Strong signals and high expectations

• Chemistry Nobel Laureate Brian Kobilka on the future of drug development
• 63rd Lindau Nobel Laureate Meeting: 30 June–5 July 2013 
• 35 laureates and more than 600 young scientists from almost 80 countries

Ch. Flemming/Lindau Nobel Laureate Meetings;
The Lindau Nobel Laureate Meetings foster the inter-generational
 dialogue among excellent scientists.
Physicist Brian Schmidt (left) was among the participants in 2012

A clear indication for more effective and better-tolerated drugs is what many are hoping for. Since the mid-1980s, expectations surrounding the decoding of the genetic blueprint of G protein- coupled receptors (GPCRs) have been high, given that half of all medicinal drugs deploy their effect through these molecular antennae. GPCRs are specially embedded in the surface of cells in our body, passing through the cell membrane seven times and activating proteins, known as G proteins, on the inside of the cell membrane. It is these that transmit the signals from most hormones and neurotransmitters. Without GPCRs we would not be able to see, taste or smell. American physicians Brian Kobilka and Robert Lefkowitz were honoured with the 2012 Nobel Prize in Chemistry for the discovery and structural elucidation of GPCRs. However, the number of innovative drugs that work on the basis of GPCRs and have been approved for use to date is fewer than had been expected. Brian Kobilka’s speech, which will open the scientific programme of the 63rd Lindau Nobel Laureate Meeting in the first week of July, will illustrate the challenges and difficulties facing drug discovery today. The significance of the relatively new knowledge about spatial structure and three-dimensional functionality of GPCRs for the future of drug development holds great interest not only for the 600 young scientists and researchers at this meeting.

As a medical student, Brian Kobilka worked in a hospital’s intensive care unit, where one of the things he learned was how the hormone adrenaline can save a person’s life by increasing their heart rate. Just a few years before, Robert Lefkowitz was the first to demonstrate the presence of adrenaline receptors, whose existence had been disputed up to then. The topic caught Kobilka’s imagination and he resolved to study these receptors in more detail. As a post-doc in Lefkowitz’s lab, Kobilka helped to decode the genetic blueprint of the beta2 adrenaline receptor. But only tiny amounts of the receptor could be isolated, making it impossible to reconstruct any more than individual fragments of the complete blueprint. Nevertheless, he did manage to use these fragments as probes in a genetic library and decode the complete structure of the beta2 adrenaline receptor gene by employing an immensely creative and incredibly tedious method.

The results of his analyses, published in 1986, were intriguing: the adrenaline receptor actually resembled rhodopsin, the retina’s light receptor which is folded seven times. The two receptors were evidently related despite having completely different functions -- both being members of the GPCR family, which as we now know incorporates almost 800 distinct receptors in humans.

From then on, Brian Kobilka was obsessed with GPCRs. Filled with ‘‘irrational optimism’’, as he puts it, he set his mind to elucidating the form and functionality of the adrenaline receptor with the help of X-ray crystallography. He had few competitors in the early days; most scientists considered it a futile endeavour. It took 18 years for Kobilka to grow tiny crystals of the receptor, finally accomplishing that in 2004. Still, the crystals yielded no useful structural data. Another three years passed before Kobilka was able to decode the adrenaline receptor’s atomic structure in 2007. In 2011 he he successfully visualised the structure of a receptor in action -- a masterful performance.

The knowledge of this spatial structure and functionality finally gave pharmaceutical research scientists direct access to the atomic structure of GPCRs. Most medicinal drugs that work through GPCRs were already known before the receptor family itself had been discovered. Once their genetic code had been revealed, the intensive search for new drugs could begin with the help of high-throughput screening -- something which has been on-going for the last two decades. In further stages of the development chain, many of the discovered substances have neither proved to be effective enough nor to be sufficiently well-tolerated. A perfectly accurate, differentiated structure of active ingredients could change all that -- something which the elucidation of GPCR structures has brought within reach. At the 63rd Lindau Nobel Laureate Meeting, Brian Kobilka will be discussing with young scientists how this could be extremely promising for future drug discovery and development.

Since 1951, the annual Lindau Nobel Laureate Meetings have offered scientists an internationally acclaimed forum for exchange and networking. The intergenerational dialogue between Nobel Laureates and young scientists provides significant impetus and new ideas for universal collaboration in science and research.

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