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Organon s David Nicholson on Shanghai Genomics Deal; Nuclear Receptor Research

David Nicholson
Executive Vice President, Global Research
Organon International

At A Glance

Name: David Nicholson

Position: Executive vice president, global research, Organon International

Background: Head, department of pharmacology, UK research site; director of cardiovascular and CNS drug programs; and most recently, director of research, Organon

Dutch pharmaceutical firm Organon earlier this week announced a collaboration with Chinese biotech Shanghai Genomics that is aimed at progressing Organon's program for identifying more selective hormone receptor modulators. The initial two-year deal will see Shanghai Genomics contribute expertise in protein purification and cell-based interaction assays, and will in particular focus on the areas of rheumatoid arthritis, atherosclerosis, and oncology.

Earlier this week, David Nicholson, Organon's executive vice president of global research, discussed with CBA News some of the rationale behind the deal, how it plays into Organon's overall drug-discovery strategy, and the importance of cell-based assays in the types of nuclear receptor-based research programs being implemented at Organon.

How did the Shangahi Genomics deal come to fruition, and what is the cell-based component of the research agreement?

Within Organon Discovery Research, we have always had a keen interest in general in focusing our efforts on being outward-looking. So we're interested in … collaborations with academia, biotech, and other pharmaceutical companies worldwide.

Over the past couple of years, we've had a special project looking at collaborations with companies in India and in China. In China, we have collaborations with a company called HD Biosciences, and very recently we announced the deal with Shagnhai Genomics.

Within Discovery Research, we identify key issues where we need extra capacity, or key points in the total discovery process that we feel would benefit from external expertise. And we're always looking at how to improve our productivity, which we define as quality times quantity per dollar spent. We're always looking for ways to improve that, and we believe that China offers a good opportunity.

The press release mentions that Shanghai will contribute its 'expertise in protein purification and cell-based interaction assays to clarify the clinical relevance of a number of receptor interacting proteins and their use in drug discovery.' Can you talk a little more about this?

We're going to work with them on nuclear receptors, and more specifically, they are developing components for screening assays involving co-factors for nuclear receptor activation — so co-activators and co-repressors associated with nuclear receptors.

Using the term 'genomics' in its name doesn't seem to match the expertise Shanghai is contributing.

I'm not the best person to say whether the name Shanghai Genomics is a bit of a misnomer or not. Genomics remains a bit of a sexy term. But when we visited the company for the first time several months ago, it was part of a visit that several of us made to visit companies like HD Biosciences, like Shanghai Genomics, and we sat down with the senior scientists and explored what their expertise is, and to what extent there was a fit with our needs in discovery. Amongst other areas, Shanghai Genomics has the expertise to do this work for us.

What types of cell-based interaction assays do you use in researching nuclear receptors?

With a nuclear receptor, people are interested in how you can get tissue selectivity. Nuclear receptors are a very interesting area of biology, because although the receptor itself might be identical from tissue to tissue, drugs interacting with that receptor can have tissue-selective effects. The debate is how you get that tissue selectivity if the receptor is the same. The belief is that you get that selectivity because of a complicated interaction between the receptor and other proteins in the cell that act as co-activators or co-repressors, and different tissues have different complements of those co-factors. When an agonist binds to the receptor in different tissues, you get different recruitment of different co-factors. So although the agonist is the same, and the receptor is the same, the compound can be active in one tissue and not another. That necessitates a rather different assay system than a typical assay system you would use for a G-protein coupled receptor, for instance, or for an enzyme, because you need to play with the molecular biology of cells not only to incorporate this receptor, but also relevant complements of co-activators and co-repressors.

So this type of work absolutely requires cell-based assays?


This receptor-based drug-discovery program, is this an area that Organon has been focused on for a while?

Absolutely. The company Organon was founded in 1923, and we were one of the first companies in the world to work on steroid hormones — estrogen and testosterone — decades ago. So we had been working in this area before people knew anything about the receptors that steroids work through. So this is a real key area of expertise for Organon, and right in the heart of our commercial area of reproductive medicine, contraceptives, hormone therapy, and related areas.

There has been a recent increase in higher throughput and high-content cell-based assays in drug discovery. How has this been reflected at Organon?

We never bought into ultra high-throughput screening. It was never part of our research strategy. We were never convinced by going for — in-house, anyway — very large compound collections and ultra high-throughput screening. Our approach was: Yes, high-throughput screening; yes, using modern robotics to utilize an in-house compound collection that always focused on drug-like molecules, at least for our small-compound drug discovery, because we have our biological discovery, as well, where we're developing monoclonal antibodies. But within our small-molecule drug discovery, we were always focused on drug-like molecules, and part of our strategy was always nuclear receptors. If you're working with nuclear receptors, you always go for high-content screening, because of the need for rather more complex assays to evaluate tissue selectivity. We've always gone for integrated approaches where we're looking for validated targets, and we've always had rather vigorous criteria for the targets that we'll bring into our screening systems. But we're always looking for targets where we have a hypothesis linking them to disease, to pathophysiology.

So if Organon has been using this approach for some time, how has it changed recently with the development of new technologies for these types of assays? What did Organon do before that, and how is it changing?

Everything has been an evolution. Back in the late 1990s, like many companies, we started to embrace genomics. We had a deal with Incyte Genomics, where we had access to their databases, and we initiated high-throughput screening. Over time, of course, our thinking has evolved. At the moment, we focus very much on translational science, and the link between clinical and animal studies, and therefore screening is very high in our minds. We're always looking for systems and readouts in early biology that ultimately can also be used in the clinic, or clinical samples, so we can make that bridge between discovery research and early development studies. So the studies that we're doing in our cellular systems or in animal models can be repeated to some extent in the clinic, and we try to put that at the heart of our research activities.

Are there any specific improvements on the horizon that a program such as yours that is heavy on cellular assays…

Well, we do have lots of other assays, as well. The cellular assays form a key part of our approach, but it's not by any means the only approach. Animal studies, small molecules, biological discovery… But for the nuclear receptors, yes, the cellular assays are important.

OK — are there technological improvements that can be made in this area?

I don't think so right now — I think the need is to find tissue-selective compounds for a whole range of nuclear receptors, which remain a very interesting gene family, with lots of possibilities for drug discovery. And then the steroid hormone receptors are one part of the nuclear receptor family, but there is a whole other part with potential in inflammation, cardiovascular disorders, and metabolic disorders. So it remains a fascinating and somewhat under-explored area in drug discovery.

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