Dirk W van Bekkum 1925–2015 | Bone Marrow Transplantation

You have full access to this article via your institution. Download PDF On July 17 2015, Dirk W van Bekkum (Dirk), one of the pioneers of bone marrow transplantation (BMT), who helped to

shape the discipline of stem cell transplantation, passed away after a short illness. He had begun making plans to celebrate his upcoming 90th anniversary 2 weeks later. HIS LIFE Dirk van

Bekkum was born in the Netherlands Indies, today Indonesia, where his father worked. He graduated as an MD at Leiden University (1950) and completed his thesis on D-amino acid oxidase in

1952 cum laude (with honors) after having spent a year at the Department of Biochemistry in Oxford with Professor Rudolf Peters. Dirk worked initially as head of Radiobiology at the Medical

Biological Laboratory of the National Defense Organization TNO in Rijswijk. But Dirk with his flow of scientific ideas and plans considered the conditions at the Medical Biological

Laboratory too restricted for him so that he decided to establish his own institute next door. In 1960, at age 35, Dirk founded the Radiobiological Institute of the Dutch Health Organization

TNO in Rijswijk and became its director. Before the building was completed he had already moved into the basement of the building and started doing experiments; he was just too impatient to

wait any longer. This institute would become one of the leading scientific institutions with prominent scientific programs on radiobiology, BMT, stem cell research and experimental leukemia

research. Radiobiology had become a hot topic after the atom bombing on Hiroshima and Nagasaki at the end of World War II and radioprotection of the bone marrow syndrome following excess

radiation exposure would become a central scientific subject of his research. The atmosphere in the Institute typically carried the Van Bekkum stamp. There was an ambitious spirit of team

work and scientific entrepreneurship. The seminar evenings preceded by the Indonesian Rijsttafel were famous and attracted attendees from far away as scientists elsewhere did not want to

miss the stimulating presentations and discussions. There was also a lot of fun and humor in the air of the institute. Cabarets were produced at party evenings in which Van Bekkum himself

would play a major part. Table tennis during lunch hours offered a popular break. Dirk himself actively participated in these activities. The international workshops that he organized in the

Institute to assemble leading scientists with opposing viewpoints or conflicting research data were unique and are memorable. For instance, the Workshop on _In Vitro_ Colony Forming Cells

held in 1971 at the exciting time of the emerging field of progenitor cell research prompted researchers like Ray Bradley, Don Metcalf, Malcolm Moore, Dov Pluznik, Ernest McCullough, John

Till, Fred Stohlman and others to bring their culture systems to the lab, actively perform their experiments at the bench and demonstrate their assays for data comparisons. These were unique

events. In 1966 Dirk van Bekkum became Professor of Radiobiology at the newly founded Medical Faculty of Erasmus University Rotterdam and in 1967 he also became Professor of Experimental

Transplantation Biology in Leiden. In 1973 Van Bekkum was elected to the Royal Academy of Arts and Sciences of The Netherlands. In 1987 he received a royal honor: Knight of the Order of the

Lion of the Netherlands. In 1990 he received the highest award of the City of Rotterdam (Wolfert van Borsele Medal). Dirk was involved in the early phase of the foundation of European Bone

Marrow Transplantation Group, CIBMTR (International Bone Marrow Transplantation Registry) and the International Society of Experimental Hematology, and he is also one of the founders of the

Dutch Society of Immunology. Van Bekkum was one of the founders of EORTC (European Organization for Research on Treatment of Cancer) and served as its President from 1969 to 1975. In 1975 he

was awarded a Fogarthy Scholarship, which he spent at the National Cancer Institute in Bethesda. He took that opportunity to study the US National Cancer Program ‘Conquest of Cancer’ that

had been initiated 5 years before, in particular the functioning of the Comprehensive Cancer Centers. Upon his return to the Netherlands he initiated the organization of a network of similar

centers in the Netherlands and founded in 1977 at Rotterdam the first ‘Comprehensive Cancer Center’, of which he would become Executive Director for 20 years. After retiring from TNO, Van

Bekkum was cofounder with Dinko Valerio and Bob Löwenberg of the biotech company IntroGene to develop gene therapy for stem cell diseases and cancer. In 2000 IntroGene merged with U-BiSys BV

(Utrecht) to become Crucell BV, which currently develops vaccines and monoclonal antibodies. In 2010, at age 85, he founded Cinderella Therapeutics, the first not-for-profit organization in

the Netherlands that would promote the availability of orphan drugs for an acceptable price. Cinderella pursued an innovative approach to tackle the commercial business model of Pharma

industry and eliminate obstacles in access to orphan drugs for patients. Dirk van Bekkum has written several books, but the book _Radiation Chimaeras_ published in 1967 by Dirk van Bekkum

and MJ de Vries can be seen as the ‘Bible’ of the experimental bases of BMT. The book discusses the discovery of hematopoietic chimerism resulting from intravenous injection of bone marrow

cells into lethally irradiated recipients, the comparative pathology and immunologic complications after stem cell transplantation, the basis of pretransplant conditioning with radiation,

antigenic differences between host and donor, stability of chimeric state and various transplantation methods. It describes acute graft versus host disease (GvHD) and secondary disease, and

their clinical laboratory and pathologic presentations. The Van Bekkum Lecture at the annual scientific meeting of the European Bone Marrow Transplantation Congress has been established in

honor of his seminal contributions to stem cell transplantation science. Dirk is survived by his four daughters, Marion, Pleuntje, Joos, Nienke, and 11 grandchildren and several great

grandchildren, and his lifetime companion, his wife Ada. SCIENTIFIC HIGHLIGHTS OF DIRK VAN BEKKUM—A HISTORY OF TRANSPLANTATION AND STEM CELL RESEARCH THE FOUNDATION OF HEMATOPOIETIC STEM

CELL TRANSPLANTATION Van Bekkum, simultaneously with workers in Oxford and San Francisco, published in 1956 the first convincing evidence for the cellular mechanism—that is, the occurrence

of chimerism—to explain the protective effect of BMT in lethally irradiated animals. Van Bekkum was the first to report that engraftment and the degree of chimerism is not only dependent on

the degree of myelo-lympho-ablation induced by the conditioning of the recipient, but also increases with the number of bone marrow cells transplanted, and that for the engraftment of

allogeneic marrow many more cells are needed than in the case of syngeneic marrow. During the period 1956–1966 his laboratory, in collaboration with O Vos, LM van Putten, H Balner, MJ de

Vries and G Mathé (Paris), produced the by now classical description of the pathology and the pathogenesis of GvHD in mice, rats, monkeys and man and established the similarity of GvHD with

transplant rejection and cellular autoimmune reactions. Using parent to F1 and the reverse donor–host combinations in mice he provided proof of the mechanism of ‘secondary disease’ being due

to an immune attack by the grafted lymphocytes on the host tissues. He demonstrated quantitatively the direct relation between the number of grafted allogeneic lymphoid cells and the

severity and incidence of GvHD. He also showed that the bone marrow of monkeys, like that of man, contains a much higher proportion of GHD initiating lymphocytes than that of rodents, which

explained the difference in patterns of GvHD between these species. Accordingly, van Bekkum showed, first in mice and later in rhesus monkeys and dogs, that selective elimination of

(PHA-reactive) lymphocytes from the allogeneic graft could effectively prevent GvHD. For this purpose he developed with Karel A Dirke a method for the purification of stem cells on

discontinuous albumen density gradients. The fractions enriched in stem cells were depleted of lymphocytes. They demonstrated in several animal models that successful engraftment of

T-cell-depleted allogeneic marrow requires a somewhat stronger immunosuppressive conditioning regimen. These fundamental relationships were subsequently confirmed in pediatric patients in

collaboration with Leo Jan Dooren and JaakM Vossen (Leiden) and in adult patients in collaboration with Bob Löwenberg (Rotterdam). CLINICAL TRANSLATION OF STEM CELL TRANSPLANTATION CONCEPTS

During the years 1966–1976 Dirk van Bekkum and his team demonstrated that anti-lymphocyte serum effectively prevents GvHD and mitigates existing GvHD in mice as well as monkeys. This led to

the application of anti-lymphocyte serum in various conditioning and post-transplant regimens and its use for treating patients with GvHD. In the course of his studies on the temporary

immune deficiency that develops following allogeneic BMT, especially during GvHD, van Bekkum became interested in the role of the thymus in these processes and in similarities with some of

the congenital immune deficiency diseases of children, in particular severe combined immune deficiency disease (SCID). At that time SCID was thought to be caused by a developmental defect of

the thymus. Based on their observations in hematopoietic chimeras, neonatally thymectomized animals and autopsy material of SCID patients, van Bekkum _et al._ postulated that SCID was

instead due to a defect of the hematopoietic stem cell, resulting in failure of thymocyte precursor cells to mature in the thymus into competent lymphocytes, and consequently that cure of

these children should be possible by transplanting stem cells from a normal donor. In 1967 the team of Vann Bekkum, Jon van Rood, and the pediatricians Leo van Dooren and Jaak Vossen

performed the first successful allogeneic BMT (with purified stem cells, which prevented GvHD) in man in a baby with SCID in Leiden. Baby Marijt would grow up with healthy marrow cells from

a sibling donor. A US team led by Robert Good also succeeded at the same time in transplanting an infant with SCID in Minneapolis. Subsequently, BMT became a standard treatment for patients

with SCID. In a separate line of experimental studies the role of micro-organisms in the development of GvHD was investigated by van Bekkum, initially with Dirk van der Waay. With the use of

germfree animals, the histological lesions of GvHD were delineated from those due to infection. Subsequently, it was shown that certain constituents of the Gram-negative flora of the

intestinal tract exert a triggering influence on the donor-derived immune-competent cells, which aggravates or even initiates the GvH reaction. The team showed in mice, dogs and monkeys that

bacterial decontamination prior to BMT with nursing of the recipients in isolators reduces the incidence and severity of GvHD. STEM CELL AND RADIATION RESEARCH Having developed the means to

concentrate stem cells, van Bekkum and collaborators were the first in 1971 to define the morphological and submicroscopical features of the stem cells in highly purified fractions. They

showed that these features were similar for the stem cells of mice, rats, monkeys and man and distinct from those of the so-called small lymphocytes, which were at that time thought to be

the hematopoietic stem cells. With the arrival of the method of fluorescent light-activated cell sorting van Bekkum took the opportunity to further develop the identification of stem cells

and early precursor cells. Due to the achievements of coworkers Ger van den Engh and Jan Visser, his laboratory became a leader in this field during the late 70’s. The most recent

contribution by van Bekkum relates to the application of BMT for the treatment of autoimmune diseases. Using animal models of arthritis he showed that these diseases can be cured by

myelo-ablative treatment and BMT. He also discovered that autologous bone marrow grafts, provided these are T cell depleted, are as effective as allogeneic bone marrow. This finding paved

the way for explorative clinical trials of BMT for treating a variety of severe autoimmune diseases. From this knowledge of radiation biology van Bekkum contributed important preclinical

data in support of BMT. Examples are the determination of the dose correction factor required for comparing doses of fractionated total body irradiation with single-dose exposures, and

establishing the maximal radiation doses that are tolerated by infant monkeys without causing inhibition of skeletal growth and cataract. Finally, in response to the uncertainties that arose

after the Chernobyl nuclear reactor accident about the safety and efficacy of the administration of stable Iodine for protecting human fetuses and infants against radioactive contamination,

van Bekkum and colleagues carried out a series of studies in chimpanzees. The results published in 1997 provide a solid experimental base for protection guidelines in cases of radiation

accidents. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Erasmus University Medical Center, Rotterdam, Netherlands B Löwenberg Authors * B Löwenberg View author publications You can also

search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to B Löwenberg. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Löwenberg, B. Dirk W van Bekkum 1925–2015. _Bone Marrow Transplant_ 50, 1493–1494 (2015). https://doi.org/10.1038/bmt.2015.209 Download citation * Published: 14 September 2015 * Issue Date:

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