Life under the microscope.

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Science. Although the basic research of the European Molecular Biology Laboratory (EMBL) in Heidelberg has a major influence on modern medicine, it is relatively little known to the public. What hardly anyone knows: Private sponsors and sponsors can make an important contribution to the success of the institute. And investors even have the opportunity to participate in individual, lucrative spin-offs.

Photo above: Martin Hogbom_Royal Swedish Academy of Sciences

The publications from the European Molecular Biology Laboratory (EMBL) have little exciting headlines. It's about "The vitrification of pure water for electron microscopy". Or "mutations that affect the number of segments and polarity". But what only elicits a shrug of the shoulders from laymen electrifies the professional world. This is because it conceals discoveries that were awarded Nobel Prizes a few years later.

Publication number one laid the foundation for cryo electron microscopy. It enables researchers to take snapshots of biomolecules in action. This will help you to understand how they work much better. Using the fruit fly as an example, number two explained for the first time the mechanisms involved in embryonic development, i.e. the formation of a finished organism from an egg.

The respective authors, Jacques Dubochet, Eric Wieschaus and Christiane Nüsslein-Volhard, gained their insights as heads of working groups at EMBL. "These are only the best known works," says Astrid von Soosten, Head of Resource Development at EMBL. "In 2016 alone, the EMBL produced almost 700 scientific publications. Three EMBL publications are included in the list of the one hundred most cited and thus most influential publications of all time worldwide".

The EMBL was founded in 1974 by nine EU countries and Israel as an international organisation to provide a home for talented researchers in the then brand-new field of molecular biology. Until then, many scientists had moved to the USA.

The EMBL is now one of the most renowned molecular biology research laboratories in the world and is supported by 24 European countries as well as Australia and Argentina. Over 1600 people work there. There are more than 85 interdisciplinary working groups for cell biology and biophysics, developmental biology, genomics, structural biology and bioinformatics. Central facilities for DNA sequencing, microscopy, monoclonal antibodies or protein purification. The EMBL's expertise is so sought after by researchers that the Institute has created service centres for scientists so that as many as possible can benefit from it.

In addition, branch offices are operated in Barcelona, Grenoble, Hamburg, Cambridge and Rome. The EMBL is primarily financed by public research funds from the member states. "But we also increasingly want to give donors the opportunity to support our work," explains von Soosten.

Anyone who wants to get involved has a wide range of possibilities. On the one hand there are the Friends of EMBL. For an annual membership of 1000 Euro or more, the philanthropist receives a regular newsletter with deeper insights into the world of science and the EMBL. At the same time, it is an admission ticket to public and private events that often lead to personal relationships with EMBL scientists and their research projects. Companies can become Business Friends of EMBL from an annual donation of 5000 Euro and then also participate in the exclusive EMBL events.

"Another very interesting funding option is the support of groundbreaking research projects," explains von Soosten. "Philanthropists can choose from a wide range of opportunities at home and abroad."

One of these very special projects is the Ocean Diversity Program. It is based on samples from the Tara Oceans Expedition, a modern version of Charles Darwin's legendary research cruise on the HMS "Beagle". The young Darwin began his journey to evolution in 1831. Almost 180 years later, on a 300,000 kilometre journey through the world's oceans, researchers systematically collected water samples, which were then sent to the EMBL-EBI in Cambridge together with the plankton they contained - including bacteria and viruses - for sequencing and analysis of the genome.

Millions of hitherto unknown genes have been discovered - findings that are just as important for understanding the food chain in the ocean as they are for climate research. Plankton absorbs more than 50 percent of carbon dioxide from the atmosphere - more than all rainforests combined.

"The sequencing of the tare data gives us an insight into the diversity of life in the oceans," explains Rob Finn, team leader at EMBL-EBI. "The first set of 40 million genes that we identified in the Tara data comes mainly from bacteria that were previously completely unknown to us. In the second data source we have so far identified more than 117 million genes of higher organisms. And we're far from finished. There's a huge amount of genetic data out there that we need to study. What do these genes do, to which species do they belong? How does this fit into the larger picture? We will deal with these fascinating questions for years to come."

Other data projects am EMBL-EBI deal with the three-dimensional representation of biomolecules. They create an atlas that provides information on when and under what conditions genes are read in different organisms, or provide data on the binding properties, function and degradation of biomolecules.

EMBL is currently building another building at its Heidelberg site. The Imaging Centre will bring together state-of-the-art equipment, technology experts and data analysis under one roof and will be available to EMBL researchers, industry and up to 300 visiting researchers annually.

Thermo Fisher Scientific, Leica and Zeiss Microscopy are supporting the construction of the centre in addition to the German government and the state of Baden-Württemberg. HeidelbergCement donates building materials. The non-profit Boehringer Ingelheim Foundation is providing five million euros for the training and work of scientists on microscopes. Private donors and donors can also participate in construction and maintenance measures or in the purchase of large-scale equipment.

The aim is to provide scientists from all over the world with the ultra-high resolution light and electron microscopy methods from the EMBL. "So far, access to these technologies has been limited to a few researchers. Firstly, the devices are very expensive and secondly, they are so complex that special knowledge must first be imparted in order to operate them and evaluate the huge amounts of data. The majority of researchers are therefore excluded from the technical revolution in imaging, so that important questions cannot be answered or even asked."

EMBL is also strongly involved in cancer research. For example, the research group "From genome variation to molecular mechanisms" led by Jan Korbel is involved in the international project "Pan-Cancer Analysis of Whole Genomes" (PCAWG), which aims to analyse and compare the genome of more than 2800 different tumours.

The result will help to better understand what makes cancer cells so aggressive and how they manage to undermine the body's immune defence. This could lead to new treatment options.

Another project of the Korbel Group is the analysis of the genetic material of prostate cancer. The main objective is to develop a procedure that supports patients in their decision for or against a prostatectomy. Statistically speaking, the removal of the prostate, which can be associated with considerable side effects, is not necessary in up to 75 percent of cases. Aber currently there is no way to find out when and with whom this is the case. Korbel and his team are working on a method that reliably predicts the development of prostate carcinomas based on conspicuous changes in the DNA of the affected tissue.

The researcher wants to compare genome sequence data of tumors with known progression with those of healthy prostate tissue in order to develop a type of identifier based on the deviations, on the basis of which a recommendation for or against a prostatectomy can be made.

If the sequencing of the cancer tissue does not show any signs of a rapid deterioration of the condition, the patient can initially dispense with surgery. He is then regularly monitored and in most cases, according to the researcher, also has a long and fulfilled life ahead of him with his tumour. Donors can also specifically support this project.

"But this is only a small selection of our work," explains von Soosten. "A total of 85 research groups are currently working on a large number of projects. The EMBL thus offers scientifically interested people numerous opportunities to participate in basic research or specific projects."

But EMBL is not only an interesting address for philanthropists. Investments with a clear intention to generate a return are also possible. Investors can, for example, participate in company start-ups to commercialise research results from the EMBL. "Our findings from publicly funded basic research should be used economically and thus benefit the general public," von Soosten makes clear. EMBL Enterprise Management Technology Transfer GmbH (EMBLEM), founded in 1999, is in charge of this project.

In principle, this works via two models: Either the new technology is transferred to existing companies under licence or the researchers set up their own company. The latter has been achieved in more than 19 cases to date.

These spin-offs include such successful companies as Cellzome and Luxendo. Cellzome, which analyzes the mechanisms of action of drugs, was spun off from EMBL in 2000 and was quickly able to enter into lucrative alliances with leading pharmaceutical companies such as Bayer, GlaxoSmithKline (GSK), Johnson & Johnson and Novartis. In 2012 the company was taken over by GSK for 61 million pounds. Luxendo, a specialist for multiple light sheet microscopy, which enables sensitive living objects to be displayed three-dimensionally, was founded in 2015 and sold to the US Bruker Group for an unknown sum after only 18 months. Early participation would have paid off for both companies.

In order to provide company founders with capital from private investors not only on a case-by-case basis but also systematically, the European Technology Fund was launched in 2001 on the initiative of EMBL and EMBL Ventures GmbH was founded. It now manages 120 million euros in three funds on behalf of European institutional and private investors. EMBL Ventures invests a maximum of ten million euros in a company.

Portfolio companies include innovative biotechnology companies such as immatics from Tübingen, Luxendo and Opsona Therapeutics. EMBL Ventures also invests in non-EMBL companies, but uses EMBL's expertise to evaluate and manage portfolio companies. The three funds are now closed, but a new one is to be launched in the near future. Participation is possible from an amount of five million euros.

Anything is possible in the European Molecular Biology Laboratory. Donors, benefactors, entrepreneurs and investors will find exciting projects and interesting investments there. And one or the other will be able to say in the future:

"I've helped win the Nobel Prize."

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What can cryo electron microscopy do?

For a long time, only the structure and structure of the large molecules of life - DNA, RNA and above all proteins - were known. To make them visible, electron microscopy was used, but the molecules had to be prepared, dried and coated with heavy metal salts. So they were known only in solidified, crystalline form, but not as they buzz around inside cells, bend and interact with other molecules. It was like having statues of many ballet dancers, but no idea how they work together as an ensemble.

This changed when researchers began experimenting with liquids, such as sugar solutions, to stabilize the molecules. The breakthrough came when EMBL discovered that the solutions could be shock frozen. The molecules froze in the middle of the movement, and the process took place so quickly that no ice crystals could form that would destroy the sensitive molecules. The solution solidified into a glass-like solid which enables the image of the enclosed molecule. In 1984, Jacques Dubochet and his colleagues used this method to map viruses in solution for the first time. After further improvements, the method became routine and today makes it possible to understand the exact motion sequences inside cells and watch how molecules interact with each other - for the first time, the ballet of molecules becomes visible.

Medicine has profited from this to this day. A recent example comes from research on HIV, the trigger of AIDS. Using cryo-electron microscopy, EMBL researchers were able for the first time to visualise the exact atomic structure of the viral structures involved in maturation and their interaction with a drug called Bevirimat. From this they were able to deduce how the last maturation step takes place, how Bevirimat influences it and how genetic mutations alter the structure and thus lead to resistances.

De facto the virus can be kept in check by Bevirimat. It blocks the final ripening step in the formation of new viruses, interrupting the infection chain. Unfortunately, HI viruses also develop resistance to them over time. Cryoelectron microscopy again plays an important role in the development of means that undermine these resistances.

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Author: Dr. Ludger Wess

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