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Obituary

Josef WarkanyDr Josef Warkany, who died on June 22, was for forty

years one of the world’s leading experts on the aetiology andpathogenesis of congenital malformations.

In 1948 Warkany reported, together with D. M. Hubbard,(Lancet 1948; i: 829-30) that mercury causes acrodynia. With therecognition of its causes, this dreadful disease was soon eradicated.During the 1940s he showed that congenital malformations can beinduced in fetal rats by maternal malnutrition or deficiency ofvarious vitamins. Experimental proof that congenitalmalformations can be due to an exogenous cause was important at atime when congenital malformations were generally regarded asgenetically determined. In 1961 Warkany and co-workersestablished intrauterine growth retardation as an important, albeitheterogeneous, condition. A seminal paper with B. B. Monroe andB. S. Sutherland (Am J Dis Child 1961; 102: 249-79) focusedattention on both exogenous and genetic causes of retardedintrauterine development. Warkany recognised that human fetalexposure to aminopterin can induce a distinct phenotype (1960).The appearance in 1971 of the monumental review CongenitalMalformations. Notes and Comments was a landmark in modemteratology. It combines clinical observations and experimental datain a unique way. Mental retardation, congenital hydrocephalus, andopen neural tube defects were the subjects of Warkany’s laterstudies.Bom in 1902, Warkany attended Vienna Medical School

1920-25 and received paediatric training under von Pirquet andMoll. On account of his Jewish ancestry he was forced out of Viennaand arrived at Cincinnati Children’s Hospital in 1935. There heestablished the division of teratology at the Children’s HospitalResearch Foundation and was director of mental retardationresearch of the Institute for Developmental Research at Children’sHospital Research Foundation from 1966 to 1976.

Josef Warkany was an artist in his own right. "A child ofnon-disjunction", reproduced here, shows his sympathy withpatients.

Eberhard Passarge

Noticeboard

Haematology—back to basics

"All that man is, All mere complexities, The fury and the mire of humanveins"-W. B. Yeats.

Perhaps the message of the tmal day (Aug 28) ot the 24th congressof the Intemation] Society of Haematology was that an

understanding of the normal control of haemopoiesis is essentialbefore new rational therapies can be introduced for dysregulation ofthis complex system. Speaker after speaker stressed the importanceof investigating molecular biology before patients are treated withwhat are still, virtually, empiric treatments.Therapy with monoclonal antibodies (Mabs) always had

predictable difficulties, mostly because rodent Mabs are

immunogenic and the route of administration is inconvenient.

"Humanisation" of Mabs, described by Prof Herman Waldmann,University of Cambridge, which involves de-allotyping or

"silencing" and variable-region grafting in the antibody molecule,may allow administration of repeat courses but is not yet an idealsolution. Another disappointment is that there is no good preclinicalmodel for studying Mab therapy. Whether in-vitro systems canpredict in-vivo effects is largely unknown, and Ig isotypes vary infunction between rodents and man. Tolerising lymphocytes toblock normal lymphocytes is another approach. Antibodies to theadhesion molecules CD4 and CD8 allow mice to accept a foreigngraft indefinitely, and a second graft long after the Mabs have beencleared. "We are looking", says Waldmann, "for long-term effectsof short-term treatment. But all this engineering is of no matter untilwe understand the biology".The presidential symposium was about the control of

haemopoiesis. Some of the colony-stimulating factors (CSF) areused clinically, especially to enhance cell recovery after

myeloablation. Clinically, combinations of CSFs will probably bemore useful than the cytokines used alone. Prof Donald Metcalf,Melbourne, described molecular and structural studies of CSFs inmice. But combinations in mice are not necessarily additive in theireffects; indeed some are antagonistic. About twenty regulators arenow available, but it would be impossible to study all thecombinations in the laboratory let alone in patients. So the in-vitrobiology must be understood to assess the best combinations.

Prof Harvey Lodish, MIT, and his colleagues have investigatedthe isolation and mechanism of action of the erythropoietin receptor(EPO-R). The possibility of mutated cytokine receptors acting asoncogenes would be intriguing, since oncogenes are usuallykinase-dependent. A point mutation in the EPO-R gene was foundto allow hormone-independent cell proliferation. An EPO-Rmutant led to proliferation of megakaryocytes in mouse spleen butdid not cause tumours. Mutants of cytokine receptors, especially inman, are unknown.

Antisense makes good sense

The first in-vivo description of antisense oligonucleotide therapyis reported this week from a collaborative group of chemical

engineers, biologists, and physicians.’ A key event in atherogenesisis intimal smooth muscle cell proliferation. Inhibition of this processmight eliminate an important factor contributing not only toatheroma formation but also to coronary artery bypass graft failureand recurrence of lesions after angioplasty. In-vitro smooth musclecell proliferation can be inhibited by antisense oligonucleotides thatsuppress mRNA transcription of the c-myb proto-oncogene. In a ratmodel of carotid artery atheroma-induced by damaging the vesselwall with balloon angioplasty-local delivery of a solution of an 18nucleotide antisense molecule to the arterial lesion led to completesuppression of c-myb mRNA. Two weeks after angioplasty,substantially less intimal smooth muscle cell accumulation wasfound in rats treated with antisense oligonucleotides compared withcontrol animals. The specificity of this inhibition was confirmed bygiving a two-base-pair mismatch oligonucleotide: there was nodiminution of smooth muscle cell proliferation in the same ratmodel. Of more clinical relevance, were experiments completed inrabbits. These animals were given a single intravascular injection ofantisense molecules after catheter-induced arterial injury.Angiographic evidence of a significant reduction in smooth musclecell growth was found two months after treatment.

1. Simons M, Edelman ER, DeKeyser JL, Langer R, Rosenberg RD.Antisense c-myb oligonucleotides inhibit intimal arterial smoothmuscle cell accumulation in vivo. Nature 1992; 359: 67-70.

Wrangle over Polish pharmaciesPoland’s Constitutional Tribunal has condemned a

parliamentary decree that ownership of pharmacies should berestricted to those with a Master’s degree in pharmacology. Thedecree, issued in October, 1991, dealt with the changeover of the