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May 30, 2008

Merck halts natural products research

Streptomyces cattleya, a microbe that produces thienamycinBad news: Merck has decided to close down its natural product research facilities. This means the end of CIBE (Centro de Investigación Básica de España) — or Spanish Center for Biological Research — located in Madrid, Spain. Since its creation in 1954, this center has been dedicated to the discovery of new compounds of therapeutical potential produced by microbes. These efforts led to the development of several useful medicines, including antibiotics (fosfomycin, cefoxitin, thienamycin), cholesterol-lowering drugs (lovastatin), and antifungal agents (caspofungin). In May 2006, Merck researchers hit the news with the discovery of platensimycin, a natural product belonging to a new class of antibiotics.

According to Chemical & Engineering News, the high costs are behind the decision to eliminate natural products research. Merck spokesman Ian R. McConnell explains to C&EN:
"The investment involved in finding these chemicals in the environment is significant. The products that came out of our effort have been significant as well, but that was over a 50-year period"
Sad, but true. Many thousands of natural samples need to be screened in order to detect a bunch of potentially useful compounds, most of which will never become a marketed drug. Turning a promising natural product into a useful medicine takes much effort and time (over 10 years) and, hence, money. So, perhaps it is understandable that most pharmaceutical companies dedicate only a very small fraction of their resources, if any, to natural product drug discovery.

However, even with that little dedication, many medicines in the market have a natural origin, being based in substances originally isolated from plants, microbes, etc. Can we imagine the possible results of investing in natural product research as many resources as those dedicated to chemical synthesis?

Natural compounds often have bizarre, complicated chemical structures and exert their biological effects through unexpected mechanisms. They are the result of an on-going combinatorial chemistry performed by organisms since the origin of life.

Are chemists that good?



Related links

A) About job cuts at Merck:
B) About CIBE:
C) About natural products in drug discovery:


Image credits:
Digital Atlas of Actinomycetes. Copyright: Society for Actinomycetes Japan. Contributor: S. Mochales. This strain produces β-lactam antibiotics, thienamycins. It has the color of cattleya orchids.
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4 comments:

  1. Manuel SánchezJune 2, 2008 at 11:50 AM

    Hi

    That's really bad news, but I wonder if Merck has close only the spanish facility or is a general policy and they are closed other facilities around the world.

    On the other hand, the research on natural sources is still on the way but with new tools as metagenomics or genome shuffling. Even the classical approach of trial and error seems to work if we see at the Pharmamar case.

    Is a pity

    Regards

    ReplyDelete
  2. Cesar SanchezJune 2, 2008 at 12:10 PM

    Merck eliminated most of its natural products research some years ago. Now they get rid of the last remains of it: approximately 50 researchers in Spain (CIBE) and a significantly smaller number in Rahway, N.J. (USA). It's the end of in-house drug discovery programs at Merck.

    ReplyDelete
  3. AnonymousJune 3, 2008 at 11:25 PM

    Hi César,

    one point that merits discussion is how the natural compound collections have been usually obtained by big pharma, and obviously it is not my intention to point at any of them in particular.

    Over ten years ago I was present at a forum in which the discussion on patentability issues lead to the question that in several instances natural compounds may have been derived from unauthorised sampling of sources in developing nations. It was discussed that future sampling had to be properly authorised, and the question was if this could be done for past ones.

    An educated guess is that it already is, or will soon be, difficult to maintain the geographical origin of many samples containing a positive lead undisclosed. If this happens it could possibly raise a number of claims from governments that big pharma will have to face, either in court or by settlement.

    This will add to other claims based on secondary effects of drugs, Merck, for example, has an ongoing one for Vioxx, an anti-inflammatory drug. An advantage of synthetic compounds, independently of their final clinical success, is that their origin may be fully documented and may then help to better control these IPR issues.

    From the industrial viewpoint, it may not be so unwise, after all, to downplay the use of natural compound collections. Once more it is not my intention to direct this comment to any case in particular. But I am afraid that drug discovery has too many facets and all of them may not be strictly scientific.

    Best

    Miguel

    ReplyDelete
  4. Cesar SanchezJune 6, 2008 at 7:47 PM

    Of course, drug discovery has many facets and many of them are not strictly scientific. The reasons to close down CIBE and eliminate 1,200 sales jobs are not scientific. I agree that patentability issues related to the origin of the samples may have contributed to the downsizing of natural product research by big pharma. Interested readers can find information at Wikipedia: Biopiracy and Convention on Biological Diversity.

    The following text is extracted from The evolving role of natural products in drug discovery:

    **********************
    The decreased emphasis in the pharmaceutical industry on the discovery of natural products during the past decade can be attributed to a number of factors:
    first, the introduction of high-throughput screening (HTS) against defined molecular targets, which prompted many companies to move from natural products extract libraries towards so-called ‘screen friendly’ synthetic chemical libraries;
    second, the development of combinatorial chemistry, which at first offered the prospect of simpler, more drug-like screening libraries of wide chemical diversity;
    third, advances in molecular biology, cellular biology and genomics, which increased the number of molecular targets and prompted shorter drug discovery timelines;
    fourth, a declining emphasis among major pharmaceutical companies on infectious disease therapy, a traditional area of strength for natural products;
    and last, possible uncertainties with regard to collection of biomaterials as a result of the 1992 Rio Convention on Biological Diversity.

    The underlying reasons for these industry trends are as much commercial as they are scientific, particularly in the case of research into infectious disease. As a result of these factors, today’s drug discovery environment calls for rapid screening, hit identification and hit-to-lead development. In this environment, traditional resource-intensive natural-product programmes that are based on extract-library screening, bioassay-guided isolation, structure elucidation and subsequent production scale-up face a distinct competitive disadvantage when compared with approaches that utilize defined synthetic chemical libraries. However, emerging trends, coupled with unrealized expectations from current R&D strategies, are prompting a renewed interest in natural products as a source of chemical diversity and lead generation.
    *******[end of cite]*******
    (Source: The evolving role of natural products in drug discovery. Frank E. Koehn & Guy T. Carter. Nature Reviews Drug Discovery (2005) 4, 206-220.

    Note that the "declining emphasis among major pharmaceutical companies on infectious disease therapy" is mainly due to economical reasons. Given the enormous cost associated to the discovery and development of a new drug, most companies focus on therapies directed to chronic diseases that are common in the "First World" (diabetes, heart diseases, etc.). A person with a chronic disease will hopefully use the medicine (and pay for it) for many years. On the other side, little benefit is foreseen in the development of new drugs for infections, if that means that a single (or relatively short) treatment may eliminate the infectious agent. If the infectious disease is only common in developing countries, just forget about it...

    ReplyDelete