1 The LEGO® brick road to Open Science and Biotechnology 1 2 Etienne Boulter 1, @, Julien Colombelli 2, Ricardo Henriques 3,4,5* and Chloé C. Féral 1,5** 3 1Université Côte d’Azur, INSERM, CNRS, IRCAN, 28 avenue de Valombrose, 06107 Nice Cédex 2, France 4 2Institute for Research in Biomedicine - IRB Barcelona, Barcelona Institute of Science and 5 Technology – BIST, Baldiri Reixac, 10, E-08028 Barcelona, Spain 6 3Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, Oeiras, P-2780-156, Portugal 7 4MRC-Laboratory for Molecular Cell Biology, University College London, Gower Street , 8 London WC1E 6BT, United Kingdom 9 5Co-corresponding 10 11 *Correspondence: rjhenriques@igc.gulbenkian.pt 12 ** Correspondence: chloe.feral@inserm.fr 13 @Twitter: @EtienneBoulter (E.Boulter). 14 15 Keywords 2 to 6 16 LEGO® bricks, frugal science, Open Science 17 18 Abstract 19 LEGO® is a brand of toys that, for decades, have entertained generations of children. Beyond 20 amusement, LEGO® bricks also constitute a building ecosystem of their own that creators from 21 the general public, as well as scientists and engineers, can use to design and assemble devices 22 for all purposes, including scientific research and biotechnology. 23 Here, we describe several of these constructions to highlight LEGO® building properties, their 24 advantages, caveats, and impact in biotechnology. We also discuss how this emerging trend 25 in LEGO® building pairs with a growing interest in open-access and frugal science, which aims 26 to provide access to technology to all scientists regardless of financial wealth and 27 technological prowess. 28 29 30 ----!@#$NewPage!@#$---- 2 31 LEGO® bricks: from the toy box to the lab bench 32 33 “I loved to play with LEGO®,” recalled the 2001 Physics Nobel Laureate Wolfgang Ketterle 34 during his lecture at the 69th Lindau Nobel Laureate Meeting. “In my days, LEGO® was just a 35 box of bricks and you had to use your imagination to build very very complicated things out of 36 very few building blocks” [1]. Many scientists and engineers carry the same nostalgia from 37 their youth and the same passion for LEGO® constructions today. In many cases, LEGO® bricks 38 have fueled their curiosity and creativity early on and motivated their appeal to science and 39 research later. In fact, there are many similarities between a child playing with LEGO® bricks 40 and a scientist planning an experiment: both with a limited number of resources and their 41 imagination need to find an optimal way to build or experiment. Therefore, it is not surprising 42 that many scientists who played with LEGO® bricks as kids are now interested to use them to 43 create tools and biotechnology devices, effectively turning LEGO® bricks into a powerful 44 building ecosystem. 45 As it turns out, LEGO®-based systems abolish the boundaries between expensive technological 46 tools and financially constrained investigators, between experimental requirements and their 47 practical realization. Here, we will attempt to review the variety of systems that have been 48 developed with LEGO® parts both in the general public and in Science. We will identify the 49 benefits and limitations of building with LEGO® parts and show how these can be used to 50 design inexpensive, robust and professional-grade tools or experimental strategies. Finally, 51 we will discuss how this new trend questions some of the recent science evolutions and 52 promotes Open Science. 53 54 55 Building, creating and inventing with LEGO® bricks 56 57 Traditionally, LEGO® bricks have been widely publicized as toys for kids (see Box 1). However, 58 over time, a group of dedicated and independent builders (AFOL for Adults Fans Of LEGO®, 59 see Glossary) have started to consider them unique building units that can be used to 60 assemble diverse objects, very much in the spirit of the original Automatic Binding Brick (ABB), 61 and not necessarily only toys. This concept has now been explored to establish design and 62 ----!@#$NewPage!@#$---- 3 assembly principles summarized in a seminal book [2]. Although initially not officially endorsed 63 or commercially promoted by The LEGO Group, this emerging prospect has somehow become 64 tacitly acknowledged. In recent years, The LEGO Group has endorsed several professional 65 AFOLs as LEGO® Certified Professionals (21 individuals as of 2021, https://www.lego.com/fr- 66 fr/aboutus/lego-certified-professionals/). The LEGO Group has also progressively released 67 several sets and collections that support this DIY approach, such as the LEGO® Architecture 68 Studio set (#21050) and the LEGO® Ideas series. In this section, focused on the general public, 69 we will highlight a few examples of these constructions and their creators to establish that 70 LEGO® bricks are unique building units that can help achieve craftsman’s creativity at all 71 performance levels . 72 73 Some creations are only designed for entertainment (see Box 2) and to showcase the 74 mechanical prowess achieved with simple LEGO® bricks. Automatons and mechanical 75 constructions have been developed by independent creators such as JK Brickworks with its 76 LEGO® Ideas set “the Maze” (#21305) or its “Hoberman Sphere” (Fig. 1A). Other creators 77 rather specialize in LEGO® Technic building, which provides electric- or pneumatic-powered 78 capabilities and more intricate building options. For instance, these include Wolf Zipp and his 79 re-creation of the SLJ900 bridge girder erection machine, a masterpiece of LEGO® Technic 80 engineering (https://www.youtube.com/channel/UC2vjCc0CiaxF8bHHaOPQUXw). Besides 81 these relatively simple entertaining creations, others stand out by their unexpected level of 82 performance and refinement, suggesting that professional-grade quality devices could be 83 achieved from LEGO® parts. This is the case of Cubestormer 3, an automated Rubik’s Cube 84 solver, created by David Gilday and Mike Dobson, that temporarily held the world record for 85 fastest solving a Rubik’s Cube by a robotic system at 3.253s. Cubestormer 3 was almost solely 86 based on LEGO® parts, including a LEGO® Mindstorms system and a Samsung Galaxy S4 for 87 video input. Also, as a testimony to the precision and mechanical reliability of LEGO® parts, 88 the air-powered LEGO® car designed by Raul Oaida and Steve Sammartino is the first life-sized 89 functioning car assembled from LEGO® parts, except tires, which is powered up to 30 km/h by 90 an engine built from LEGO® pneumatic motors. Over the years, similar cars were assembled 91 by The LEGO Group, including a replica of the most potent road car of its time, the iconic 92 Bugatti Chiron. 93 ----!@#$NewPage!@#$---- 4 Finally, it turns out that some systems combine both professional-grade built and real-life use, 94 such as the Braigo Braille printer designed and assembled by Shubham Banerjee with 350 USD 95 worth of LEGO® parts, which compares to the price of conventional Braille printers in the 2000 96 USD range. This highlights that besides their quality, LEGO® creations may be built at a fraction 97 of the cost of commercially available systems. 98 99 All these creations, which fall under the general public scope, are a testimony to the level of 100 performance and reliability that can be achieved by combining LEGO® parts and one’s 101 creativity. This fueled researchers and creators from different fields to consider LEGO® parts 102 as building units to design and assemble simple to complex scientific tools and systems for 103 scientific research and biotechnology. 104 David Aguilar, aka “Hand Solo”, is an inspiring example of a creator bridging these two worlds. 105 David, who was born without a right forearm, has designed and assembled his series of fully 106 functional LEGO®-based prosthetic arms, which he named MK after the armor suits of Iron 107 Man from the Marvel® Universe (Fig. 1B). His creativity resounded in the media and David, 108 now a bioengineering student, recently engineered a simple and light LEGO® prosthetic arm 109 for a young Kazakh boy. 110 111 Biotechnology research and education with LEGO® 112 Owing to their extreme versatility, reliability and performance, LEGO® parts have emerged as 113 particularly relevant building units for designing systems and tools for research, education, 114 and science. Indeed, over the past decade, scientists have designed, characterized, and 115 reported many systems from all fields (Table 2). These systems range from very simple, almost 116 simplistic [3,4] to complex and intricate [5]. In all cases, they turn out to be very effective at 117 what they were designed for and bear a low cost to efficiency ratio. Here, we briefly review 118 some of these systems to highlight the unifying principles guiding their design and assembly, 119 the advantages, and the caveats. For clarity’s sake, we will discuss them field by field below 120 and in Box 3 for scientific fields beyond biological research and Biotechnology. 121 122 Education/STEM 123 ----!@#$NewPage!@#$---- 5 Besides building curiosity and critical thinking, a paramount role of education is to introduce 124 students to fundamental concepts and principles, to essential knowledge and experimental 125 techniques, all of which can be achieved or contributed to, using LEGO® parts. 126 Concepts and principles are often abstract and figuring out a mental projection of these can 127 be challenging for students. Sometimes, physical representation and manipulation can help. 128 This educational strategy can be implemented with LEGO® bricks to showcase simple scientific 129 tools such as a colorimeter [6] or a liquid handling robot [7]. It can also be used to explain 130 concepts such as the evolution and variability of the viral genome of influenza associated with 131 antigenic drift using LEGO® bricks that represent swappable blocks of genetic material [8]. 132 Similarly, historical concepts and techniques can be presented more figuratively. For instance, 133 DNA sequencing and associated bioinformatics resources can be introduced using the 134 brickopore system, which replaces nucleotides with LEGO® bricks (www.brickopore.co.uk). 135 Finally, the scientific principles behind the operation of complex scientific systems can be 136 explained using a device based on LEGO® such as the 'conceptual AFM', for example, a fully 137 functional LEGO® AFM replica [9]. For advanced students, professional-grade LEGO® systems 138 are also an educational opportunity to learn design and assembly principles in addition to 139 scientific principles. Such educational projects include LEGO®-based microscopes such as 140 MicroscoPy, for instance, a LEGO®- and 3D-printed parts-based open source transmitted light 141 microscope that can introduce students to both design, LEGO® building, electronics assembly, 142 and programming (Table 2). LEGOLish is another fully functional microscope that brings the 143 concept to a yet unsurpassed level as a LEGO®-based light-sheet microscope equipped with a 144 smartphone as a camera that can scan real biological samples to demonstrate the properties 145 of that type of microscopy (www.legolish.org). 146 Altogether, LEGO® parts provide instructors with various tools to illustrate concepts, principles 147 and provide a framework for their application. 148 149 150 Instrumentation 151 In an appeal to the more technical aspects of LEGO® parts, creative researchers have 152 engineered several pieces of general lab equipment of all levels of complexity to address 153 specific needs or provide alternatives for cheaper equipment. Some of those are relatively 154 simple, yet effective, such as the peristaltic pump engineered by Martin Haase 155 ----!@#$NewPage!@#$---- 6 (https://www.youtube.com/watch?v=N0Cj0D3M-9E ) or the spectrophotometer from Pereira and 156 Hosker [10]. Others are frankly complex, such as the automated LEGO® Mindstorms fraction 157 collector [11]. In all cases, they provide highly reliable equipment, inexpensive to purchase 158 and maintain. 159 Besides these very generic pieces of equipment, more specialized instrumentation is directly 160 designed or inspired by LEGO® building. For example, microfluidics have been inspired by the 161 assembly properties and versatility of LEGO® bricks and developed some LEGO®-like building 162 systems on a microfluidics scale. µOrgano is a LEGO®-like plug-and-play system to create 163 modular multi-organ chips [12]. This system, much like LEGO® systems, is based on the 164 assembly of building modules, master-organ-chips, and plug-and-play connectors. Similarly, 165 Morgan et al developed a modular LEGO®-based microfluidics system with an FDM 3D printer 166 illustrating the power of the combination of LEGO® building and 3D printing. Ma et al brought 167 the concept of modular assembly to another level and scale by generating reversible 168 supramolecular LEGO®-like bonds to assemble hydrogels [13]. This system has not been 169 showcased in any experimental application yet but explores the possibility to use a modular 170 brick design at the molecular scale to assemble microfluidics compatible parts. 171 172 Biological research 173 It is in biological research that LEGO® parts display the prime of their versatility, contributing 174 to systems and tools in fields ranging from entomology to plant sciences to cell biology. 175 Traditionally, in entomology and natural history collections, insect specimens were dry pinned 176 for conservation and documentation. This resulted in extensive, delicate, and space- 177 consuming collections such as the 27 million pinned insect specimens at the Natural History 178 Museum of London. Now, in the digital era, specimen digitization constitutes a means to 179 archive them and prevent their manipulation. This requires specimen holding tools not always 180 readily available to researchers. To address this matter, Dupont et al created the Insect 181 specimen manipulator (Imp) from LEGO® Technic parts [14], a versatile and customizable 182 holding system to perform observation or digital acquisition. 183 In a completely different setting, in plant science, studying plant growth requires live 184 monitoring of the organism in a controlled environment. To this end, Lind et al imagined using 185 transparent LEGO® walls to assemble cubes in which gel-like growth medium can be poured 186 and plant growth monitored over time [15]. Here, the key features of LEGO® parts were their 187 ----!@#$NewPage!@#$---- 7 flexibility and versatility in terms of assembly and combination, as well as the possibility to 188 sterilize and reuse them. These are examples of straightforward tools designed to fulfil a 189 specific need while incorporating the ingredients to an excellent DIY recipe: design flexibility 190 and versatility, affordability and wide availability of LEGO® parts. 191 LEGO® parts proved useful to design and assemble stretching systems. The Féral lab 192 engineered a uniaxial cyclic stretcher for cells in tissue culture [3,4] which applies uniaxial 193 cyclic stretch to a monolayer of cells cultivated on a PDMS plate. Besides the PDMS plate, the 194 system is assembled only from LEGO® parts. While this system cannot provide all the range of 195 stimulations of commercial systems, within its range, it does provide consistent and reliable 196 stimulation at a fraction of the cost of these systems. This turns out to be a general property 197 of such DIY systems: they may not necessarily provide the same refinements as high-end 198 systems, which, incidentally, the user does not always need but offer reliability and 199 consistency at a fraction of the cost. A radically different, the LEGO® stretcher designed by 200 Teemu Ihalainen, named Brick Strex, provides similar features with the noticeable 201 improvement to perform simultaneous cell stretching and live-cell imaging [18]. 202 By following the same philosophy, the Henriques lab developed a robotized fluidic system that 203 could control the liquid environment of a biological sample while observed under a 204 microscope [5]. This fluidic system was named NanoJ-Fluidics but nicknamed Pumpy 205 McPumpface by the authors. Pumpy corresponds to a set of LEGO®-based syringe pump units 206 that can assemble into an array. Each unit is responsible for injecting a chemical agent into an 207 imaging chamber. An Arduino board stacked with a motor control shield drives all the DC 208 motors and interfaces with custom automation software. Pumpy is driven by micromanager 209 [19] and NanoJ [20], which presents an interface that allows users to automate complex 210 reagent exchange protocols synchronized with image acquisition in a microscope. Pumpy can 211 carry out event-driven experiments, where a visual cue on the sample will trigger a fluidic 212 protocol. This allows the microscope to capture both live-cell temporal data up to fixation, 213 and fixed-cell data for the same field-of-view, generally with a large number of molecular 214 types labelled. The authors also carried out similar experiments with super-resolution imaging 215 within the same field of view showing the ability to switch from live cell SRRF [21] imaging of 216 a single fluorophore to fixed cell nanoscale resolution imaging of 5 different fluorophores 217 through STORM [22] and DNA-PAINT [23]. 218 ----!@#$NewPage!@#$---- 8 One step further in technological complexity, LEMOLish (www.legolish.org/lemolish) is the 219 scientific professional -grade version of the educational lightsheet microscope LEGOLish. Built 220 into a fully automated lightsheet system, the LEGO® assembly (1400 bricks!) enables to image 221 optically cleared samples with unexpected sample-size-to-resolution performance, to achieve 222 mesoscopic imaging of organs and organisms from millimeters to centimeters in size with 223 cellular resolution. Following a strict DIY and cost-efficient philosophy, the authors hacked the 224 LEGO® EV3 module, or “intelligent brick”, to synchronize lasers, sample movement and 225 camera trigger, in a final layout that automatically acquires 3D stacks at the action of one 226 button. The authors report 3D images of mouse -embryos, -tumors, -brains, -vasculature or 227 full chicken embryos exceeding 4cm in size, and advocate for LEMOLISH to become a benchtop 228 entry point into lightsheet imaging, and an affordable (2-orders of magnitude below 229 commercial systems) companion for laboratories aiming to start with the complex task of 230 tissue-clearing protocols. While lightsheet microscopy has revolutionized several life science 231 disciplines such as developmental biology or neuroscience, the access to research-grade 232 equipment is still an economical leap for a majority of laboratories, thus demonstrating again 233 the potential of LEGO®-based inventions to democratize high-end technology with acceptable 234 scientific performance. 235 236 LEGO® design in Science: 237 Aside from the joy and fun of building scientific tools with LEGO® bricks, one may wonder the 238 rationale, benefits, and relevance of using kids' toys to assemble scientific equipment. The 239 reasons to build with LEGO® bricks range from the nature of the LEGO® brick and the LEGO® 240 brick system themselves to the ethical beliefs and principles of the creators. 241 At the core of every LEGO® creation are the LEGO® bricks and the LEGO® building system, 242 which harbor several specific properties and associated benefits. One exciting feature of 243 LEGO® parts for biotechnology is their compatibility with the assembly of mechanical systems 244 for biology. As mentioned earlier, LEGO® parts are made from ABS, a thermoplastic used in 245 injection molding. ABS and its derivatives are routinely used in household appliances, 246 consumer goods and anecdotally constituted the bodywork of the iconic Citroen Méhari. ABS 247 is also the mainstream material for FFF (also known as FDM®) 3D printing and is generally 248 considered a biocompatible material. In general, ABS properties allow LEGO® parts to 249 ----!@#$NewPage!@#$---- 9 withstand high mechanical loads and resist high impacts, relative to the scale of the creations. 250 This resistance to breakage and wear is an essential factor in mechanical systems, particularly 251 in gearboxes exposed to high mechanical loads and repetitive motion. In contrast, the high 252 production standards of LEGO® parts limit gearwheel wobbling and backlash. In addition, ABS 253 can be easily decontaminated and sanitized, which is critical in cell biology. 254 Another substantial benefit for creators is the wide range of parts constituting the LEGO® 255 collection and their combinatorial possibilities. As of 2011, there were at least 2350 different 256 LEGO® parts officially listed which combined to user-designed 3d printed parts gives a glimpse 257 of the almost infinite combinations offered from such parts. 258 259 Beyond the specific properties of each LEGO® part, the LEGO® brick system is a unique building 260 framework with its principles and metrics, including the clutch power and the LEGO® stud 261 metric system. This provides a building space with its geometry and metrics that have been 262 explored and conceptualized [2]. As we show in Figure 3, the design of LEGO® scientific 263 instruments often relies on a very simple core mechanical function (pushing, pulling, 264 translating, rotating, …) achieved with very few gears, axles and one or more stepper motors, 265 while the bulk of the other bricks merely serves to position or stabilize the elements to be 266 actuated upon (here, a substrate, a syringe or a cuvette). Noteworthy, taken apart known 267 backlash issues that can be compensated, such basic assemblies can reach surprising micron 268 or microliter precisions (Fig. 2). Moreover, the LEGO® Mindstorms and Power Function 269 collections add automation and computing power to the LEGO® ecosystem, motorization and 270 remote control. Altogether, the technical features of LEGO® parts and the ecosystem they 271 provide constitute an ideal environment to design and assemble mechanical systems. 272 273 274 Concluding remarks and future perspectives 275 276 The use of LEGO® parts to design scientific systems provides practical tools and strategies that 277 can be used to address curiosity-driven scientific questions. These systems do not necessarily 278 offer all the refinements of commercial systems, but they provide scientifically robust, open- 279 access, and customizable tools. The rationale for designing and assembling LEGO® systems for 280 ----!@#$NewPage!@#$---- 10 science was generally based on specific requirements from their creators that were not 281 fulfilled by any commercial systems. 282 There are an estimated 2350 different official LEGO® parts available today, which provide 283 almost endless design possibilities and questions what systems could not be, at least in part, 284 assembled from LEGO® parts. For instance, systems as complex as the LEMOlish light sheet 285 microscope have been assembled. With the emergence of LEGO® part design software and 3D 286 printing, we foresee that any custom LEGO® compatible brick could be designed and produced 287 [25], further expanding the design possibilities. 288 Besides The LEGO Group, which commercializes individual bricks, it is hard to imagine how 289 any company could financially and logistically support the large-scale commercial 290 implementation of these systems. At the core of these systems, the LEGO® bricks design is 291 patented, and they are only produced by The LEGO Group. Furthermore, the cost of these 292 systems, which constitute one of their main interests for individual researchers, makes them 293 much less profitable for companies, especially if they cannot produce LEGO® bricks. The LEGO 294 Group has historically been very open to creators and their alternative use of LEGO® bricks, 295 without actively supporting them through any institutionalized program though. While we do 296 not necessarily call upon The LEGO Group to actively support this trend, we cannot help 297 wondering how the association of such intellectual creativity with the industrial and designing 298 prowess of The LEGO Group would propel this field forward and benefit science as a whole, 299 much in the spirit of the LEGO® Ideas collection. 300 301 Beyond their diversity, these LEGO® systems are characterized by mutual features, including 302 customization, affordability, and open access. Interestingly, these characteristics constitute 303 the core values of an emerging trend that aims to promote DIY science and open access. These 304 core values underlie an ideology that implicitly questions recent developments and evolution 305 in science (see Outstanding Questions). This also very much relates to the movement of 306 frugality in science as presented by George Whitesides [26] and Martin Kaltenbrunner [27]. 307 They argue, and we second them, that there is a rush towards expensive and complex 308 technology in research, and we could add in society, which is a luxury of western countries 309 that low-income nations or financially constrained institutions cannot afford. In the western 310 world, this escalating trend is likely fueled, and possibly plagued, by the unfounded belief that 311 expensive equipment is a prerequisite for good science, that compelling amounts of data and 312 ----!@#$NewPage!@#$---- 11 uttermost precision are safeguards for quality. As recently addressed by Nobel prize recipient 313 Sir Paul Nurse [28], many scientists now challenge this belief and promote a curiosity-driven 314 and concept-based science that would use proportionate and appropriate technological tools 315 to address scientific problems. Proportionate and appropriate use of technology can also be 316 extended to technology-based applications in society. While the benefits of technological 317 advance for scientific research and for the society are not debated, once again, the human 318 behaviors, beliefs and practices surrounding these progresses may hamper their benefits for 319 mankind and create drawbacks. 320 For instance, the temptation and competitive pressure to use the most cutting-edge 321 technology to publish in the most prestigious journals, de facto exclude or impede financially 322 and technologically constrained researchers from voicing their conceptual and experimental 323 contributions to science to similar levels as wealthy researchers. Similarly, some cutting-edge 324 biotechnological applications remain exclusive to the western world while they would greatly 325 benefit developing countries and their population such as the SARS-CoV-2 vaccines in the 326 wake of the current COVID-19 pandemic. In response, some researchers have taken it upon 327 themselves to develop practical and affordable alternatives to some technological tools 328 [29,30]. In times of recent economic meltdown and financial constraints, it may also be 329 particularly relevant to address and implement a fair and reasoned use of limited financial 330 resources provided either by the taxpayer or by donations in the case of charities. Indeed, this 331 reasoning may apply to all resources, and as mentioned by Whitesides and Kaltenbrunner, less 332 is more; resources, of all kinds, are generally limited, and proportionate use of these resources 333 should allow us to do more not at the cost of quality, now, and potentially tomorrow as these 334 resources may wane. 335 These really are two sides of the same coin with technological progress benefitting scientific 336 research and society on one side while human bias and behavior generate limitations and 337 malpractice, on the other. We also feel that frugal science and LEGO® building, for instance, 338 may constitute a balanced position trying to reconcile technological needs with practical 339 benefits and fair use of resources. These two views of science are not exclusive and may be 340 complementary, constituting the edge of this two-sided coin. For instance, the worldwide 341 COVID-19 crisis pushed the development of cutting-edge technology such as the RNA vaccines 342 in parallel to the individual or collective initiatives to develop and provide PPE, ventilators and 343 ----!@#$NewPage!@#$---- 12 diagnostic tests in times of restrictions, ultimately showing that these two visions of Science 344 may coexist. 345 Much as barefoot stepping on a LEGO® brick has become a universal meme, LEGO® building 346 in open science and Biotechnology has all the ingredients and spice to become a universal 347 ecosystem to design and assemble innovative, robust and inexpensive systems available for 348 the whole scientific community. 349 350 351 352 Text Boxes 353 Box 1 – Historical perspective 354 LEGO® is a brand of toys founded by Ole Kirk Kristiansen back in 1932, which belongs to The 355 LEGO Group, a Danish company based in Billund, DK. Ole Kirk Kristiansen (1891-1958) was a 356 Danish master carpenter who originally bought a carpentry factory in Billund, DK, in 1916. 357 Following the 1929 stock market crash and the ensuing Great Recession, Kristiansen was 358 almost forced out of business and had to adjust his production to include easily saleable 359 products such as kid toys. By 1934, Kristiansen had decided to focus his production on toys 360 and decided to name the company LEGO®, based on the contraction of the two Danish words 361 Leg Godt which mean « play well ». From the beginning, one of the obsessions of Kristiansen 362 was the utmost quality of his productions, a legacy that stands to this day as attested by The 363 LEGO Group motto, «only the best is good enough » (det bedste er ikke for godt). In June 1946, 364 upon the demonstration of an injection molding machine, he converted his production to 365 plastic, first with cellulose acetate, then using ABS. Around the same time, he witnessed a 366 demonstration of the brick item that Hilary Fisher Page had invented at his company 367 Kiddicraft. This sparked the creation of the Automatic Binding Brick (ABB), the ancestor of the 368 LEGO® brick as we know it today. A pivotal moment came in January 1958 when The LEGO 369 Group submitted a patent application for a « toy building element » which described the stud 370 and tube design which replaced the structurally unstable hollow design of the ABB and 371 introduced the concept of clutch power as well as the new interlocking principle of LEGO® 372 bricks. This design provides stability and almost endless possibilities for combining bricks: six 373 2x4 bricks can combine in up to 915103765 different ways. Ever since, The LEGO Group has 374 expanded at all levels, employing thousands of people across several countries and shipping 375 ----!@#$NewPage!@#$---- 13 billions of bricks around the world. Following Kristiansen’s footstep, The LEGO Group has had 376 a long-lasting interest in science, especially engineering, programming, and space. Indeed, 377 over time, The LEGO Group has introduced several different LEGO® collections appealing to 378 science and engineering including the LEGO® Technic collection in 1977 and the LEGO® 379 Mindstorms collection developed through collaboration and partnership with MIT in 1998. 380 They also contributed to the promotion of science and STEM in education with the LEGO® 381 education program. 382 383 384 Box 2 - LEGO® bricks Artwork 385 Despite being once denied the status of Art [31], LEGO® bricks are indeed elements that can 386 be used to create pieces of Art. Arguably, the artwork nature of individual bricks may be 387 discussed, since these are building units much like other materials such as paint, clay, bronze, 388 or wood. However, this view could be challenged, as their design itself is a reflection of the 389 human mind and creativity. However, inarguably they can be assembled into pieces that 390 express one’s creative mind and emotions. In fact, several creators or artists have used LEGO® 391 bricks to create artefacts of all nature (Table Box 2). For instance, John Muntean has combined 392 LEGO® brick into abstract sculptures called Magic Angle Sculptures© which, upon lighting and 393 rotation, can project a variety of different artistic shadows (https://www.jvmuntean.com) 394 (Figure Box2). The concept behind these sculptures is that our 'interpretation of Nature 395 depends on our point of view' and that 'perspective matters'. Another creator, Nathan 396 Sawaya, assembles LEGO® bricks into monumental sculptures and reproduces classical 397 paintings which have been displayed in his world-touring exhibition The Art of the Brick 398 (https://www.brickartist.com). Contemporary urban artist Jan Vormann found another artistic 399 use of LEGO® bricks which ironically recalls to their fundamental nature, filling wall holes of 400 historic constructions with multicolor assemblies (https://www.janvormann.com). LEGO® 401 mosaics are also widespread: for instance, Eric Harshbarger creates reproductions of classical 402 paintings as well as original pieces while the late Arthur Gugick contributed with the assembly 403 of stunning lenticular mosaics. Altogether, these creators have also indirectly inspired, by their 404 design, the creation of LEGO®-like artworks such as the sculptures of Antony Gormley, for 405 instance. Jeff Sanders’ brickbending artworks defy geometric rules by assembling straight 406 LEGO® parts into bended creations which testifies of the mechanical resistance of individual 407 ----!@#$NewPage!@#$---- 14 LEGO® bricks. Beside those renowned artists, anonymous individuals also engage in LEGO® art 408 creation under various forms including LEGO® mosaics or stop-motion movies for instance. 409 The LEGO Group itself now supports and promotes LEGO® artwork as it just announced the 410 release of the LEGO® Art collection and the LEGO® Brick Sketches™, hybrid constructions 411 between paintings and puzzles. 412 413 Box 3 – LEGO® bricks in other scientific fields 414 415 Behavioral Sciences 416 LEGO® bricks and behavioral sciences may seem like an odd association. In this field, it is not 417 necessarily the technical and mechanical aspects of LEGO® parts that appealed to researchers 418 but also the behavioral consequences of using LEGO® bricks. 419 For instance, LEGO® has been used in cognitive psychology in the context of choice reaching 420 task (CRT) which may provide insights into underlying cognitive processes (Table box 3). This 421 behavior has been extensively investigated, and a LEGO® robotic system that implements the 422 model has been assembled to investigate the implications and predictions of the model 423 [32,33]. 424 Slightly apart from behavioral sciences, LEGO® bricks have also been used to address autistic 425 spectrum disorders and associated social interactions. Dr Daniel LeGoff, a pediatric 426 neuropsychologist, invented the LEGO® Therapy aimed at improving the social skills of 427 children with autism spectrum disorder [32,33]. 428 429 Physics 430 Much like in other fields, the physicists’ primary interest in LEGO® parts has stemmed from 431 the possibility to create custom tools and systems for scientific research. For instance, LEGO® 432 bricks have been instrumental in the creation of two alike tensile testers [16,17]. Conceptually, 433 it is interesting to note that these two systems have independently evolved into a very similar 434 design. Celli and Gonella have reported a straightforward yet versatile experimental platform 435 for investigating phononic phenomena in metamaterial architecture [37]. 436 Prestigious institutions also fancy LEGO® constructions: besides building a miniature LEGO® 437 LHC for the LEGO® Ideas series, researchers at CERN have used LEGO® parts to prototype and 438 include a LEGO® device to the NA61/SHINE experiment 439 ----!@#$NewPage!@#$---- 15 (https://home.cern/news/news/experiments/using-lego-study-building-blocks-universe ). 440 Experimenting with LEGO® bricks has also yielded unexpected discoveries about their 441 properties. Chawner et al. report that LEGO® bricks are in fact particularly potent thermal 442 insulators [38]. This is an exciting feature for quantum computing which relies on isolated low 443 temperatures, providing cheaper alternatives to expensive materials currently in use in the 444 field. 445 446 Chemistry 447 In contrast to physicists, chemists have scarcely relied on LEGO® bricks to generate 448 experimental systems. This is not surprising since their activity does not depend so heavily on 449 mechanical systems. However, in some cases, LEGO® bricks were helpful in the design of 450 systems with unusual specifications. For instance, LEGO® bricks and plates were used to 451 assemble a dark box able to handle 96-well plates in a field-deployable spectrofluorometric 452 system aimed at detecting nerve gas [39]. In this case, the use of LEGO® parts provides specific 453 properties to the system that were the central requirements of the creators. 454 455 456 Acknowledgements 457 We would like to apologize to those creators whose work could not be mentioned in this 458 review. We acknowledge John Muntean, Jeff Sanders, Jason and Kristal Alleman, David and 459 Ferran Aguilar, and Jose Sanchez for kindly providing pictures of their work. This work was 460 supported by INCA (Institut National du Cancer) [PL-Bio #2019-11/368/NI-HO to C.C.F.]. C.C.F. 461 is supported by the French Government through the Investments in the Future projects 462 [LABEX SIGNALIFE ref. ANR-11-LABX-0028-01 and UCAJEDI ref. ANR-15-IDEX-01] managed by 463 Agence Nationale de la Recherche. R.H. is supported by Gulbenkian Foundation and received 464 funding from the European Research Council under the European Union’s Horizon 2020 465 research and innovation programme (grant agreement no. 101001332), the European 466 Molecular Biology Organization Installation Grant (EMBO-2020-IG-4734) and the Wellcome 467 Trust (203276/Z/16/Z) (R.H.). 468 469 Disclaimer 470 ----!@#$NewPage!@#$---- 16 LEGO® and LEGO TECHNIC are trademarks of the LEGO Group, which did not sponsor, 471 authorize or endorse this work. 472 473 474 Bibliography 475 476 1 Skuse, B. (2019) , Building New Forms of Matter Brick by LEGO® Brick | The Lindau Nobel 477 Laureate Meetings. . [Online]. Available: https://www.lindau-nobel.org/blog-building-new- 478 forms-of-matter-brick-by-lego-brick/. [Accessed: 27-Aug-2020] 479 2 Kmiec, P. (2013) THE UNOFFICIAL LEGO® TECHNIC BUILDER’S GUIDE, 480 3 Boulter, E. and Féral, C.C. 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ACS 554 Central Science 4, 854–861 555 556 557 Figure Legends 558 Figure 1 – LEGO® creations in the general public and arts. (A) LEGO® prosthetic arm creator 559 David Aguilar (with permission from David Aguilar, Jose Sanchez – Estudi la Seu d’Urgell). (B) 560 The “Hoberman Sphere” in motion or motionless from creators JK Brickworks (with 561 permission from Jason Alleman). 562 563 ----!@#$NewPage!@#$---- 18 Figure 2 – The uniaxial cell stretcher (top), the Pumpy microfluidics system (center) and 564 LEMOLISH (bottom). In each box, the left part shows the few core mechanical elements that 565 drive the main function (blue text) of the instrument shown to the right, with indicators of 566 performance. Common to all, one stepper motor converts (“Drive” with red arrows) a large 567 rotation angle into final high-precision movements (blue arrows) by means of suitable gear 568 reduction ratios. 569 570 571 Table 1 – List of LEGO® creations from the general public 572 573 Table 2 – List of LEGO® creations in Biotechnology and biological research. 574 575 Figure Box 2 – LEGO® artwork. (A) Creator Jeff Sanders and Brickbending creation Spiral 576 Annulus. (B) Extreme Brickbending creation the Rhombicuboctahedron (with permission 577 from Jeff Sanders). (C) and (D) LEGO® artwork the Knight Mermaid Pirate-ship Magic Angle 578 Sculpture and creator John V. Muntean (with permission from John V. Muntean). 579 580 Table Box 2 – List of LEGO® artwork creators 581 582 Table Box 3 – List of LEGO® creations in Science 583 584 ----!@#$NewPage!@#$---- Glossary ABB: Automatic Binding Brick, the ancestor of the regular LEGO® brick as we know it today without the stud and tube design and therefore with much less clutch power and stability. ABS: Acrylonitrile Butadiene Styrene, a thermoplastic polymer which transition temperature is around 104°C, widely used for injection molding in various industries AFM: Atomic Force Microscopy is a type of scanning probe microscopy that uses a cantilever and a probe to scan the surface of a sample in order to generate a topographic map or assess its mechanical properties by indentation. AFOL: Adults Fan Of LEGO®, adults, by opposition to kids who are the original targeted audience of LEGO® toys, that engage in LEGO® building of all sorts and create a community with gatherings, etc. They have now also become a major market since they can afford more expensive models. Clutch power: the interlocking assembly of LEGO® bricks which is based on the stud and tube design creates a high “clutch power” that hold individual bricks together in multimeric assemblies. DIY: Do It Yourself, this is the process of generating parts or performing repairs/modifications on a system without intervention of commercial/industrial counterparts. FFF: Fused filament fabrication, widely referred to as FDM® (Fused Deposition Modeling) which is trademarked by Stratasys, is a 3D printing process that uses a melted thermoplastic filament to deposit material. Frugal science: it is a trend that promotes cost-conscious research-based and application- driven science in order to include and engage all qualified individuals in research and benefit all publics. LCP: LEGO® Certified Professional are professional creators and LEGO®-related business owners officially endorsed and supported by The LEGO Group. There are a handful number of LCP positions that are country specific for professionals fulfilling specific criteria. PDMS: PolyDiMethylSiloxane is a silicone-based organic polymer which has many uses in science and in the industry. Notably, it is used as an optically clear elastomer for microfluidics devices. ----!@#$NewPage!@#$---- Highlights LEGO® bricks constitute a building ecosystem that can be used by the general public, science researchers and engineers to design and assemble systems of all kinds. The variety of LEGO® creations from the general public, spanning from artwork to automated systems, demonstrate the versatility and quality of LEGO® systems. In parallel, an increasing number of custom LEGO® systems for science are designed to fulfil the specific requirements of experimental scientists from all fields. The development of LEGO® building in science and biotechnology constitutes an emerging trend that aims to provide widely available professional-grade tools and systems to all researchers regardless of financial and technological constraints. ----!@#$NewPage!@#$---- Outstanding Questions Box What are the technological or creative limits of LEGO® building? What can be designed and built using LEGO® parts? How will the LEGO® building accommodate the emergence of 3D printing? Will 3D printing provide a platform to design and produce new innovative parts for LEGO® building, or will it provide an alternative to LEGO® building that may surpass it at some point? Will 3D printing help in bypassing the aforementioned LEGO® building limits? How will this open-access trend in developing LEGO® systems merge with other open-access trends in software development, microscopy? Will there be any commercial endeavor to scale up this trend to industrial levels? Will any company take it upon itself to promote and distribute these tools? In particular, will The LEGO Group support this trend? Related to the previous point, will creators keep providing their systems as open-access, or will they start patenting them? How would this patenting process cope with The LEGO Group, which has historically been very protective of its patents? Along this line, what will the position of The LEGO Group regarding this alternative use of LEGO® parts? Will they actively support it by creating a LEGO® science collection, supporting a select number of Certified Science Professional Builders, for instance, or setting up a support program (financially supported grant program or free access to LEGO® parts)? Alternatively, will they tacitly acknowledge it without providing incentives? The rationale for LEGO® building calls out for bigger and more fundamental questions in science. There obviously is an escalating trend towards highly refined technologies and devices which are associated with substantially increasing financial costs. To what extent this trend is financially and humanly sustainable? What is the balance between the benefits from such technologies and their human and financial cost? Does science ultimately benefit from ----!@#$NewPage!@#$---- the highest possible technological advance, and when does it become detrimental to its advancement? ----!@#$NewPage!@#$---- (A) (B) Figure 1 - Boulter et al ----!@#$NewPage!@#$---- Fixed (guiding bore) Cyclic Translation (pulling arm) Compressing Translation (pulling arm) Fixed (stopper) Guided micrometric translation (platform) Drive Drive Drive Substrate Stretching / Cell Signaling & Biomechanics Syringe Action / Micro�uidics & imaging 10º -> 2º -> 0.4º -> 3.556 µm 0.2-1 Hz 12% stretch reproducible: 20µL 1:5 1:5 10º -> 0.256 µL (1mL syringe) 1:3 Fixed (rails) 360º -> 1 cycle 1:1 8-rack 2-rack LEMOLISH Rotation (platform) Drive Free in-plane movement Sample Translation, Sample Rotation / 3D lightsheet & mesoscopic imaging 10º -> 0.357 º 1:1 1:28 Fixed (guiding bore) ----!@#$NewPage!@#$---- Creation Inventor/artist Reference Miscellaneous Creations Various creations ranging from tensegrity sculpture to Hoberman sphere JKBrickworks (Jason and Kristal Allemann) https://jkbrickworks.com Braigo (Braille printer) Braigo Labs - Shubham Banerjee https://www.braigolabs.com/products/ Cubestormer 3 (Rubik’s cube solver) David Gilday and Mike Dobson https://youtu.be/cO5DLbpp3-M Super Awesome Micro Project aka air powered LEGO® car Steve Sammartino and Raul Oaida https://youtu.be/_ObE4_nMCjE Real LEGO® Bugatti Chiron The LEGO Group https://www.lego.com/en- us/campaigns/technic/bugatti- chiron/build-for-real Bridge Girder erection machine SLJ900 Wolf Zipp https://www.youtube.com/channel/ UC2vjCc0CiaxF8bHHaOPQUXw Various creations including clocks, braiding machines, etc… Nico71 http://www.nico71.fr Prosthetic Arm David Aguilar https://www.mrhandsolo.com Table 1 – List of LEGO® creations from the general public ----!@#$NewPage!@#$---- System/Tool Description Creator/Reference Education/STEM Conceptual AFM AFM designed to scan LEGO® plates (Hsieh et al., 2014) Colorimeter Two LEDs colorimeter (Asheim et al., 2014) Brickopore Brick-based DNA sequencing www.brickopore.co.uk Influenza model (Marintcheva, 2016) LEGOLish Light sheet microscope built from LEGO® parts www.legolish.org Liquid-handling robots Liquid dispensing robot (Gerber et al., 2017) Instrumentation General lab equipment General lab equipment Martin F Haase LEGO Fraction Collector Mindstorms-based fraction collector (Caputo et al., 2020) Spectrophotometer (Pereira & Hosker, 2019) MicroscoPy Research Brightfield Microscope made of LEGO, 3D printing, arduino and raspberryPI https://github.com/IBM/MicroscoPy Microfluidics µorgano LEGO®-like system for multi-organ chips (Loskill et al., 2015) Supramolecular LEGO Assembly LEGO®-like assembly of hydrogels (Ma et al., 2014) 3D printed microfluidics LEGO®-like microfluidics system (Morgan et al., 2016) Biological Research Plant Growth System Transparent tanks for monitoring plant growth (Lind et al., 2014) IMp 3D insect manipulator for observation (Dupont et al., 2015) LEMOLISH LEGO®-based Motorized Lightsheet Microscope for 3D mesoscopic imaging of transparent organs www.legolish.org/lemolish (ms. in prep) Pumpy Multimodal microscopy system (Almada et al., 2019) Stretchy Cyclic Uniaxial cell stretcher (Boulter et al., 2019) Brick Strex Motorized Cell Stretcher (Mäntylä & Ihalainen, 2021) Table 2 – List of LEGO® creations in Biotechnology and biological research. ----!@#$NewPage!@#$---- Figure 2 - Boulter et al B A C D ----!@#$NewPage!@#$---- Creation/Artwork Title Inventor/artist Reference Art Sculptures/Shadow Art John V. Muntean https://www.jvmuntean.com Geometric Art Jeff Sanders http://www.brickbending.com Sculptures/paintings Nathan Sawaya https://www.brickartist.com Mosaics Eric Harshbarger http://www.ericharshbarger.org Street art Jan Vormann https://www.janvormann.com Lenticular mosaic Arthur Gugick Table Box 2 – List of LEGO® artwork creators ----!@#$NewPage!@#$---- System/Tool Description Creator/Reference Behavioral sciences/Neurological Sciences CoRLEGO Choice reaching task modeling using LEGO®robot (Strauss et al., 2015) LEGO® Therapy Engage autistic spectrum disorder kids into social interactions (DB, 2004; DB & M, 2006; LeGoff et al., n.d.) LEGO Robots Remote labs for experimenting with a team of robots (Casini et al., 2014) Physics CERN model New parts prototyping https://home.cern/news/ news/experiments/using-lego- study-building-blocks-universe Thermal Insulator Characterization of LEGO® bricks as thermal insulators (Chawner et al., 2019) Tensile testers Two models of tensile testers (Moser et al., 2016; Talib et al., 2019) Wave manipulator Experimental platform for the investigation of phononic phenomena (Celli & Gonella, 2015) Chemistry Nerve gas detector (Sun et al., 2018) Table Box 3 – List of LEGO® creations in Science