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Biology on a chip: the emerging field of interactive biotechnology is changing the way education and research are conducted.

When Charles Darwin sailed on the Beagle to the Galapagos Islands, did he know his studies there would turn him into the father of evolution? What about when Gregor Mendel studied the inheritance of traits in pea plants--did he envision the start of Mendelism and the father of genetics marker?

It's interesting to look back on the founders of the sciences--those who paved the way. But it's also interesting to look forward--to today's scientists who may very well be tomorrow's founders.

If his research team has anything to say about it, Ingmar Riedel-Kruse may one day be known as the father of "interactive biotechnology." The Riedel-Kruse Lab in the department of bioengineering at Stanford University is pioneering this new scientific field, which is dedicated to the development of real-time systems that interact with microscopic biological components, such as protist swarms or bacterial biofilms. In other words, the lab designs practical devices that facilitate easy interaction between a macroscopic human and microscopic cells.

Specifically, members of the Riedel-Kruse Lab have engineered biotic games and cloud experimentation laboratories. Biotic games involve a variety of basic biological processes and live single-celled organisms in combination with a user-driven biotechnology device.

The cloud experimentation laboratory is a wet lab that can be controlled remotely over the Internet--with automated biotic processing units serving as a researcher proxy. Together, these recent biotic projects from the Riedel-Kruse Lab are helping define the new field of interactive biotechnology.

After all, why shouldn't microbiology be--as Riedel-Kruse puts it--"playful?"

Biotic in the classroom

The biggest potential for interactive biotechnology, at least in the short-term, lies in education.

"The way humans learn, especially children, is via interaction--changing things and observing the response, and doing that again and again," Riedel-Kruse told Laboratory Equipment. "The easier this interaction is and the more interesting the response, the higher the motivation and excitement to 'play,' and hence to learn."

Nate Cira, Stanford bioengineering doctoral student, took this idea and ran with it, designing a 10-week course on biotic game implementation for undergraduates.

The curriculum was divided equally between a set of technical units and a project-based section where students were asked to build their own biotic games.

The technical section of the course focused on developing hands-on skills and theoretical understanding related to the biological devices. This means students were introduced to fundamental electronic concepts, such as LEDs, microcontrollers, filters, etc. Structuring these electronic components to correctly interact with a living organism provided the bioengineering students with a healthy dose of life science.

"There is an increasing need to bring the traditional engineering and life science disciplines together," reads Cira's paper, which was published in March in the journal FLOS One. "In order to fill these gaps, we present the concept of a biotic game design project to foster student development in a broad set of engineering and life science skills in an integrated manner. "

"If you're really good at biology but can't make a device to better test biological questions, you are at a bit of a disadvantage. Or, if you can only make devices but are not able to apply them to biology, you are also at a disadvantage," Cira told Laboratory Equipment. "Having both skill sets and being experienced at integrating them makes you a more competent researcher."

The biotic games Cira's class designed involved the single-celled flagellate protist Euglena gracilis, which were housed in a microfluidic chip and displayed on a screen via magnified image. The games the students ultimately produced were diverse, including single and multiplayer scenarios, games where Euglena hit virtual targets and games where Euglena pushed virtual objects.

An additional component of Cira's curriculum challenges students to consider the ethical implications of their work. Although experiments with Euglena are commonplace in schools and laboratories, the idea of playing "games" with living organisms raised a few red flags initially.

"[Bioethics] is something scientists and engineers should be thinking about on a regular basis, regardless of what they are doing," Cira said. "It's important to consider, 'what are the implications of this work from a societal context?' Anytime you are working with a living thing, it is imperative to think carefully about what you are doing."

In the end, all students found the games acceptable, pointing out that Euglena are nonsentient and cannot feel pain. Additionally, many students self-reported that they enjoyed the project and it led to increased motivation and effort throughout the course--which speaks to Cira's original intent to "motivate student learning at the interface of life sciences and device engineering."

Biotic in a museum

Euglena gracilis also serve as the model organism in another Riedel-Kruse Lab game--this one installed as an interactive museum exhibit.

"Trap it!" is a human-biology interaction (HBI) medium that allows visitors to The Tech Museum of Innovation in San Jose, Calif., to interact in real-time with living microorganisms. According to a paper on the research, users draw patterns on a touchscreen over a magnified view of light-sensitive Euglena gracilis. The user's drawing is then projected onto the microorganisms as light beams, which the cells sense and respond to by changing their swimming motion and pattern.

In this context, the biotic processing unit (BPU) is a set of hardware comprising a microfluidic chip sandwiched between modified electronic devices and optical components. Optical microscopy bridges the gap between human and microorganism- projecting a view of both the subject and drawn pattern onto a touchscreen monitor, through which the user controls the BPU.

Visitors could use blue, green or red light to draw patterns and subsequently observe how the Euglena reacted. The microorganisms are known to avoid blue light, so drawing a circle around one of the microbes would trap it--giving the museum exhibit its name.

Other mini-games were also developed for the museum exhibit, including one called Apple, which asks participants to guide the microorganisms to virtual apples on the screen. In a third game called Box, players seek to trap as many cells as possible in a virtual box in a limited amount of time.

In their paper, the researchers concluded that the setup successfully enabled HBI as a novel type of museum activity in which visitors could experience true interactions with the microscopic world without complex biological knowledge or laboratory skills.

"Interaction with the system invoked users' curiosity about organisms and the technical principles underpinning the activity," reads the paper, of which Cira is a co-author. "With proper scaffolding, it can lead to educational outcomes not only in the transfer of relevant knowledge but also in provoking interests about biology in general."

An interactive remote lab

Interacting with biological systems via real (not simulated) experiments is an important research component for academia, industry and especially education. However, according to Stanford Ph.D. student Zahid Hossain, many access barriers exist that prevent such a facilitation, such as training requirements, cost, safety, time and logistics.

So, Hossain devised a lowcost, "hands-on"solution--an interactive cloud experimentation laboratory for biology, which enables multiple remote users to execute live biology experiments over the Internet by efficiently sharing necessary resources.

To test the idea of an interactive remote lab, Hossain conducted a 10-week user study in a graduate-level biophysics class.

First, Hossain had to come up with a design philosophy since you can't build a robot that can do every kind of experiment--not yet, at least. The research team settled on developing a biotic processing unit (BPU) that could carry out automated liquid handling and imaging experiments with P. polycephalum, a slide mold commonly used as a model or ganism for movement studies. Since the single-celled organism is known to move dramatically toward food sources, trails of liquid oatmeal were pipetted in patterns onto an agar surface in a Petri dish. A scanner then recorded how P. polycephalum followed each trail of oatmeal dots.

"We used LEGO Mindstroms for the BPU proto type," Hossain explained to Laboratory Equipment. "We took apart a regular office scanner and used that as an imaging device, so you would place Petri dishes on top of the scanner and the imaging would happen underneath. We also built a gantry on top to position the liquid pipettor."

In this system, each Petri dish represents a well that houses a single experiment to be shared by multiple users.

To achieve both interactivity and concurrent execution of the experiments, users were asked to provide instructions in "blocks," where each block comprises a small sequence that needs to be performed at a future time.

According to Hossain's paper, total time order of the instructions is achieved by scheduling the blocks at different points in a timeline. Instructions from several users are queued in the server until the BPUs are ready to poll in a synchronous manner. Each BPU polls the server at a regular interval of 10 minutes, aggregating blocks that pertain to a certain time before executing all pending pipetting instructions from several users in a way that is optimal for batch execution. Manual intervention is needed at the beginning of the experiment to prepare the plates and place them in the machine, as well as at the end of the experiment to clean up the work.

For the project, Riedel-Kruse, Elossain and lab members built three BPUs, each holding six Petri dishes. All three units were housed in a server rack used commonly in computing.

"A single BPU can be shared among at least six people, so the prototype supported 18 users," Hossain said. "That is important because biology equipment like high-throughput pipettors can do a lot of pipetting at one time, but there is no way for multiple users to use them at the same time."

According to the paper, stu dent feedback indicated that, compared with conventional labs, the cloud experimentation platform "lowered the threshold of entry to biology experimentation" by: 1) empowering non-biologists to perform wet lab experiments without safety or training concerns; 2) allowing students to concentrate on experimental strategies and data analysis without wet lab details; and 3) providing convenience by allowing students to access the experiments from any place at any time.

Just like Cira's biotic games and museum exhibit, Hossain's cloud experimentation laboratory shows great potential in education, especially online course instruction. Online education is a growing field, but as of now there is no way for an online course to teach about the biology wet lab or biological experimentation.

"If the course is about teaching how to do a wet lab, this will not work," Hossain said," but it will if it's a biophysics course about how to model different biological phenomena. To understand the model, you have to run real experiments and verify the results. Here, the main focus is learning how to model biological phenomena while studying the real system alongside."

Another reason education is a great fit is because, by its very nature, there are thousands of users doing the same exact thing. Everyone is following the same curriculum, therefore conducting the same experiments, using the same equipment and models, etc. Running the same course over and over again also affords the technology the opportunity to improve itself over time.

Of course, education is not the only suited application.

"When we started out, our main goal and vision was to build this technology for trained biologists and researchers," Hossain said. "It will take some time to develop that technology but in the future, when the technology is stable enough, a real biologist can use this system for their research."

While the short-term plan is to develop a stable system for online education that allows thousands of students to conduct real biology over the Internet, Hossain said he is working on two approaches for his-long term plan for trained biologists.

One approach involves establishing a giant lab with differing equipment that can run pre-determined experiments and protocols, with users accessing the equipment remotely via the Internet. The second option is a tabletop approach, where a mini-lab with simple robotics is set up for local researchers to share. In this circumstance, only one device is needed to cater to a number of researchers in a specific locale.

An emerging field

Studies show that while younger children are generally interested in science, the excitement drops off dramatically by their teenage years, which is when decisions about career paths are made.

"There needs to be more attention and innovation on how to carry this excitement along as children grow," Rie del-Kruse said. "Take teaching children how to read, for example. The biggest success comes when children learn the basics, but then get so excited about reading books--and have a wide variety to choose from--that they want to do it at home on their own. Hence, we need to provide diverse interactive media related to STEM that are 'fun' and that children can have easy access to." Riedel-Kruse Lab members are already working on ways to extend interactive biotechnology to the masses. They have developed low-cost kits that allow hobbyists to construct their own micro-aquariums, as well as smartphone kits that allow kids to play biotic games--on a familiar device that is often within arm's reach.

"In education, the kits can be distributed to any school or any interested individual," Cira said. "Once the price drops, they will become pretty widespread.

"As far as research goes, I think interactive biotechnology is a very exciting area. As these components and solutions become more routine and widespread, our capacity to do more, to do better and conduct higher-throughput, more impactful and more exciting research will only increase."
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Author:Taylor, Michelle
Publication:Laboratory Equipment
Article Type:Cover story
Date:Aug 1, 2015
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