorism theory (Chen, 2009). This is true where discrete short modules of experience are built to enable the student to revisit concepts or theories over a period of time. Behaviorism holds to the theory of knowledge reproduction and this approach will be another important aspect of VR design in the education sector. VR may also provide an opportunity for academics to explore non-disciplinary models in their scholarship of teaching and learning. For example, the clarify, ideate, develop, implement creative design model espoused by David Goligorsky can be facilitated through VR, particularly where students become codesigners of their learning process (Goligorsky, 2012).

RESEARCH METHODOLOGIES AND IMMERSIVE VIRTUAL REALITY
Capturing the true impact of VR on the teaching and learning landscape has been challenging, and novel approaches to research methodology may be required for this experiential technology. Ambrose states that learning is a process and not a product (Ambrose et al., 2010), and it follows that one must understand each element of that process before one can understand its true impact. Many research studies have focused primarily on preand post-testing of students; however, there are constraints to this approach within an academic institution where ethical constraints pervade. One must also consider that VR by its very nature challenges the conceptual definition of a learning environment insofar as one could never envisage a lecture room in the shape of a complex protein structure. In assessing the pedagogical utility of VR in teaching and learning, one must seek to capture data on age, task difficulty, applications, experience, engagement, broader learning capacity, follow on application of new knowledge and ability to extend learning to related theory, amongst other aspects. This complexity raises the issue of the pre-existing data and the importance of understanding the limitations in how the studies that populate the literature were designed. Hamilton and colleagues reported that 69% of studies they evaluated featured random allocation between control and experimental groups, meaning 31% could only be described as quasi-experimental (Hamilton et al., 2020). The authors considered the greatest weakness in the studies presented to date to be the validity of the evaluation instrumentation used to assess the learning outcomes. Methodological descriptions on the design of quizzes, tests, or questionnaires were limited, and validation of these approaches was absent in 66% of the studies (Hamilton et al., 2020). Therefore, careful consideration of the research design and, in particular, how success of these approaches can be assessed is needed to address the central question of how VR can best be integrated within the curriculum for virology and molecular/cellular biology in higher education (Figure 1).

DISCUSSION
If this literature review was written at the end of 2019 how different the context would have been. Twelve months ago may well be seen as a utterly distinct teaching landscape before Covid-19 (Rospigliosi, 2020). All appears changed but one wonders whether the switch to online and blended learning will be retained given the external motivator. Xie and colleagues previously proposed that institutional change requires a sustained, threshold commitment of a 10% minority (Xie et al., 2011).
Perhaps with the unprecedented challenge of Covid-19 has come the parallel opportunity to herald a new dawn for interactive learning, where the student becomes the focus, and the independent learner is fostered and encouraged. One can only hope.
In summarizing and providing a context for the work to follow, there are two elements to be considered: 1) the literature from the perspective of scholarship of teaching and learning i.e. what the research tells us about VR and immersive learning and 2) how common mixed reality and virtual systems are in the teaching and learning of challenging scientific concepts. In both elements, it is clear that while VR and immersive education will not replace classical teaching modalities, they offer a real opportunity for the enhancement of same, and the opening of new horizons. It is equally clear that there is a strong bias in the literature towards the use of VR for practical lab teaching. The use of VR for teaching of challenging theoretical concepts remains largely unexplored. This has huge potential to support and underpin the move towards multi-disciplinary research and could cross conventional disciplinary boundaries in teaching and learning. Knowledge gaps between computer science experts and expert biologists can be seen as challenges to collaboration. An ideal platform for bridging this gap is working together to create immersive VR learning experiences for the students we teach; learning from each other as we go. The anticipated surge in global demand for Advanced Therapy Medicinal Products is likely to be paralleled by increased digitalization of production processes. Collaboration between Computational Scientists and Life/Biological Scientists in Higher Education, particularly in the areas of Virology, FIGURE 1 | Overview of the key considerations underpinning the effective integration and implementation of immersive learning technologies in teaching and learning of challenging molecular concepts. 1) Modular roadmap bridging the introductory experience with a performance of understanding, whereby a VR experience acts as a throughline upon which to scaffold the overall learning experience. 2) The collaborative expertise required to successfully design and integrate a VR experience within modular content highlights the true potential of this multi-disciplinary approach to T&L in higher education.
Frontiers in Virtual Reality | www.frontiersin.org May 2021 | Volume 2 | Article 670909 Cellular Sciences and Molecular Biology is needed now to prepare both disciplines for the road ahead.
Research at University College Cork in Ireland is currently ongoing into the application of virtual simulations for the teaching and learning of challenging concepts in the molecular sciences. Enhanced Active LEarning in Virology, cell culture and moleculAr biotechnology (ELEVATE) seeks to develop a roadmap for integration of virtual and active learning approaches into existing and new curricula. ELEVATE represents an interdisciplinary team comprised of experts in Microbiology, Virology, Computer Science, Applied Psychology, and the Centre for the Integration of Research, Teaching, and Learning at UCC, who together have a shared vision for how VR can enable students to explore the spatial and structural complexity of e.g., viruses and next generation molecular systems. Funded through the National Forum for the Enhancement of Teaching and Learning in Higher Education in Ireland, the team have developed a series of bespoke desktop and immersive VR simulations for the teaching of virus structure, heterologous expression, recombinant plasmids and green chemistry solutions for the bioeconomy. The team adopt a codesign approach in partnership with students and disciplinary experts to create pedagogically robust learning experiences with embedded assessments. A pilot survey (n 22) completed by third year students taking a microbiology module at UCC prior to the codesign of the bespoke VR simulations showed that 88% of respondents could see potential in the use of digital technologies. This was further supported by 79% of respondents who indicated that they learn well through active learning that involves visual engagement. Somewhat surprising was the finding that less than 15% of respondents declared competency or expertise in the use of VR technologies. Together, these data highlight the huge potential for VR integration into curricula, but also the need for strong support systems to underpin student learning through this medium ( Table 1). These and other initiatives in this space will deliver a new entry point for learning for students, and new horizons of teaching approaches for academics to adopt as part of their practice. Developments in the field of molecular sciences are fast paced, leading to the introduction of new concepts into the curriculum on an ongoing basis. Keeping pace with these developments will require an equally agile and progressive approach to VR development in order to sustain the adoption of these exciting technologies in Higher Education.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Social Research Ethics Committee (SREC) University College Cork, Cork, Ireland. The participants provided their written informed consent to participate in this study.