Wednesday, October 30, 2013

Don’t Mess With Basic Science!

In this week’s NATURE Daniel Sarewitz, a well-known science policy guru, states that the rightful place of science is in service to society. While it is hard to argue against the idea that one of the main goals of research should be to benefit health care, the economy, or other aspects of societal well being, there is an unsettling underlying theme to Sarewitz’s commentary.  In this article he outlines several attempts by the federal government to more effectively harness basic research to national goals. This includes the NIH’s National Center for Advancing Translational Sciences, the DOE’s-Advanced Research Projects Agency-Energy and a new National Additive Manufacturing Institute. Sarewitz contrasts these goal-oriented efforts to what he feels has been the bloated and wasteful state of basic research, especially basic biomedical research, in this country. This theme of devaluing undirected basic research has been prominent in Sarewitz’s previous writings over the last few years.

While the NATURE commentary makes many valid points, it is fundamentally flawed because it ignores one of the key aspects of science, the unpredictable ‘Black Swan’ nature of basic research. Certainly there is merit in coupling many aspects of science to societal goals and priorities. Much research is rather mundane and consists of filling in gaps in the knowledge base. Nonetheless now and then truly unique and unexpected insights emerge that change the entire scientific paradigm.  One might point to the discovery of RNA interference by biologists or of exoplanets by astronomers as contemporary examples. If much of the nation’s basic research effort is put in harness to short to medium term technological goals, will such fundamental breakthroughs continue to emerge? While much of our investment in R&D should be directed toward pragmatic goals, it will still be essential to maintain a substantial core of unfettered, undirected basic research. 

Monday, October 14, 2013

Don't Keep Clinical Trial Adverse Events Data Secret!

Drug company attempts to repress open dissemination of Clinical Study Reports by the European Medicines Agency are quite shortsighted. In addition to the obvious public benefit of providing comprehensive safety data to academic researchers, the transparent approach would be of value to the drug companies themselves. One of the major factors in the high cost of new drugs is the expense involved in failed late-stage clinical trials.  In many cases several companies will conduct trials on similar medications with each trial being veiled by corporate secrecy. In contrast, prompt dissemination of full CSRs could prevent late entrants into a therapeutic field from making the same mistakes in trial design as earlier entrants. While this might be perceived as rather negative for the pioneer in any particular case, over time the advantages would average out to the benefit of the entire industry. Surely steps can be taken to protect key intellectual property involved in clinical trials while still disseminating important information on adverse events. The EMA is very forward looking on this issue; one would hope that the FDA would follow, but don’t count on it!

Thursday, October 3, 2013

Scientist? Public Servant? You Lose!

Scientists are public servants. Whether employed by a public institution or a private one, most likely much of a scientist’s research support comes form public funds, and the essence of a scientist’s job is to contribute new knowledge to the public domain. To effectively carry out his/her mission a scientist needs to make a sustained effort over a long period of time. Now comes the sequester, and then the shutdown! Much of the infrastructure for doing science in this country is now in disarray and many careers are at risk.

What kind of a message does this send to young scientists or indeed to any young person who aspires to a career in public service? The message clearly is that you are a pawn that can be manipulated by powerful interests and that your contributions are not valued. In our current bizarre political and economic system the only thing that counts is money!

A breakthrough for siRNA based therapy?

A report in The Lancet this week describes an important milestone in the evolution of siRNA oligonucleotides as therapeutic agents (1). PCSK9 is a protein that binds to and causes degradation of the Low Density Lipoprotein-Receptor that is involved in cholesterol regulation. Patients with mutations in PSCK9 have increased LDL-R and very low levels of blood cholesterol thus validating the importance of this protein. Researchers at Alnylam Pharmaceuticals have developed a siRNA that triggers destruction of the messenger RNA for PCSK9 and have tested it in a small clinical trial. The siRNA was delivered to liver cells (where PCSK9 is made) using a lipid-based nanoparticle. The study showed a substantial reduction in PCSK9 levels and corresponding decreases in serum cholesterol. Effects were seen with doses of siRNA in the 0.15 mg/kg range, quite a low dose for this type of molecule.

The eventual intended use of the PCSK9 siRNA would be in patients refractory to statins, the drugs commonly used to reduce cholesterol. Apparently there are quite a few such patients since by some estimates there is a $4B yearly market in this area. The siRNA drug will have competition from anti-PCSK9 monoclonal antibodies that are undergoing clinical testing by other companies.

Single stranded antisense oligonucleotides can also trigger destruction of messenger RNA, although by a different mechanism than siRNA. There are competing views on whether antisense or siRNA offers the superior approach for new drug development. An antisense oligonucleotide was recently approved by the FDA (2). Interestingly, this agent is also designed to regulate cholesterol in statin-refractory patients but works by reducing expression of a key component of LDL itself.

In both of these cases, the target of the oligonucleotide drug was in the liver. This highlights a key problem in the development of antisense or siRNA as therapeutic agents. It is very difficult to deliver adequate amounts of these types of molecules to any tissue other than the liver.  While there are certainly many liver-associated diseases that might be approached with this technology, it would be a great step forward if efficient delivery to other tissues could be attained.