23 February 2017

In start-up companies, getting it done is a matter of survival

Biology Medical Science Human Health

A pharmaceuticals manager at Roche for a long time, now he is the founder of a biotech firm on the campus of the Paul Scherrer Institute PSI: Michael Hennig knows the trends in the medical sector. In this interview he explains why the medicine of the future needs the innovation power of publicly funded research, and why he chose to locate his start-up leadXpro so close to PSI.

Present-day drugs have extremely long development times. That makes them expensive, and often they still have serious side-effects. Does it have to be this way? Or can the pharmaceutical industry change direction?

It is true, the development of truly innovative drugs requires a lot of research, many experiments. It takes a good interplay between biology and chemistry as well as innovative technologies to discover new and pharmaceutically active molecules, characterise them with precision, and then select the best new potential drug molecules for testing with patients. Today these tests — that is, clinical studies — are very comprehensive: They need to meet a large number of regulatory and legal requirements in order to meet today’s extremely high safety requirements. All that takes a lot of time, and it needs very large investments. I am convinced that the leadXpro approach will facilitate the discovery and optimisation of better, more specific drug molecules and thus reduce both development time and side-effects.

What does your new approach offer?

Our company leadXpro, founded in 2015, will realise the approach of structure-based drug design for so-called membrane proteins: We are selecting proteins that are important signaling points of the human body for the use as drug targets. Already today many drugs – psychopharmaceuticals and beta blockers, for example – work by binding to these target proteins and alter their signaling activitiy. These drugs were developed, though, without precise knowledge of the target proteins' structure. For this reason, it has not been possible to optimally exploit the principle of a key that fits perfectly into a lock. At leadXpro, our expertise in the structural analysis of membrane proteins enables us to achieve exactly that, and to focus on the identification of novel drug molecules for difficult membrane proteins.

And what diseases do you want to use it to tackle?

In the field of oncology, we have taken on the challenge of fighting cancer more effectively through activation of the immune system. Also, we want to develop new antibiotics. In the past 30 years, no single antibiotic with a completely new mode of action has reached the market. The focus has always been the optimisation or combination of known principles. We want to change that, because a lot of resistances have developed against the established antibiotics and more and more often they are no longer effective. Therefore, we are now working on antibiotic-resistant bacteria that represent an increasing problem in hospitals. Along this line, we want to use new target molecules that can be used by modern drugs.

Will these new drug molecules also be safer and cause fewer side-effects?

Given that we know the structure of the target molecule precisely and can analyse how the the target molecule and the drug molecule interact, we are able to find specific active agents that really attack only the target molecule that we have in our sights. The human body is very complicated and has many biological mechanisms that drugs can also interfere with – that's how side-effects arise. But if the key really fits into just one lock and not into others as well, this danger is reduced. This is also the reason for the success of the antibodies: They can't be taken in tablet form because they are large molecules, but they act more specifically than the small molecules that you can take orally as a pill. With the use of structure-based approaches, I am confident, small molecules can also be found and optimised that are more specific and thus cause fewer side-effects.

What other trends do you see?

The pharmaceutical industry is becoming ever more specialised. I like to compare it with the car industry: VW and BMW assemble the cars and sell them. The components are produced by suppliers, and that's where the real innovation comes in. I see a similar trend in the pharmaceutical industry. Big pharmaceutical companies focus on clinical research and marketing. The early stage of research, the drug discovery, is increasingly done in collaboration with other institutions: universities, research centers, and small biotech firms.

Why? Are the major pharmaceutical companies running out of ideas?

No. I am convinced that good research can still be done in the big pharmaceutical companies, maybe even the best research, because the whole range of technologies and expert knowledge is available. On the other hand, it is a big and complex organization and it is more challenging for really new ideas to win recognition. Consequently, it's possible to get lost in discussions before anything actually gets done. In start-up companies like ours, getting it done is a matter of survival: We simply can't afford never-ending discussions and decision processes. For pharmaceutical research in general, what is the role of cooperation between industrial and public research? Academic research is really strong in basic research. Fundamental insights are discovered and new methods developed. Pharmaceutical industry can pick up and apply these innovations. Thus, by promoting basic research, public funding can contribute to the development of drugs, which in turn will be of benefit for the society.

Why did you decide to locate your company at the Paul Scherrer Institute?

For us, co-location with the large-scale research facilities such as the Swiss Light Source SLS and the X-ray free-electron laser SwissFEL is very important. These days, structural analysis can only be done on a professional level if you have access to such facilities. In addition, it is also crucial to be close to Gebhard Schertler's PSI research division in biology and chemistry. There are nearly 50 scientists working exclusively with membrane proteins. We work together closely, and have established a series of collaborations with mutual benefit. Consequently, we make advances in new experimental methods and get new structural information more quickly and efficiently.

What advantages does a research-based firm like yours gain from being located in Switzerland?

Besides the proximity to PSI, Switzerland offers extremely good infrastructure as well as legal and other kinds of security. Another important aspect for us is the possibility to recruit the best talents internationally. Companies in Switzerland are much more international than, for example, in Germany or France. I am always impressed when I see that Switzerland is an internationally top-ranked place to live and work, attracting the best talents from all over. That's the way it was at Roche, and it is also the case here: Already now our leadXpro team consists of talents originating from four different countries. In addition, we profit greatly from the excellent education provided by the Swiss universities.

Text: Judith Rauch

Background

Membrane proteins are part of the external shell of a cell – the membrane. Membrane proteins regulate exchanges between the cell's surroundings and its interior. They transport substances or signals into the cell or deliver these to the outside. One such signal can, for example, be mediated by a particular hormone that docks from the outside on a membrane protein and thus causes the protein to initiate a certain process inside the cell. For example, if an adrenaline molecule docks on the fitting membrane protein of a heart muscle, it induces stronger activity in the cell so that, in the end, the heart beats harder. Each hormone fits exactly to one particular kind of membrane protein – the way a key fits into a lock. Many medicinal agents, too, dock on selected membrane proteins; thus these membrane proteins are the drugs' target proteins. Often these drugs work by docking on the membrane protein in place of a particular hormone and thus denying the hormone access or taking over its function. So, for example, beta blockers stick to those membrane proteins on which adrenaline otherwise would dock, thus inhibiting the action of the adrenaline. After such a drug is taken, the beating of the heart is not as strong. If the shape of the drug molecule does not fit the respective target protein precisely, though, it is possible for other proteins in the body, which have a completely different function, to dock there. The mostly unwanted changes that are triggered in this way are the side-effects of taking a drug. Therefore a very exact, specific bond with only one target molecule in the body is an essential part of the discovery and optimisation of new drugs.

About the person

Prof. Dr. Michael Hennig, 53, comes originally from Berlin. After initial studies in physics and biochemistry he did his phd as a structural biologist in the field of X-ray structural analysis of proteins, in Hamburg and at the university hospital Charité in Berlin. He worked for more than 20 years in drug discovery at Roche in Basel, finally as the head of a global team of 130 employees.
In December 2015, together with ETH professor and PSI division head Prof. Dr. Gebhard Schertler and Dr. Rafael Abela, the former scientific head of the SLS and SwissFEL projects, he founded the biotech firm leadXpro AG co-located with PSI. Hennig and his colleagues work on new, custom-tailored active pharmaceutical agents for drugs aiming to significantly improve the treatment of diseases such as cancer and infections.
Additional information
Website of leadXpro