Automatic laboratories

Bright future of natural science research

Yulia Kondratenko, "Biomolecule"

Anyone can take a pen and a piece of paper and try to prove Goldbach's conjecture. Anyone has the opportunity to write a philosophical treatise or put forward a new economic theory, there would be ideas and desire. However, not everyone has the opportunity to conduct natural science experiments. Even serious studies of biological macro–objects – animals and plants - now include elements of molecular diagnostics: genotyping of the studied individuals, the search for mutations that cause changes noticeable to the naked eye. Molecular diagnostics, after all, requires expensive reagents and expensive equipment that you need to be able to handle. Therefore, modern natural science research is an area in which not everyone has a chance to try themselves.

Recently, two trends have appeared in biology, which aim to bring natural science research closer to people who do not work in the laboratory and are not ready to devote all their time to laboratory experiments. The first is the biohacker movement that emerged in the USA a few years ago [1]. Biohackers practiced biology in garages, buying used equipment and conducting rather complex experiments "on the knee". They wanted to show people that science can get closer if you use a creative approach – after all, you can use equipment that is not the most expensive, you can buy used, you can not buy it at all, but change it for something or even get it for free. And "aerobatics" from the point of view of a biohacker is to understand the principles of operation of the device and design its simple, cheap, but working version yourself. These ideas are undoubtedly healthy and productive, but it should be recognized that the biohacker approach to science requires a lot of effort and time and is not suitable for everyone.

A completely opposite approach to biological research is offered by new "cloud laboratories" that have recently begun to appear in the USA, for example, Transcriptic (Fig. 1) and Emerald Cloud Laboratory.

Figure 1. Transcriptic Robotic Laboratory website,
offering everyone to conduct their experiments.

Video from the Emerald Cloud Laboratory website.

Their ideas are completely opposite to biohacker ones: they offer anyone who wants to conduct their experiments without touching test tubes and pipettes at all. It is important that these laboratories are not just groups of scientists who do other people's experiments for money. If you visit their websites, you will see automatic pipettes moving in the air, tripods with test tubes and other mechanical devices traveling by themselves, regularly transfusing liquids and scanning samples. And this is not for nothing, because the peculiarity of these laboratories is the use of robotics, which guarantees users the most accurate and reproducible results.

In order to conduct your experiment, you can choose a protocol from a ready-made set or translate your own protocol into the language of machine commands using a special interface. It seems that the day is not far off when a service will appear, similar to the American Magic [2] fulfilling any wishes of scientists. It will be possible to send a text message: "Synthesize the X gene, clone it into the Y vector, transfect Z cells with it and count the fluorescent ones at the lambda wavelength." There is no such service yet, but already now the process of ordering experiments in "cloud labs" is not much more complicated. The results of the experiments come by e-mail in a very short time: the Emerald Cloud laboratory, for example, already promises to conduct a study by any method from its list within a day. What is on this list? The set of proposed methods includes several dozen names (from primitive autoclaving and thermometry to all kinds of chromatography and PCR), and in the near future, according to the promises of the founders of the laboratory, it should double. At the moment, robots can already do most of the routine laboratory tasks for a person, freeing up people's time for the creative components of research – planning and analyzing the results.

Robots have long been able to dig up solutions with perfect accuracy in test tubes and dies, mix their contents, change and maintain the temperature. They are also able to do more complex things – for example, growing mammalian cell culture and staging transfections. But this is just the level of an ordinary student (who, however, never makes mistakes), and his robots are long gone. They can do more and more thanks to the development of systems that integrate the operation of several devices, which makes it possible to fully automate the whole experiment.

For example, the Tecan platform can be equipped with a variety of modules: for moving the die, for digging solutions on it, for washing it, for mixing and incubation at different temperatures. This allows you to fully automate, for example, the process of immunoblotting. Leica devices independently produce preparations for microscopy – it is enough just to load tissue samples into them. Qiagen offers a ready-made system that can carry out all stages of DNA extraction from cells, and then also carry out PCR with it. Machines can already independently synthesize biological polymers – nucleic acids, peptides and oligosaccharides.

And on March 13, 2015, an article was published in the journal Science telling about the creation of a machine that allows automating the synthesis of most natural small molecules (for example, non-peptide antibiotics) [3]. This is a remarkable achievement, since individual blocks of non–polymer molecules are connected by many different types of bonds – unlike polymer ones, the synthesis of which is similar to the assembly of a train, whose identical cars can be changed in any order. Therefore, it was always necessary to approach the synthesis of natural small molecules creatively, often going through many stages, at each of which a part of the substance was inevitably lost. Until now, it seemed incredible that the processes of synthesis of such molecules could be automated, especially using a single device. However, recently Martin Burke from the University of Illinois (USA) succeeded: his Machine collects a huge number of molecules if it is provided with the right building blocks (Fig. 2). At the junction of the blocks, one of them should contain a residue of boric acid, and the other – a halogen atom. In a palladium-catalyzed reaction, such blocks combine, discarding boric acid and halogen [4]. Now there are about 200 suitable building blocks on sale, and with an increase in their number, the repertoire of the Machine will continue to expand.

Figure 2. Test tubes with components for the synthesis of small organic molecules,
which Martin Burke's Machine conducts completely independently. Figure from [3].

The founders of cloud labs are developing the direction of automation of increasingly complex processes, creating systems for robots to interact with each other. These are additional machines that transfer samples between robots, and software that allows the devices to "speak the same language." The result is a fully automatic laboratory in which all experiments are performed as accurately and quickly as possible.

Robots have other advantages – they make it easier to select experimental conditions, because automata can change only one parameter, leaving the values of the others exactly the same as before. And of course, they can do more repetitions of experiments without getting confused due to the fact that there are too many test tubes. With the transition to robotic laboratories, we have hope to get out of the crisis of reproducibility of results, in which natural sciences are now. Natural science experiments have become so complex that often other scientists cannot reproduce the results of colleagues, not because they have manipulated them, but because colleagues cannot describe their actions in absolute detail. When it comes to life research at the molecular level, every insignificant error in the volume of the solution, every minor difference in laboratory conditions, every habit of a scientist that he no longer pays attention to, can affect the result. With the advent of robotic laboratories, these moments will no longer confuse us. And of course, the automaton will not falsify the results: neither because it's time for him to defend his dissertation, nor because he has his own vision of which result is more beautiful.

Another important advantage of robots is the storage and search of samples and data. Automated systems can not only store all samples in suitable conditions, but they can also tell you how long ago the sample was received and what kind of enzyme packaging it is time to stop storing for a rainy day. If such a system is part of a robotic laboratory, then for each sample it will also be known in detail as a result of which operations it was obtained. For ordinary "human" laboratories, such systems can also be useful. Both Transcriptic and Emerald Cloud Laboratory are engaged in their development [5, 6]. Leica produces special devices for convenient sample search.

Interestingly, even now, research in robotic laboratories is not significantly more expensive or even cheaper than experiments conducted in a classical way. Scientists are gradually beginning to trust robots with routine work: for example, cloning, mutagenesis and screenings were carried out in a robotic laboratory to create a biosensor that determines the chemical composition of oil (for this development, scientists who invented the sensor even received a prize) [7]. The lucky ones did not have to repeat many routine molecular biological procedures to realize their idea. There are more and more publications whose data were obtained using automated systems, because even individual devices installed in conventional laboratories make the work of scientists less boring and their data more accurate.

Will robots displace people from laboratories altogether? Hardly, because the creative process of flipping through Pubmed over a morning cup of tea, clicking through dozens of links, after which you don't even remember where it all started, and, finally, insight into what you should do immediately, is absolutely impossible to describe by computational methods [8]. And with the spread of robotic laboratories that are ready to conduct accurate experiments for everyone, these subtle pleasures will become available to an increasing number of people.

Literature

1. biomolecule: "Biohackers: Do-it-yourself molecular Biology";
2. Fiegerman S. (2015). Magic by SMS. How the Magic wish fulfillment service works (translated from English);
3. Service R.F. (2015). The synthesis Machine. Science. 347, 1190–1193;
4. Biomolecule: "Palladium Nobel Prize in Chemistry (2010)";
5. Transcriptic: The LIMS Data Model: Sample Management;
6. Emerald Cloud Laboratory: Explore data;
7. Hayden E.C. (2014). The automated lab. Nature. 516, 131–132;
8. Penrose R. Shadows of the Mind: in Search of the Science of Consciousness. Moscow-Izhevsk: Institute of Computer Research, 2005. – 688 p.

Portal "Eternal youth" http://vechnayamolodost.ru27.03.2015