Monday, February 11, 2008

Peter Linsley Leaves Merck to Become Chief Scientific Officer of Regulus Therapeutics

When the Regulus CEO, during Alnylam’s quarterly conference call last week, expressed his satisfaction about their ability to attract top talent to the microRNA therapeutics start-up, Peter Linsley, who it was announced today that he would become the CSO of Regulus, must have been foremost on his mind.

Peter Linsley is the perfect CSO of Regulus in many respects. His group at Merck’s bioinformatics subsidiary Rosetta Inpharmatics was the one who seemed to abruptly end dreams of a perfectly on-target RNAi Therapeutics platform when they revealed in a 2003 paper widespread off-targeting by standard siRNAs using expression profiling (Jackson et al. 2003 “Expression profiling reveals off-target gene regulation by RNAi”). After extensive follow-up work by his group and others, we now know that much of this off-targeting is related to unmodified siRNAs being able to recognize targets based on limited base-pair complementarity in a manner essentially identical to how microRNAs recognize their targets. As such, he will bring with him to Regulus the knowledge and tools needed to predict and characterize the consequences of mimicking and inhibiting microRNAs that Regulus aims to exploit therapeutically. In addition to his bioinformatics background and experience with high-throughput technologies, he has acquired extensive knowledge on the biology of microRNAs through numerous co-authored publications.

Linsley’s know-how may also benefit the parent companies, particularly Alnylam, since his work also involved applying strategies to minimize the microRNA-like behavior of siRNAs, such as by modifying them, so that their activity would be largely limited to targets with perfect complementarity (Jackson et al. 2006 “Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing.”), therefore rendering siRNA therapeutics potentially safer. He should also bring with him expertise in identifying transcript profiles following microRNA and siRNA delivery that either indicate therapeutic promise or, even more importantly, potential harm.

Linsley’s decision to leave Merck further highlights the difficulty of Big Pharma in retaining top talent after acquiring biotech companies, particularly due to a bureaucracy that appears to be so pervasive in today’s Big Pharma and is at risk of choking innovation. Rosetta Inpharmatics and Sirna Therapeutics were part of Merck’s strategy of becoming a powerhouse in RNA therapeutics by combining leading expertise in gene regulatory networks/systems biology with oligonucleotide technologies. It now seems that much of the human capital that made these companies so attractive in the first place have left, and this, together with Alnylam’s decision last fall to terminate their RNAi Therapeutics alliance with Merck, is likely to add to the criticism that Merck overpaid for and mismanaged their acquisitions and is now at risk of losing their leadership position by insisting on going it alone.

This contrasts with Roche’s decision to let Alnylam’s former European subsidiary to operate as a semi-independent “Center of Excellence”, and is echoed by the intention of Pfizer and other Big Pharma and mature biotechs to establish similar center of innovations separate from headquarters. Of course, it is Roche’s success story with Genentech that serves as an example for these attempts.

The most remarkable aspect of today’s announcement to me, however, is the fact that Linsley personifies that by embracing complexity, what has started as a worrisome discovery 5 years ago has now turned into a therapeutic opportunity- the microRNA therapeutics opportunity.


Anonymous said...

So, who in your mind is the heir apparent at Merck/Rosetta?

Dirk Haussecker said...

I do not know. But it is apparent that a scientist like Peter is not easily replaced. There was a talk by Rosetta Inpharmatics at this year's Keystone meeting. Usually, most of the speaker invitations go out a year ahead, and that invitation was likely addressed to Peter. Somewhat disappointingly, the presentation had very little to do with the purpose of the conference. The rest I leave to your imagination.

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