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Samples - Fascinated by protein architecture (for newsletter Chemical Sciences)

For dr. Anastassis Perrakis at the Netherlands Cancer Institute (NKI), 2008 is a memorable year. A large NWO subsidy will allow NKI to greatly extend its “Protein Facility” by purchasing state-of-the-art equipment. Studying the structure and function of proteins will become much more efficient. “It is a very exciting field with lots of open questions, and an interesting potential for applications.”

Nienke Beintema

Anastassis (Tassos) Perrakis, Greek by origin, is feeling at home in the labs of the Netherlands Cancer Institute (NKI) in Amsterdam. “This is where we have most of our biophysics instruments,” he says as he points at an impressive collection of machines, “and over there we have our crystallography equipment.” These are only some of the machines that he and his colleagues use to study proteins. When it comes to the function of proteins, as Perrakis points out, it is the way they are folded in space – their three-dimensional structure – that determines what they do and how, often in ‘teams’ with other proteins.

Back at his office, Perrakis – an energetic but easy-going scientist in his late thirties – leans back in his chair to explain why proteins are important for cancer research. “Cancer is in fact a disturbance in cell growth,” he says. “It can be caused for instance by genetic mutations or by mistakes in DNA replication. When genes are translated into proteins, these ‘genetic mistakes’ are reflected at the level of the protein structure. This in turn affects the protein’s function.” This knowledge is of crucial importance in the development of cancer drugs. If a drug is to work optimally, for instance by blocking the activity of a certain protein, it should be adapted to the structure of that protein. “Here at NKI we have several research teams working together on this: chemical biologists, molecular biologists, biochemists, medical specialists,” says Perrakis. “Knowing the structure of a protein is a crucial piece in assembling the puzzle that will lead to new drugs. However our focus is not just drug design – we also want to gain a fundamental understanding of the relationship between cancer and protein functioning.” 

‘Protein thinking’

When Perrakis studied biology in his home country Greece, he soon become most interested in the molecular side of this science. “To me biology was awfully general and descriptive,” he says. “It lacked a sense of direction. Molecules are much more straightforward.” After obtaining a PhD from the European Molecular Biology Laboratory (EMBL) in Hamburg, Perrakis was given the opportunity to work as a postdoc at NKI for two years. After a three-year intermezzo, back at the EMBL but in Grenoblethis time, the international traveller returned to NKI to start his own research group. “I like NKI,” he says. “It is very international, there are great research groups, and it is an intellectually challenging environment.” Although he hesitates when asked about his long-term plans, he can picture himself working here for at least another five years or so. “Amsterdam is great too,” he adds. “It is small and big at the same time. It has a strong neighbourhood feeling while there are lots of things going on. And, quite importantly: it is close to the main research locations in Europe.”

In May 2008, Perrakis’ group and NKI colleagues were awarded a so-called NWO-Groot subsidy: funding dedicated specifically to purchasing expensive equipment needed for top-class research. The NWO subsidy of 1.4 million euros will be matched by NKI and supplemented with personal grants to a staggering amount of close to 3.5 million euros. This will allow the research group to assemble a combined facility for protein identification, purification, characterisation and crystallisation. “The facility will combine new equipment with equipment that we already have, which will be updated and improved,” says Perrakis. “The result will be a state-of-the-art facility that covers the full repertoire of equipment needed to connect genomics and protein science. It will allow us to go from gene to function in a way that is as fast and efficient as possible, in one place and in a coordinated way. Hopefully this will help pave the way for a new culture of ‘protein thinking’.”

Perrakis also outlines another focus of his group: developing methods for determining protein structures. He and his colleagues develop computer software that helps them to ‘fold’ proteins in space using the data from their experiments. This is important for the design of any drug – not just against cancer – and also in biotechnology. “It is an exciting process,” he indicates. “There are some things that you know how to do. However, you want to improve the throughput and accuracy by getting a computer to perform these tasks. If these tasks are complicated, though, you first need to analyse the steps in your own thinking process. That is a lot of fun, although it isn’t very easy.”

At NKI Perrakis devotes most of his time to studying fundamental principles. Does he find most satisfaction in answering scientific questions, or is he driven by the prospect of useful applications? “Both,” he smiles. “I am driven by curiosity. I want to know how things work and why, even if the application is not immediately clear. That’s why I can’t picture myself working at a large commercial company. But at the same time I wouldn’t be happy without the knowledge that all of our research is directed towards applications that can be clinically relevant. In that respect NKI is the perfect working environment for me.”

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