Cross-fertilization of medical disciplines: An unfortunate victim of patent-madness and superspecialization

I write this while traveling on Amtrak, bouncing along from Minneapolis to Chicago on my way to attend the annual joint meetings of the Association of American Professors — the “old turks” — and American Society of Clinical Investigation — the “young turks.” The segue to this editorial is obvious, at least to me.

When I was a hematology fellow, and later, a young faculty member, the “turk” meetings were held in Atlantic City, N.J., where 2,000 or so clinical investigators attended plenary, as well as specialty, sessions while trading ideas and laboratory techniques with colleagues strolling the ocean boardwalk. The plenary sessions were especially ecumenical and presented superb science that encompassed all clinical disciplines. A listener could not help but consider the possible relevance of the presentations to his/her own subspecialty. Alas, the current meetings in Chicago attract only a few hundred — a withering that contrasts with (and results from) the massive increase in attendance at subspecialty meetings (our ASH and ASCO annual meetings host more than 20,000 attendees). Cross fertilization of ideas and insights between folk with disparate backgrounds and interests hardly occurs in these huge venues.

A recent personal experience exemplifies how this intellectual narrowing can inhibit therapeutic breakthroughs.

As a legacy from those long-gone Atlantic City experiences, I still enjoy reading about new pathophysiologic discoveries in non-hem/onc journals. This interest particularly quickens if a patient of mine develops disorders outside my subspecialty.

Harry S. Jacob

Five years ago, one such breast cancer patient was losing her eyesight because of age-related macular degeneration. This disorder, which is frequently familial, is the most common cause of blindness in white populations. At that time, three separate papers were published in the same issue of Science that provoked my interest. All three groups discovered that a gene producing an inhibitor of the complement cascade, Factor H, was mutant in most patients with age-related macular degeneration and many of their first-degree relatives. Heterozygotes had a threefold risk for developing the disease; homozygotes a sevenfold risk; and patients who also coinherited another mutated, proinflammatory gene had a 50-fold likelihood of suffering the disorder.

Sharing information

Recognizing that hematologists were successfully treating paroxysmal nocturnal hemoglobinuria patients by inhibiting terminal complement activation with the anti-C5 monoclonal antibody, eculizumab (Solaris, Alexion), I wrote one of the ophthalmologist authors of the papers.

It struck me that direct periretinal injection of minimal, and thus inexpensive, doses of eculizumab might benefit age-related macular degeneration patients. This cross-fertilization may or may not have taken, as I received no response. So much for collegiality in this patent-frenzied age.

In that regard, a paper published two months ago noted that new patent applications for direct injectables in age-related macular degeneration are burgeoning and exceed even those proposed for diabetic retinopathy. Evidently, most patents are for anti-VEGF agents, although I would not be surprised if eculizumab or a congener are not in the patent application pile.

In that regard, I’m happy to provide another (charge-free) fertilizer: that is, recent studies from the University of Virginia demonstrate that a newer monoclonal may be even more complement-inhibitory by blocking C3 and, thus, the alternative pathway, as well as terminal, cascade activation. I hope such altruistic cross-fertilization bears therapeutic fruit in time for my breast cancer patient to maintain reasonable vision.

Note that ophthalmologists have been injecting off-label bevacizumab (Avastin, Genentech) into the periretinal space in age-related macular degeneration patients for some time. Blocking neovascularization might not be as rational as blocking complement-mediated inflammation, which likely underlies such neovascularization. But what would a hematologist know about the back of the eye?

There are a couple more recent examples where hematologist/oncologists might buzz our colleagues in other fields with insights that would have been more easily shared on the Atlantic City boardwalk a half century ago.

For instance, Scotten and his British, German and American pulmonologist co-workers have recently demonstrated that “our” clotting factor, Factor Xa, is a major incitor of fibrosis in the lungs of patients with primary pulmonary fibrosis. It acts not by its procoagulant effects, but by its ability to activate TGF beta, which, in turn, converts fibroblasts into fibrosis-accentuating myofibroblasts.

These data render understandable the previously curious association of hereditary hemorragic telangectasia with idiopathic pulmonary fibrosis. Moreover, we can provide our pulmonologist friends with advice as to selection and dosing of oral Factor Xa inhibitors for their pulmonary fibrosing patients.

Additionally, we should alert surgeons to these studies and suggest that Factor X inhibitors might prevent the excessive formation of adhesions that accompany bloody abdominal procedures and that such inhibitors also might inhibit keloid formation in patients prone to this disfiguring fibrotic malady.

Finally, I recall the words of Lewis Thomas written some 25 years ago. He mused: “The one advantage that MD clinical investigators have over their PhD colleagues is that when reading a scientific paper, the former cannot help but think of its possible relevance to a unique patient of theirs.”

Ah, that was then; for now, I look forward to my weekend with “turk” friends and broadly knowledgeable colleagues.

For more information:

• Edwards AO. Science. 2005;308:421-424.
• Haines JL. Science. 2005;308:419-421.
• Klein RJ. Science. 2005;308:385-389.
• Laude A. Prog Retin Eye Res. 2010;1:19-29.
• Lindorfer MA Blood. 2010;115:2283-91.
• Mucke HA. IDrugs. 2010;1:30-37.
• Scotten CJ. J Clin Invest. 2009;119:2550-2563.