From ETH Zürich[Eidgenössische Technische Hochschule Zürich)](CH): “Cells as computers”

From ETH Zürich[Eidgenössische Technische Hochschule Zürich)](CH)

09.03.2021
Fabio Bergamin

Scientists at ETH Zürich are working to develop information-​processing switching systems in biological cells. Now, for the first time, they have developed an OR switch in human cells that reacts to different signals.

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In their research, ETH Zürich scientists bring mathematical and electronic information processing approaches into biological systems. Credit: Colourbox / Montage: Gidon Wessner.

Biological cells might one day be equipped with artificial genetic programs that work in much the same way as electronic systems. Such reprogrammed cells could perform medical tasks in our bodies, such as diagnosing diseases or providing treatment. One potential application would be altered immune cells that combat tumour cells. Since tumour cells have different genetic characteristics, the following biochemical program, for example, would have to run in the therapeutic cells: “Destroy a cell if it is type X or Y or Z”.

In mathematics and electronics such a function is called an OR gate. “These are needed in decision-​making processes whenever multiple different things lead to the same outcome, when you have to deal with alternative inputs at the same time”, explains Jiten Doshi, a doctoral student in ETH Professor Yaakov Benenson’s group in the Department of Biosystems Science and Engineering at ETH Zürich in Basel. In collaboration with colleagues, Doshi and Benenson have for the first time developed an OR gate – a molecular switching element that emits a biochemical output signal when it measures one of two or more biochemical input signals – in human cells.

Previous OR gates implemented in biological cells were quite simple, as Benenson explains. When, for example, a cell was supposed to secrete a substance in response to signal X or signal Y, scientists combined two systems: one that secreted the substance in response to signal X and another that released the substance in response to signal Y. The ETH scientists’ new OR gate, in contrast, is a true OR gate – one comprising a single system. As with all biological systems, its design takes the form of a DNA sequence. In the case of the new gate, this sequence is significantly shorter because it is one system rather than two separate ones.

Inspired by nature

To realise the OR gate the ETH researchers used transcription-the cellular process in which a gene’s information is read and stored in the form of a messenger RNA molecule. This process is initiated by a class of molecules known as transcription factors, which bind in a specific manner to an “activation sequence” (promoter) of a gene. There are also genes with several such activation sequences. One example of this is a gene called CIITA, which has four such sequences in humans.

The ETH researchers turned to this gene for inspiration and developed synthetic constructs with a gene that is responsible for the production of a fluorescent dye and that has three activation sequences. Up to two transcription factors, and one or more small RNA molecules specifically bind to and control each of these sequences. The gene construct produces the dye when transcription is initiated via at least one of the three activation sequences – i.e., via sequence 1 or sequence 2 or sequence 3. The researchers filed a patent application for this new system.

Closing a loop

As Benenson stresses, this research closes a loop. From a historical standpoint, information processing has developed in living creatures over the course of evolution: humans and animals are very good at taking in sensory input with their brains, processing it and responding accordingly. Only in the 19th century did the development of switchable electronic components began: first with the relay; later with vacuum tubes; and finally with transistors, which enabled the construction of modern computers.

In their research, the ETH bioengineers try to bring these mathematical and electronic information processing approaches back into biological systems. “For one thing, this helps us to better understand biology, such as how biochemical decision-​making processes take place in cells. For another, we can use these approaches to develop new biological functions,” Benenson says. The researchers benefit from the fact that biological cells offer ideal conditions for this.

More complex forms of diagnostics and treatment

This cellular information processing is expected to be used primarily in medical diagnostics and treatment. “Today’s medical treatments are usually rather simple: we often treat diseases with just a single drug, regardless of how complex the biology and the causes of diseases may be,” Benenson says. This stands in contrast to how an organism deals with external changes. The body’s stress reactions, for example, can be very complex.

“Our biomolecular information processing approach holds out the promise of using artificial genetic networks that can identify and process different signals to one day develop complex cellular diagnostics systems and potentially more effective forms of treatment,” Benenson says. Such forms of treatment would also identify when a normal state has been reached following successful treatment. For example, an ideal cancer treatment fights tumour cells as long as they are present in the body, but does not fight healthy tissue, because doing so would cause damage.

Science paper:
Multiple Alternative Promoters and Alternative Splicing Enable Universal Transcription-Based Logic Computation in Mammalian Cells
CELL

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ETH Zurich campus
ETH Zürich [Eidgenössische Technische Hochschule Zürich] (CH) is a public research university in the city of Zürich, Switzerland. Founded by the Swiss Federal Government in 1854 with the stated mission to educate engineers and scientists, the school focuses exclusively on science, technology, engineering and mathematics. Like its sister institution EPFL[École polytechnique fédérale de Lausanne](CH), it is part of the Swiss Federal Institutes of Technology Domain (ETH Domain), part of the Swiss Federal Department of Economic Affairs, Education and Research.

The university is an attractive destination for international students thanks to low tuition fees of 809 CHF per semester, PhD and graduate salaries that are amongst the world’s highest, and a world-class reputation in academia and industry. There are currently 22,200 students from over 120 countries, of which 4,180 are pursuing doctoral degrees. In the 2021 edition of the QS World University Rankings ETH Zürich is ranked 6th in the world and 8th by the Times Higher Education World Rankings 2020. In the 2020 QS World University Rankings by subject it is ranked 4th in the world for engineering and technology (2nd in Europe) and 1st for earth & marine science.

As of November 2019, 21 Nobel laureates, 2 Fields Medalists, 2 Pritzker Prize winners, and 1 Turing Award winner have been affiliated with the Institute, including Albert Einstein. Other notable alumni include John von Neumann and Santiago Calatrava. It is a founding member of the IDEA League and the International Alliance of Research Universities (IARU) and a member of the CESAER network.

ETH Zürich was founded on 7 February 1854 by the Swiss Confederation and began giving its first lectures on 16 October 1855 as a polytechnic institute (eidgenössische polytechnische Schule) at various sites throughout the city of Zurich. It was initially composed of six faculties: architecture, civil engineering, mechanical engineering, chemistry, forestry, and an integrated department for the fields of mathematics, natural sciences, literature, and social and political sciences.

It is locally still known as Polytechnikum, or simply as Poly, derived from the original name eidgenössische polytechnische Schule, which translates to “federal polytechnic school”.

ETH Zürich is a federal institute (i.e., under direct administration by the Swiss government), whereas the University of Zürich is a cantonal institution. The decision for a new federal university was heavily disputed at the time; the liberals pressed for a “federal university”, while the conservative forces wanted all universities to remain under cantonal control, worried that the liberals would gain more political power than they already had. In the beginning, both universities were co-located in the buildings of the University of Zürich.

From 1905 to 1908, under the presidency of Jérôme Franel, the course program of ETH Zürich was restructured to that of a real university and ETH Zürich was granted the right to award doctorates. In 1909 the first doctorates were awarded. In 1911, it was given its current name, Eidgenössische Technische Hochschule. In 1924, another reorganization structured the university in 12 departments. However, it now has 16 departments.

ETH Zürich, EPFL (Swiss Federal Institute of Technology in Lausanne) [École polytechnique fédérale de Lausanne](CH), and four associated research institutes form the “ETH Domain” with the aim of collaborating on scientific projects.

Reputation and ranking

ETH Zürich is ranked among the top universities in the world. Typically, popular rankings place the institution as the best university in continental Europe and ETH Zürich is consistently ranked among the top 1-5 universities in Europe, and among the top 3-10 best universities of the world.

Historically, ETH Zürich has achieved its reputation particularly in the fields of chemistry, mathematics and physics. There are 32 Nobel laureates who are associated with ETH Zürich, the most recent of whom is Richard F. Heck, awarded the Nobel Prize in chemistry in 2010. Albert Einstein is perhaps its most famous alumnus.

In 2018, the QS World University Rankings placed ETH Zürich at 7th overall in the world. In 2015, ETH Zürich was ranked 5th in the world in Engineering, Science and Technology, just behind the Massachusetts Institute of Technology(US), Stanford University(US) and University of Cambridge(UK). In 2015, ETH Zürich also ranked 6th in the world in Natural Sciences, and in 2016 ranked 1st in the world for Earth & Marine Sciences for the second consecutive year.

In 2016, Times Higher Education WorldUniversity Rankings ranked ETH Zürich 9th overall in the world and 8th in the world in the field of Engineering & Technology, just behind the Massachusetts Institute of Technology(US), Stanford University(US), California Institute of Technology(US), Princeton University(US), University of Cambridge(UK), Imperial College London(UK) and