In Memoriam: Jean Lindenmann (1924-2015) a Circuitous Interfering Power in Neurology

OBITUARY In Memoriam: Jean Lindenmann (1924-2015) A Circuitous Interfering Power in Neurology

Olaf Stüve, MD, PhD

ometimes, the intended consequences of scientific Mx promoter is a powerful tool to direct controlled discovery are not the ones that ultimately have the expression of a downstream gene and is now widely greatest impact on humanity. This is certainly the used in inducible gene expression in experimental S 6 case of the interferons, which were discovered jointly mice. by Jean Lindenmann and Alick Isaacs in an attempt to After 1980, research in the interferon field progressed elucidate the role of interferons in host innate immune rapidly as recombinant DNA technology clarified the responses against viral infections. relationship between the many interferon species Dr Lindenmann, a Swiss virologist who passed away on and allowed the production January 15, 2015, in Zürich, Switzerland, was an outstanding of pure interferon on the scientist whose contributions to the interferon field were kilogram scale. Most impor- groundbreaking. He joined Dr Isaacs in the mid-1950s as a tantly, the generation of postdoctoral fellow at the National Institute for Medical interferons on an industrial Research in Mill Hill in London, England. The purpose of his scale led to legitimate clini- research was to study the nature of “viral interference.” cal applications. In 1987, When he commenced his work it was already established Hillel Panitch, MD, and col- that incubation of a tissue or tissue culture with heat- leagues conducted a clinical inactivated virus could prevent the replication of a virus trial with interferon gamma that was subsequently added. Drs Lindenmann and Isaacs in patients with relapsing- subsequently demonstrated that fluid conditioned for remitting multiple sclerosis 24 hours with chick chorio-allantoic membranes exposed to (MS).7 At that time, many inactivated virus could transfer this “interfering power” to MS experts considered MS Jean Lindenmann fresh membranes, indicating that additional “interfering to be a viral, postviral, or activity” had been generated.1 Dr Lindenmann then paraviral disorder, which showed that a certain time lapse was required to obtain made interferon gamma a plausible intervention. interference, suggesting that a new protein had to be gener- Unexpectedly, a disproportionate number of patients dis- ated to achieve this. Furthermore, dilution experiments played disease exacerbations, and bioassays detected indicated a linear relationship between the concentration of an increase in circulating HLA-DR–positive monocytes interferon and its antiviral potency.2 The seminal article in peripheral blood of recipients. These observations reporting the discovery of interferons was published in strongly suggested that MS disease exacerbations 1957,3 which ultimately proved to be a family of proteins are immune mediated and not the consequence of with a very high specific activity and a broad spectrum of viral illness. biological effects. In contrast, interferon beta preparations have been Dr Lindenmann returned to Zürich but did not approved and used for the treatment of MS for more than 20 pursue the purification and structural analysis of years. The biological beneficial effects of interferon beta in interferon. He was convinced that this task would be MS, which include the reduction of disease attacks and more or less rapidly accomplished by biochemists.4 brain lesions on magnetic resonance imaging, are pleio- In retrospect, this decision may appear misguided: tropic and still incompletely understood. The recent Thousands of man-years later, in 1980, Ernest Knight approval of pegylated interferon beta-1a will likely ensure remarked that “the best way to describe the progress in that they remain a mainstay of MS therapy for decades to purification and characterization of the interferon come. Thus, Dr Lindenmann’s discovery not only opened up proteins is that it has just begun.”5 At that time, the multi- a new area of basic research, but also led to practical plicity of interferon species and the low levels of medical benefits. production proved to be an almost unsurmountable Those who knew Dr Lindenmann describe him as a barrier. Rather than purifying interferon, Dr Lindenmann gifted communicator who time and again delighted laymen explored its mechanism of action and identified a and colleagues alike with his philosophical and historical dominant autosomal gene, which he called Mx (now called discourses on scientific topics. Modest and unassuming, he Mx+), that mediated interferon-induced resistance kept out of the limelight toward which many another with against influenza and some other viruses. The his accomplishments would have striven.

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1. Lindenmann J, Burke DC, Isaacs A. Studies on the production, mode of action and properties of interferon. Br J Exp Pathol. 1957;38(5):551-562. Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas; Neurology Section, 2. Isaacs A, Lindenmann J, Valentine RC. Virus interference, II: some properties VA North Texas Health Care System, Medical Service, Dallas; Department of of interferon. Proc R Soc Lond B Biol Sci. 1957;147(927):268-273. Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, 3. Isaacs A, Lindenmann J. Virus interference, I: the interferon. Proc R Soc Lond Germany. BBiolSci. 1957;147(927):258-267. Corresponding Author: Olaf Stüve, MD, PhD, Neurology Section, VA North 4. Weissmann C. In praise of a prepared mind: a retrospective on Jean Texas Health Care System, Medical Service, 4500 S Lancaster Rd, Dallas, TX Lindenmann. J Interferon Res. 1987;7(5):439-440. 75216 ([email protected]). 5. Knight FJ. Purification and Characterization of Interferons. London, England: Academic Press; 1980. Conflict of Interest Disclosures: Dr Stüve serves on the editorial boards of JAMA Neurology, Multiple Sclerosis Journal, and Therapeutic Advances in 6. Arnheiter H, Haller O, Lindenmann J. Pathology of influenza hepatitis in Neurological Disorders. He has received grant support from Teva susceptible and genetically resistant mice. ExpCellBiol. 1976;44(2):95-107. Pharmaceuticals and Opexa Therapeutics. Dr Stüve has served on data 7. Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple monitoring committees for Pfizer and Sanofi without monetary compensation. sclerosis in patients treated with gamma interferon. Lancet. 1987;1(8538):893- He has served on an advisory board for Genzyme. Dr Stüve is funded by a Merit 895. grant from the US Department of Veterans Affairs.

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