Adolfo Ferrata 1880-1946
It is now a little over a year since Adolfo
Ferrata, the great Italian hematologist, died in Pavia where he was professor
of Clinical Medicine. Ideas, methods of research, diagnosis and therapy
have changed and progressed enormously form the days when Ferrata started
his activity in the field of blood diseases. However, his contributions
to the knowledge of blood morphology and his work as a writer of several
textbooks of hematology deserve to be recalled now that he is no longer
with us. His reputation was international.
The first hematological work of Ferrata was done after a brief period
of activity with J. Morgenroth, under the direction of, and in collaboration
with, A. Pappenheim, in Berlin (1910-11). The investigation of the blood
cells at that time was strongly influenced by the work of Paul Ehrlich,
who had introduced the first straining methods for blood. Pappenheim and
Ferrata, opposing the dominant opinions held by Ehrlich, Pinkus, Lazzarus,
Naegeli, Denys, Levaditi and with minor variations by Grawitz, Weidenreich
and Leowit that the “great mononuclear” was the first morphological step
in the evolution of the “polynuclears” were able to demonstrate that the
“mononuclear cells” of Ehrlich were an independent strain of white cells,
and they introduced for these cells the denomination, thereafter universally
accepted, of “monocytes” (1910).
The study of the origin of the monocytes led Ferrata to confront the baffling
problem of the genesis of white cells in general. In a previous paper
he had agreed with Pappenheim on the genesis of the monocytes from the
lymphocytes (1910).
Soon after, however, Ferrata modified his views, and showed that a nongranulated
immature cell, of lymphocytic appearance, may be found in the bone marrow
and in the lymph nodes. He believed that this cell was the common progenitors
of the red cells, the white granulated cell of the marrow, the monocytes
and the lymphocytes. For this stem cell he created the name “hemocytoblast”,
from then on used by the majority of the hematologists, although not always
with the same significance. His hemocytoblast in the marrow is morphologically
indistinguishable from that in the lymph nodes, but it is different in
its potentiality of maturation into respectively a medullary white cell,
a red cell or a lymphocyte. He was thus recognized as a “neounitarian”
among the theorists of hematology. The hemocytoblasts of Ferrata (1912-18)
is the “free primitive blood cell” of Cunningham, Sabin and Doan (1925).
Although legitimate doubts may be raised as to whether or not hemocytoblasts,
morphologically identical to those of the bone marrow (nongraulated myeloblasts),
are to be found in the normal lymph nodes of the adult, it is a fact that
a differentiation between the stem cells of the medullary elements and
those of the lymphocytes is not easy, as everyday experience in the leukemias
with highly undifferentiated elements shows. Nowadays clinical clinical
hematologists have found an easy but not very scientific way out of these
difficulties: they call the immature nongranulated cells “blasts”.
The progress made in the knowledge of blood morphology and blood genetics
could not fail to influence conception of blood pathology. Panchromatic
staining methods for blood cells had been proposed since the turn of this
century (Jenner 1899, Wright 1902, May-Grunwald 1902, Giemsa 1902) and
with the aid of this technic it had been almost universally recognized
that the cells present in the peripheral blood of leukemic patients were
to a far greater extent immature rather than abnormal cells. On the other
hand Banti had maintained that leukemias are neoplastic diseases, not
fundamentally different from sarcomas and had defended his thesis with
anatomophatological evidence in his “Handbook of Phatological Anatomy”
(1907) and in a report to the Italian Phatological Society (Pisa 1913).
In the discussion which followed this report, Ferrata and Micheli, two
young men at that time, rose to oppose the view of Banti, who recognized,
at least in part, the validity of their evidence. In the last years of
his life Ferrata was no longer so sure of the essential character of leukemias
as hyperplastic processes to be differentiated from true neoplastic diseases,
and in recent years some of his pupils even advanced doubts about the
systematic nature of the various leukemic lesions, unearthing ideas stubbornly
defendant by Banti in the past. Multa renascentur quae jam cecidere, indeed!
All this is good testimonial of the mental alertness, scientific honesty
and intellectual elasticity of Ferrata.
The name of the Italian hematologist has remained bound to a special type
of cell which many authors, after Naegeli, have called the Ferrata cell.
According to Ferrata, these elements, which he first saw in leukemic blood
(Ferrata and Franco 1919, Ferrata 1924), represent undifferentiated (multipotent)
connective tissue cells. Ferrata called them hemohistioblasts , implying
that they were cells capable of an evolution in both directions really
exist. They are the reticulum cells of the blood-forming organs and possibly
of other more widely distributed cells (adventitial cells of the blood
capillaries, etc.).
The significance of the particular elements described in the peripheral
bood by Ferrata under the name of hemohistioblasts has been strongly debated
and their existence as such even denied by some authors (Ringoen, Lambin).
The writer showed that cells like those described by Ferrata in leukemic
blood are also found in the bone marrow of normal human subjects and of
mammalians in general (1928). That they are not artifacts, i.e. damaged
promyelocytes and myelocytes, as postulated by Ringoen and Lambin, is
proved by their size (which in many cases is far larger than that of the
promyelocytes or myelocytes), their nuclear structure and particulary
by the fact that large elements with cytoplasmic pseudopodia, with two
blow-up nuclei, with two or three nucleoli, may be seen also in bone marrow
section, often with specific granulation in the cellular body. They represent
a form of early differentiation of the reticulum cells into granulocytic
elements.
This writer, however, has shown that their cellular characteristics are
not those of the fixed, pluripotent cells of the connective tissues (reticulum
cells), which are the hemohistioblasts in Ferrata’s sense. Both in the
second edition of this book (1933) and through the work of one of his
pupils (Vills 1929), Ferrata accepted this point. Thus it should be organized
that Ferrata not only created an appropriate name expressing a correct
idea (hemoistioblasts) but that he gave also the first description of
a hitherto undescribed type of evolution of the reticulum cell. Similar
stages of direct differentiation of the reticulum cells into megaloblasts
have also been described by the school of Ferrata in Pericious anemia
and acute erythremia (Di Guglielmo).
The contribution of Ferrata are almost totally in the field of morphological
hematology. His influence in this direction on a large number of Italian
and foreign hematologists, especially those of Spanish and Latin-American
origin, was very pronounced. The origin of the blood cells and the relationship
between the different cell types were submitted to a minute investigation
under experimental conditions, in both normal humans and phatological
material by Ferrata and these workers. Cases of blood disease were studied
with an almost exclusive interest for the morphology of the blood cells
in the peripheral blood, in the bone marrow, etc. Although the achievements
in this field were by no means slight, hematology has a wider scope than
pure cytological investigation. And yet Italian hematology has a tradition
also of the physiologic approach to the study of blood diseases, from
Bizzozzero, Marchifava, Banti down to Zoja, Mino, Greppi, Lattes, to name
only the better known men. This extreme interests in the morphologic side
of blood disorders was very evident in the work of hematologists of many
nations at that time.
This may have been due to economic limitation which hinder more expensive
methods of research. It certainly had a reason in the past. The evidence
at hand, however is to the effect that, although an exact knowledge of
blood morphology is a necessary tool for any good hematologists, future
progress in the understanding of blood diseases will come from the physiologic
approach to these problems.
The activity of Ferrat as a writer of monographs and handbooks started
very early with the “Morphology of the Normal and Phatological Blood”
(1912). This work was the forerunner of a more extensive handbook “Blood
Diseases” (Le Emopatie, 1918-23) which, clearly written and magnificently
illustrated with lithographic colored tables, had a tremendous success
among physicians familiar with the Italian language in Europe and in Latin
America.
Undoubtedly this book exercised a very great influence in developing interests
in hematology in Italy. In the period between the World Wars, Ferrata
in conjunction with several Italian authors (Di Guglielmo, Villa, Introzzi,
Greppi, Artom and others) prepared a new edition in five volumes, which
appeared between 1933 and 1935. It is to be regretted that this book is
not more widely known.
Ferrata contributed a monograph on “The Disease of the Endocrine Glands”
for the Italian “Handbook of Internal Medicine” (Milan 1931), and a “Manual
of Blood Disease”, compiled in collabortion with his pupil E. Storti,
has just appeared. This manual is also liberally illustrated with beautiful
plates.
Ferrata had a long career as a teacher. In 1922 he was named professor
of Medical Phatology at the University of Messina. He went to Siena in
1923 and the following year he was called to Pavia as Professor of Clinical
Medicine. He created a school of Hematology and left behind a distinguished
group of scientists, many of them now at the head of several university
structures.
Clear minded and warm hearted, Ferrata was a strong personality and exercised
a powerful influence beyond the sphere of his immediate activity. Both
in his clinical lectures, as when speaking in medical meetings and congresses,
his word was convincing and his intervention clarifying. His powerful
physical build, the warmth of his Lombard elocution, the evident fairness
which is characterized his approach to any controversy, all contributed
to create an atmosphere of sympathetic agreement around him. Although
not entirely exempt from the nepotistic habits prevailing in the Italian
academic world Ferrata showed himself ready to help young men coming from
other schools to realization of their academic aspiration.
M. Volterra, New York, 1946