Young researchers engineer a prospective life-saving bacterium – a possible metastatasis prevention probiotic

Department of Experimental and Health Sciences at Universitat Pompeu Fabra (DCEXS - UPF)
  • A group of students make their baptism in research: they develop a proof of concept for a probiotic to prevent cancer metastasis
  • The young researchers engineer a bacteria to take up and consume long-chain fatty acids, a major risk factor for metastasis
  • Further development could eventually have this idea give the leap into a real application saving many lives

 

iGEM and the Giant Jamboree

This is a story that starts with an announcement on a notice board at the Pompeu Fabra University (UPF). A group of young students would find and read it, forming as a result a team that would make it to Boston to participate in iGEM, an international competition in Synthetic Biology.

The culmination of the efforts of these students in the iGEM 2018 competition came with iGEM’s Giant Jamboree, that took place in Boston, Massachussets. From October 31st to November 4th, during a full 4 days of experience sharing, cooperation, competition against themselves while striving for improvement, and celebration of the achievements of participant teams.

iGEM, an independent non-profit whose name stands for “International Genetically Engineered Machine”, traces its origins back to January 2003. Then, a group of teachers of the Massachusetts Institute of Technology (MIT) devised a new study course. The initially small course, perhaps inexpectedly, grew to become a team competition the next year, further growing in size the following year and the next.

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The MIT campus in Boston, Massachussets, birthplace of iGEM.

By 2016, the competition gathered already more than 5000 participants. The growth continued, with the 2018 edition hosting over 340 teams of 40 countries, totalling 5790 participants. As of today, iGEM has become an initiative that works not only to promote the education of young scientists, but also to contribute to the progress of the field of synthetic biology, a discipline combining principles of both biology and engineering to create living systems for solving specific problems.

 

The team and how it came about

With the support of three SOMMa members, the Department of Experimental and Health Sciences at Universitat Pompeu Fabra (DCEXS - UPF), the Information and Communication Technologies Engineering Department at Universitat Pompeu Fabra (DTIC - UPF) and the Centre for Genomic Regulation (CRG) these students launched their quest, going as far back as the year 2017.

Hundreds of teams of pioneering young scientists developed their projects, in a process that would bring them up an intensive path of learning and challenge. The Barcelona team was composed of students of human biology, biomedical engineering, mathematics and telecommunications engineering of the UPF. Leveraging their collective skills and drive, they developed a proof of concept probiotic for preventing metastasis. Its eventual translation into a successful, real application, could prove its potential to save many lives: as many as 90 % of deaths by cancer are caused by metastasis.

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The iGEM 2018 Barcelona Team in Boston.

The project was launched well in advance, with a large fraction of the time dedicated to fundraising, coordinated by the students themselves. Eventually, enough funds could be secured via crowdfunding, even managing to obtain funds from a number of companies such as Promega. This was non-trivial, as the team noticed: the stronger the financial base, the more time and effort could be allocated towards the scientific development in terms of documentation, laboratory work, as well as to the computational modelling tasks involved. During the whole development of the project, the team would retain the last word for each decision to be taken, giving them a deserved feeling of ownership for their success.

 

The science and idea behind, at a glance

The originary idea came from a publication in which metastatic cells were found to be expressing a high amount of a certain cell receptor called CD36. This receptor resulted in an enhanced uptake of long-chain fatty acids (LCFA) by those cells. In addition to this, it was known that a high presence of LCFAs in the diet of humans is linked to an increased risk of developing metastasis, in case of cancer. The proposal that arose from this was to develop a bacterium that would takes up long-chain fatty acid from the diet, not only taking them up but also metabolising them more efficiently.

The team would thus engineer bacteria that, if used as a probiotic, could result in a decreased absorption of LCFA by humans, by that decreasing the risk of metastasis. This bacterium would take the name of Gargantua, in honour of the famous (and voracious) character of the XVI century French novels written by François Rabelais.

It was initially proposed for the bacterium to mimic the use of the same CD36 receptor as metastatic cells. This quickly proved not easily feasible, so an alternative was found. An equivalent bacterial alternative, the protein FadL, would have a similar effect and be an appropriate replacement with an equivalent function. Together with a group of closely related proteins, FadD and a system of complementary proteins, not only absorption but also largely enhanced degradation of fatty acids would become possible.

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The project engineered E. coli to decrease LCFA absorption in humans, potentially decreasing the risk of metastasis.

More pieces had to be added to this biological machine. Team members Marta Vilademunt and Dimitrije Ivancic brought forth, as good practice in synthetic biology, that when one intends to synthetize or degrade a compound, it is necessary for the engineered system to be able to detect the compound in order to adapt adequately. In that logic, a molecular sensor capable for detecting the influx of LCFA was built into the bacterium. Connected to a biological switch, this would turn on and off the system, allowing the bacterium to react coherently and more efficiently to the presence or absence of LCFA inside the bacterium.

Finally, the same as humans are often misled by sweet, making them ignore other nutritious food sources, many bacteria tend to favour the consumption of sugars as well. Making the bacteria unable to use sugar as fuel, their genes for sugar processing were “knocked out”. This would result in the bacterium being forced to grow and thrive on other nutrients, focusing on the desired LCFA.

 

iGEM, during and afterwards

Students Vilademunt and Ivancic explained that since the inception of the project, the maturation of the idea took almost a year. For some time, this was just a side-project for the team while each one of them was busy with other aspects of their career. Some members  were outside Spain at the time, meaning that coordination needed to be done remotely, keeping the contact alive via periodic teleconferences.

The project kept under a constant process of maturation, with lots of learning with the trial and error, gradually changing after solving the encountered issues, one after the other. The original concept would keep repeatedly re-adjusting, resulting in a far more complex and capable system than initially planned.

The effort, commitment, ability to improve, or the proposal of a genuinely original idea were all part and requirement of the whole process. Having to prove lots of patience and resilience in face of frustration, and the fact of having chance to make the jump from theory to practice, made the process of personal growth exponential. Also the need to focus a relevant fraction of their energies on fundraising, a completely different aspect, summed on top of all this process of learning. With many decisions still laying ahead and manifold possible life directions still wide open, the participation in iGEM may have given them a good head start in their future careers.

 

Aftermath of the competition

The competition of each team was, first and foremost, against itself. In this competition, the Barcelona team was awarded with a gold medal owing to their excellent idea, the development and presentation of the project, together with the feasibility of bringing the research into results with true impact. Gargantua was, as a result, also nominated as one of the best therapy-oriented projects of the competition. Room for further development exists.

iGEM opens many doors to its former participants, offering the possibility to keep engaged as ambassadors, instructors or advisors to new teams. This large community keeps growing, providing over time contributions that have over time become foundational works in the field synthetic biology. Other examples exist of remarkable success stories, with companies such as Gingko Bioworks, that started as an iGEM team, and by early 2019 had yet over 200 employees and was valued at around 1 billion dollars. Will Gargantua be the start for another such success? Let’s bet in their favour.

 

Picture credits

MIT Campus picture was downloaded from Wikipedia and licensed via an Attribution 3.0 Unported (CC BY 3.0) license.

UPF-CRG Barcelona team picture was downloaded from the team wiki at the iGEM 2018 website, and licensed via a Creative Commons Attribution (CC BY) Copyright license.

Escherichia coli picture was downloaded from Flickr and licensed via an Attribution 2.0 Generic (CC BY 2.0) license.

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