• spondylitis, ankylosing
• autoimmune diseases
• arthritis, rheumatoid

We, rheumatologists, practise in an era when the study of rheumatic diseases and the care of affected patients are rooted in rigorous scientific investigation. This was not the case before the mid-20th century, when Dr Morris Ziff and a few other Pillars of Rheumatology pioneered the application of rigorous basic and clinical science to a nascent field, in which affected people were often regarded as hopeless and incurable. It is important to recall that rheumatology is a very young discipline. Before 1937, there were only six major US centres of rheumatology, and their focus was mainly on disease description. Other than aspirin and gold salts, few specific therapies existed, and most patients were left to journey through the painful natural history of their disease without effective treatment. Three major advances transformed the field: the discovery of rheumatoid factor (RF) by Erik Waaler in 1940 (rediscovered by Harry Rose in 1948); the recognition of the utility of glucocorticoids in rheumatic diseases by Hench and colleagues in 1948; and the discovery that same year of the lupus erythematosus (LE) cell phenomenon by Hargraves. These exciting findings created the opportunity to develop a scientifically based specialty that could make a significant difference in patient lives. However, it took insightful pioneers, such as Morris Ziff, to capitalise on these advances and to provide the intellectual energy to develop the vigorous discipline we see today.

Morris Ziff was born in 1913 in the Williamsburg section of Brooklyn to recent Jewish immigrants from the Russian Empire. He grew up under modest circumstances. His hopes for a career in medicine were dashed on his father’s unexpected death during his undergraduate years, placing on young Ziff and his brother the responsibility of supporting the family during the depths of the Great Depression. Despite heavy familial responsibilities and while holding down multiple jobs, Morris earned a Ph.D. in organic chemistry at New York University (NYU) in 1937. His thesis work on the biochemistry of nerve transmission was noteworthy and he hoped to land a job in academia or industry. Yet research chemist positions were scarce, especially for Jewish applicants. To provide for his family, he taught undergraduate chemistry part time at the City College of New York. Driven by his desire to do research, he also accepted a poorly paying ‘Scientific Assistant’ position in the legendary Columbia Department of Biochemistry, working with the great Viennese biochemist Erwin Chargaff (figure 1). Chargaff would go on to make the seminal observation (‘Chargaff’s rule’) that DNA, regardless of its source, contained equimolar amounts of guanosine and cytosine, and of adenosine and thymine. This key finding led to the insights that the sequence of these nucleotide bases forms a code, and that equimolar base pairing forms the basis of DNA replication. By the late 1930s, Chargaff had not yet moved on to nucleic acids and was studying phospholipids and blood coagulation. Ziff and Chargaff published pioneering studies in this area, while in adjacent labs the fields of intermediary metabolism (Schoenheimer, Rittenberg, Bloch), bioenergetics (Nachmanson) and immunochemistry (Heidelberger and Kabat) were being born. In a recommendation letter, Chargaff, not easily given to praise, described his young postdoc as highly capable, ‘with a lively interest in the medical side of our studies’. He added ‘I would classify him as one of the nicest men with whom I have been associated….I was always impressed by his thorough decency’.

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Figure 1

Dr Ziff at the bench, 1930s.

In the end, the calling to medicine proved irresistible and Morris enrolled at age 31 in the NYU Medical School. By that time, he had married Columbia Ph.D. student Ruth A. Rawson, and a child was expected. The physical and financial burdens to Ziff and his young family proved formidable, yet he completed his medical studies with distinction and even found time to perform research in the laboratory of haematologist Sol Sherry. After graduation, he served internship and residency in internal medicine at Bellevue Hospital. At last, eager to apply his scientific training to clinical investigation, he accepted an NYU faculty appointment in 1949.

Those were heady days in the newly recognised specialty of rheumatology. Under the leadership of Currier McEwen, NYU had established a Rheumatic Diseases Study Group in 1932, the fourth such programme in the country. Following a multidisciplinary approach involving many specialties, this programme initiated a tradition of clinical investigation that lives on to this day at NYU, providing a milieu for Morris and senior colleague Joseph Bunim to produce pathbreaking work in inflammation and immunology. In particular, the strong association of RF with rheumatoid arthritis (RA) called out for further basic and clinical investigation. Ziff demonstrated that the ‘factor’ was contained within the euglobulin fraction of serum and thus, presumably, was itself an antibody.1 2 This finding was by no means obvious, and convinced many sceptics that not only did autoantibodies exist, but that they played a role in disease. Further research established the concept of autoimmune disease, distinguishing rheumatic autoimmune diseases from other conditions with similar clinical manifestations. The broadened significance of RF was marked by the discovery that it formed cold-insoluble immune complexes in patients with the newly recognised vasculitic disease mixed cryoglobulinaemia.3

An early appreciation for the important role of genetics in rheumatic disease pathogenesis came from Ziff’s recognition that RA (and even the mere presence of RF) occurred frequently in close relatives of patients.4 Ziff also presciently noted the importance of genetics in the pathogenesis of the spondyloarthropathies.5

Morris was particularly proud of his work in ‘collagen disease’. At that time, there was a widely held view that abnormalities in collagen metabolism leading to fibrinoid necrosis formed the basis for many rheumatic diseases. This term had been promoted in the 1920s by the pathologist Klemperer to reflect this concept. Ziff et al put this idea to rest (although the term inappropriately survives) by showing that metabolism of hydroxproline in inflammatory rheumatic disease patients was no different in patients than in normal individuals.6

Skilled clinicians as well as investigators, Ziff and NYU colleagues set world standards for the thoughtful use of the then-new corticosteroid drugs in rheumatology.7 The first use of intra-articular cortisone can be traced to early work from the NYU group, accompanied by careful studies of glucocorticoid metabolism in health and disease.8

In 1953, Joe Bunim was named the first director of the new intramural branch of the National Institute of Arthritis and Metabolic Diseases in Bethesda, Maryland. Morris was designated his successor at NYU. Over the next few years, Ziff came to believe he might accomplish even more in rheumatology if given the resources to establish a brand-new rheumatic diseases unit of his own (figure 2). In 1958, despite opportunities at more established centres, he was persuaded by Donald Seldin, the forceful, brilliant and charismatic Chairman of Internal Medicine to establish a Rheumatic Diseases Unit at the upstart University of Texas Southwestern Medical School in Dallas, then 15 years old. Seldin was intent on building one of the world’s pre-eminent medical centres in Texas, located far away from America’s elite institutions. Ziff’s new unit thrived in the stimulating scientific environment in Dallas, joining other noteworthy sections of the remarkable Department of Internal Medicine in their focus on bringing science to the understanding of disease.

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Figure 2

The future Texan overlooking the upper Manhattan landscape, about 1958.

Important advances in autoimmunity continued in the new rheumatic diseases unit. Working in Morris’ lab, Stastny discovered antilymphocyte antibodies in SLE9 and demonstrated the presence of inflammatory cytokines in rheumatoid synovitis.10 The first model for human scleroderma (homologous disease in rats) was another landmark achievement.11 Stastny, who stayed in Dallas as a renowned independent investigator, discovering the key HLA DR4 association with RA.12 Hugo Jasin, who also joined the faculty, performed important studies on collagen and immune complexes in arthritis. J. Donald Smiley demonstrated local RF and IgG synthesis by RA synovia13 Ziff and trainees were also among the first to perform EM ultrastructural studies of the synovium, laying the groundwork for future advances.14

The UT Southwestern Rheumatic Disease Unit, with its growing reputation as a centre for addressing rheumatic disease pathogenesis with the latest findings from basic science, attracted postdoctoral fellows from around the world. Trainees came from Japan, UK, France, Peru, Mexico, Chile, Israel, Switzerland, Ireland, Canada, South Africa, Greece, Germany—and from the USA. They were attracted by the science and stimulating intellectual milieu, but in no small measure also by the charm and warmth of Morris’s personality. He took a deep and sincere interest in the personal lives of his trainees and in the well-being of their families, even serving as best man for the Greek Orthodox wedding of a now celebrated fellow, Argyrios Theofilopoulos. Many fellows became leaders of divisions and departments, disseminating the Ziff approach to scientifically based Rheumatology throughout the world (figure 3).

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Figure 3

The University of Texas Southwestern Rheumatic Diseases Unit, 1977. Seated (from left), Mario Andreis, James Gilliam, Eric Hurd, Morris Ziff, Don Smiley, Hugo Jasin, Robert Wolf. Standing: Alvin Fox, Andrew Chubick, Philip Cohen, Peter Lipsky, Fred Finkelman, David Sager, William Ginsburg and Ulrich Botzenhardt.

Morris loved travel and was widely known and honoured throughout the world of academic medicine. Former trainees will recall his witty, erudite and enthusiastic accounts of his journeys abroad, including many trips to Russia as the leader of a cooperative programme with the Soviet Union. He made special efforts to contact political dissidents, and, at some personal risk, conveyed to the West a key contraband manuscript by the Slovak statesman Alexander Dubcek, who led the Prague revolution of 1968.

Morris served on many important committees and advisory boards, and with distinction as the President of the American Rheumatism Association. Himself one of the first trainees supported by the Arthritis Foundation, Morris contributed much to its outstanding programme of support for future academic rheumatologists. In 1983, the University of Texas designated him as the first Ashbel Smith Professor, its highest honour, and later added the title of Morris Ziff Professor of Rheumatology.

Ziff’s contributions to the UT Southwestern Medical Center extended beyond the Department of Internal Medicine. Recognising that a strong programme in immunology was essential to the success of Rheumatology and other clinical sciences, he was instrumental in recruiting Jonathan Uhr as Chairman of Microbiology and supporting Uhr’s ambitious plans. Uhr, one of the leading figures in immunology, built a world-class group in Microbiology, including Ellen Vitetta, Don Capra, James Forman and Jack Kettman. He played a key role in bringing to the Cell Biology Department the Nobelist Rupert Billingham, and the distinguished transplantation immunologist Wayne Streilein. The combined Graduate Programme in Immunology soon became one of the most sought after in the country.

Morris was also instrumental in recruiting the Stanford-trained Texan James Gilliam, who held appointments both in Dermatology and in Rheumatology. Gilliam and trainee Rick Sontheimer (now himself an esteemed dermatologist) described in a rigorous fashion the many dermatological manifestations of SLE and their significance in a classification still in standard use today.15 By fully integrating Jim and Rick into the activities of the Rheumatology unit, Morris established a model multidisciplinary approach to the study and treatment of rheumatic diseases. Morris went on to include Chester Fink, a pioneer in paediatric rheumatology, further enriching the rheumatology landscape of UT Southwestern.

In the early 1980s, a generous bequest to the rheumatic disease unit led to The Harold C. Simmons Research Center. New avenues of research probed the causes of inflammatory spondylitis, an underappreciated area of rheumatology. The centre sponsored important work by Joel Taurog and many others and has nurtured the field in general through symposia and publications, as well as by generation of the standard model of the spondyloarthropathies, Taurog’s famous HLA-B27 transgenic rat.16

Morris was an active leader of the rheumatic diseases unit, not just an administrator. Every day he made ‘rounds’ of every laboratory, asking ‘What have you discovered for me today?’ If the answer was a promising one, a lengthy conversation ensued about its nuances and how it might be advanced. If the answer was negative, the result was further encouragement. For those who tried to escape ‘rounds’, a search was organised. It was not uncommon for results to be discussed in the cafeteria or even the washroom. Weekly journal club and research in progress meetings were legendary, often generating unforeseen collaborative interactions and meaningful progress. Throughout his long career, Morris remained blessed with a child-like enthusiasm for science and how it could improve care of patients.

Morris’s family was very dear to him. His met his first wife Ruth Alice Rawson Ziff while she was a Columbia Physiology Ph.D. student, and he was working as a postdoc with Chargaff. She became a respected scientist in her own right and had a long career at UT Southwestern. Immensely proud and supportive of Morris, she encouraged his move to Dallas. Her passing, in 1969, left a great gap in his life. Ruth and Morris took great pride in their two sons. Edward became a renowned neurobiologist in New York, and his brother David, now retired, a respected clinical psychologist in Chapel Hill, NC. Nothing delighted Morris more than informing other scientists that it was Edward Ziff, and not he, who had published an important paper or presented a key scientific finding. Morris’ second wife Jackie was the indispensable beloved bedrock of the rheumatic diseases unit, serving ably as Administrator, deftly freeing Morris from bureaucratic concerns, and organising the schedule of her somewhat absent-minded husband. Her unit parties were eagerly anticipated and always happy occasions (figure 4).

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Figure 4

Ziff family, 1980s. David is at the left, then Jackie, Morris and Edward.

Vivid among the many memories former fellows share of their Dallas years is Saturday morning consulting rounds with Dr. Ziff. Beginning at 7:30 hours and often extending well into the afternoon, cases were presented to Dr Ziff, who stood, chalk in right hand in front of a large blackboard. In the left hand was his Dictaphone, through which he seemed to be having a conversation with Jackie, discussing all the interesting rheumatology cases that had been admitted the previous week to Parkland Hospital. After case presentations, Dr Ziff led a ‘thundering herd’ of attendings, fellows, residents, students and assorted others to see the patients in Parkland Hospital, a centre for indigent patient care. He then took a detailed history and carried out a physical exam on every patient and spoke with each in a reassuring manner. In this unusual setting with as many as 20 people surrounding the patient in a two bed room, Dr Ziff had a knack of connecting with each patient. Many patients refused to be discharged until they had seen Dr Ziff on Saturday morning. During rounds, he seemed not to notice, however, the stragglers who abandoned the exercise as noon approached, nor the snacks passed around by Fred Finkelman (now a distinguished professor), along with many other fellows. Rounds provided unique hands-on training not only about rheumatic diseases but also about the impact of these diseases on individual patients and their families. Versions of these rounds are still carried out in numerous institutions by former trainees.

Morris stepped down as director in 1983 after three decades of leadership of the rheumatic diseases unit. Not ready for retirement and appreciating the dawn of a new era of cytokine biology, he assembled a new group to address their role in endothelial cell interactions with inflammatory cells. Under Morris’ guidance, trainees Pierre Miossec, Druie Cavendar, Dorian Haskard, Nancy Oppenheimer-Marks and others produced important studies in this new field of inflammation research.17 All the while, Morris continued to maintain a small private rheumatology practice at UT Southwestern.

Morris Ziff passed away at age 91, yet his impact endures not only as a pioneer rheumatologist, but especially as the physician-scientist who paved the way for the transformation of rheumatology from a nascent specialty to a shining example of how basic science advances can lead to better understanding and treatment of human disease. Morris was the original ‘quadruple threat’ in rheumatology, excelling as a scientist, clinician, teacher and public servant. He was not just a role model, but rather a very human person who loved to be personally engaged with his trainees, his family, his colleagues, his patients and his friends. His greatest joy would be the knowledge that he leaves behind legions of former trainees who emulate his finest qualities for the benefit of the discipline and for humanity in general.