the paranoid position…

Posted on Monday 17 October 2011


Transforming Drug Development
Focus: Harvard Medical School
by R. Alan Leo
October 17, 2011

Harvard Medical School launches major initiative to address crisis in drug development

Taking aim at the alarming slowdown in the development of new and lifesaving drugs, Harvard Medical School is launching an Initiative in Systems Pharmacology, a comprehensive strategy to transform drug discovery by convening biologists, chemists, pharmacologists, physicists, computer scientists and clinicians to explore together how drugs work in complex systems. “With this Initiative in Systems Pharmacology, Harvard Medical School is reframing classical pharmacology and marshaling its unparalleled intellectual resources to take a novel approach to an urgent problem,” said Jeffrey S. Flier, dean of the Faculty of Medicine at Harvard University, “one that has never been tried either in industry or academia.”

Modern drug discovery has focused on the interaction between a candidate drug and its immediate cellular target. That target is part of a vast and complex biological network, but because studying the drug in the context of a living system is profoundly difficult, scientists have largely avoided this approach. As a result, predicting the effects of a particular candidate drug in humans is currently all but impossible, and many initially promising drugs have been found to lack efficacy or to have unsupportable levels of toxicity — typically at a late stage of a clinical trial, at a cost of years of effort and up to $1 billion.

“Right now in the world of drug discovery, it’s as if we have a map of a highway system that only contains small pieces extending a few miles here and there, without any connectivity on a large scale,” said Marc Kirschner, the John Franklin Enders University Professor of Systems Biology and chairman of the HMS Department of Systems Biology. “If you try to plan a trip on such fragmentary information, you’ll fail. It’s our inability to develop a coherent picture that has stymied drug discovery for so long.” As drug makers exhaust the most promising candidate areas, the number of new drugs brought to patients has actually decreased in recent years, even as the cost of discovery has soared.…

The science of analyzing specific biological processes within the context of an entire living system, called systems biology, is relatively new. Harvard Medical School is a world-leader in this area, having established one of the first department-level programs in 2003. Building on this success, Harvard’s new effort will apply systems biology’s innovative approaches to the understanding and prediction of drug activity, drawing on the vast range of biomedical expertise available at the medical school and its affiliated teaching hospitals and research institutes.

Led by Kirschner and systems biology professors Peter Sorger and Tim Mitchison, the Initiative in Systems Pharmacology will include faculty from a broad array of disciplines: systems biology, cell biology, genetics, immunology, neurobiology, pharmacology, medicine, physics, computer science and mathematics. The initiative will be fueled by a strong and diverse group of existing faculty and new recruits who will be based in several departments, and will be supported by an ambitious fundraising effort.  New approaches could include use of chemical biology to develop probes of biological pathways and failure analysis on unsuccessful drugs, similar to how the aviation industry scrupulously analyzes accidents to learn what went wrong. Such a practice is not common in today’s pharmaceutical industry…

The Initiative in Systems Pharmacology is a signature component of an HMS Program in Translational Science and Therapeutics. There are two broad goals: first, to increase significantly our knowledge of human disease mechanisms, the nature of heterogeneity of disease expression in different individuals, and how therapeutics act in the human system; and second — based on this knowledge — to provide more effective translation of ideas to our patients, by improving the quality of drug candidates as they enter the clinical testing and regulatory approval process, aiming to increase the number of efficacious diagnostics and therapies reaching patients…
The world seems divided into two camps on the issue of the slowdown in new drug development. Some see it as a national emergency requiring something like the Manhattan Project or DARPA – an initiative to keep the drugs coming our way like the "spice trade" in Herbert’s sci-fi classic, Dune. Others see the hiatus as a godsend – a break to catch our breath and put safeguards back in place for patient safety and the ethical medicine – a time to get the pharmaceutical industry out of academic research departments. So my first reaction to this article was a mild cringe, a near shudder, something like that. "Uh Oh. Here we go again."

But reading it over again, I noticed an absence. It didn’t say "partnering with industry…" anywhere, and I began to change my mind a bit. It didn’t say they weren’t going to do that, but at least it didn’t say they were. The open door was there, however, in the phrase "and will be supported by an ambitious fundraising effort." I’m surprised at how suspicious I’ve become over the months of reading about clinical trials, key opinion leaders, ghostwriting, just plain fraud. My immediate reaction to this announcement was to start looking for the angle – another TMAP? another Childhood Bipolar craze? more stealth? which PHARMA is funding it? etc.

One of the early psychoanalytic theoreticians, Melanie Klein, proposed that part of development was passing through a developmental stage she called the paranoid position. Well, I’m back there when it comes to pharmaceuticals, at least in psychiatry. Guilty until proven innocent. The ball’s in their court. etc. If Harvard is actually proposing that bonefide academic science is going to take on drug development and Harvard is willing  to play it straight, it’s the right thing [he said, filled with a fear and trembling and the sickness unto death that it is just another conduit for corruption]. …
aek 
  1.  
    aek
    October 17, 2011 | 11:24 PM
     

    I’ll have to dig around the Harvard sites, but almost all, if not all, of the faculties listed are involved in directly related profits. One has to walk around to understand that Merck’s research campus is integrated with the HMS R&D campus, and that the Longwood Medical Area is an integral geographic part of the same campus – Harvard Medical, Dental, Public Health schools along with Dana Farber Cancer Institute, Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, Children’s Hospital, the VA Medical Center and New England Baptist (Ortho, neuro and neurosurg). MIT, the Broad Institute and many joint Harvard/MIT initiatives usually affiliate with Massachusetts General Hospital and the Cambridge-based pharmas (Novartis, Genzyme, Merck, and a lot of small independents doing niche work and flying under the radar) that are integrated within the MIT campus and butt up against Harvard’s main and Allston campuses. Many faculty not only have joint appointments, but they may have Harvard, MIT, HMS, pharma and clinical appointments simultaneously.

    Tufts and Boston University also have medical schools in the city, but they do not have these tentacle like holds to industry.

    Finding these relationships is harder than hades because the institutes and entities that are formed have independent web sites or web sites that fall under Harvard’s umbrella but which aren’t listed in the public directory. If you stumble on one, you can get in, but if you don’t know it exists, you’ll probably not find it.

  2.  
    October 17, 2011 | 11:29 PM
     

    Like I said, fear and trembling

  3.  
    Bernard Carroll
    October 17, 2011 | 11:52 PM
     

    Dr. Flier’s announcement is remarkable for what we might call poverty of content of speech. More charitably, we might call it a promissory note without substance. This is not the first time the systems approach has seduced the planners: I recall a time when General Systems Theory reigned. At U. Michigan in Ann Arbor Ralph Gerard and others created the Mental Health Research Institute (MHRI). They designed it on the principles of General Systems Theory. The top floor housed sociologists and political scientists (the level of society). The ground floor housed experimental psychologists (the level of the person). The basement floor housed basic behavioral science and biochemistry laboratories (the level of the cell). The general idea was that flashes of insight were meant to pass among these levels, leading to incisive advances. The reality was rather different. Look for the same fate to befall Systems Pharmacology.

    Maybe the best one can hope for is that the speechifiers will bring in resources and then get out of the way while some bright young persons do their things and contribute some incisive advances.

    As for any kind of firewall against industry, forget about it – this is Harvard after all, where Thomas Stossel is a full professor.

  4.  
    October 17, 2011 | 11:58 PM
     

    and the sickness unto death

  5.  
    aek
    October 18, 2011 | 2:00 AM
     

    From this evening’s Globe’s business section:
    http://www.boston.com/business/healthcare/articles/2011/10/17/harvard_medical_initiative_to_analyze_how_drugs_work_in_the_body/?page=1

    “The approach is part of a larger rethinking of how new tools can be used to understand drugs. Two workshops have been held at the National Institutes of Health to bring together people from academia, industry, and government to discuss the emerging field.”

    ~snip~

    “Novartis is interested in understanding whole networks of interactions, he said, with the goal of determining what parts of the circuit are most essential. He compared it to the financial market, where some banks can fail without a significant impact, while others may bring down the whole system.

    Novartis is also collaborating with researchers at Harvard, including Galit Lahav, an associate professor of systems biology. Lahav is trying to understand why chemotherapy drugs are so fickle – sometimes working well to kill cancer cells, and sometimes not.”
    ~snip~
    “Dr. William Chin, executive dean for research at Harvard Medical School, said the systems pharmacology initiative would be the first pillar in a plan to translate basic research into findings that could benefit patients.

    “This is not just a problem for Harvard Medical School; this is not just a problem for pharmaceutical companies. In many ways,’’ Chin said, “the lack of new drugs is a problem for society.’”

    And so it goes…

  6.  
    October 18, 2011 | 11:07 AM
     

    Worse than even I imagined. So much for the morbid anxieties of Melanie Klein and Søren Kierkegaard, it’s just reality after all…

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