Medical Mycology in the United States

A Historical Analysis (1894-1996)

MEDICAL MYCOLOGY IN THE UNITED STATES

A HISTORICAL ANALYSIS (1894-1996)

by

Ana Victoria Espinel-Ingroff

Medical College of Virginia Campus of Virginia Commonwealth University

Richmond, VA USA

SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.

Library of Congress Cataloging-in-Publication Data is available.

ISBN 978-90-481-6196-6 ISBN 978-94-017-0311-6 (eBook) DOI 10.1007/978-94-017-0311-6

Printed an acid:!ree paper

All Rights Reserved © 2003 Springer Science+Business Media Dordrecht

Originally published by Kluwer Academic Publishers in 2003 Softcover reprint of the hardcover 1 st edition 2003

No part of this publication may be reproduced Of

utilized in any form or by any means, electronic, mechanical, including photocopying, recording or by any information storage and

retrieval systern, without written permission rrom the copyright owner.

Table of contents

Foreword

Acknowledgments

Preface

Introduction

Summary chart

CHAPTER I: The origin of mycology

CHAPTER II: The era of discovery: 1894 to 1919

CHAPTER III: The formative years: 1920 to 1949

CHAPTER IV: The advent of antifungal and immunosuppressive therapies: 1950 to 1969

CHAPTER V: The years of expansion: 1970 to 1979

CHAPTER VI: The era of transition: 1980 to 1996

CHAPTER VII: Summary and conclusions

References

Appendix A: Questionnaire analysis summary

Analysis

Tables

Appendix B: Genealogic "Training Trees"

Appendix C: Medical mycology books

Appendix D: Historical publications by other authors

Appendix E: List of questionnaire respondents and interviews

Author Index

Subject Index

v

vii

Vlll

ix

xi

XV

10

23

49

79

101

126

130

143

143

146

149

203

205

206

210

218

Foreword

In our contemporary world, scientific heritage is often forgotten. Many important contributions dur­ing the past 100 years in research, teaching, and diagnosis have had a profound impact upon the evolution of Medical Mycology in the United States.

This book, written by Dr Espinel-Ingroff, makes a significant contribution towards ensuring that those who have laid the foundation for our current Medi-

vii

cal Mycology infrastructure are recognized for their scholarly and authoritative contributions. This book is truly a landmark publication towards ensuring that the past, present, and future are connected to each other.

Libero Aje/lo, Ph.D Michael R. McGinnis, Ph.D

Acknowledgments

The invaluable editorial assistance and creative reinforcement of my husband, David Ingroff, was especially important during the preparation of this book. Special thanks go to Drs Libero Ajello, Michael McGinnis, and William Blake for their support, guidance, encouragement, and continuous editorial assistance. I would like to thank the numer­ous medical mycologists who responded to the questionnaire and/ or made themselves available for interviews. Also, Drs Glenn Bulmer, Timothy Cleary, Arthur DiSalvo, Judith Domer, Norman Goodman, Morris Gordon, Carlyn Halde, Richard Hector, Dexter Howard, Leo Kaufman, George Kobayashi, Kyung Joo Kwon-Chung, Geffrey Land, Donald MacKenzie, Thomas Mitchell, John Rippon, Stanley Rosenthal, Ira Salkin, Wiley Schell, Margarita Silva-Hutner, Jim Sinski, Paul Szaniszlo, John P. Utz, and Mrs Norman Conant provided invaluable archival documents, personal papers, photographs and unpublished historical documents that gave greater depth to this study.

viii

I owe a debt of appreciation to the following individuals for their assistance during the gathering of the data including the mailing of the question­naires: Drs Michael Rinaldi and William Merz, President and Treasurer, respectively, of the Medical Mycological Society of the Americas in 1994; the Medical College of Virginia Tompkins McCaw's Library week-end staff and the Library Interloan Service; J. Kerr, Archivist of the American Society for Microbiology; Drs W. Dismukes and M. Saag and Ms C. Thomas of the NIAID, Mycoses Study Group; Dr Dan Sheehan and T. Webster of Pfizer Inc., USA, Pharmaceuticals and Mr. Robert Scott from Merck, US Human Health. Sincere apprecia­tion is due to Ms Joan Peters for her secretarial assistance during the preparation of this manu­script.

Finally, special recognition is due Dr Arthur DiSalvo, whose persistent support was most valu­able in accomplishing the publication of this book.

Preface

The genesis of this work began with my desire to determine how medical mycology has developed as a science in the United States. This idea evolved from my search for a topic for my doctoral dissertation. My original idea was to conduct historical research on the development of antifungal drugs, which has been the primary focus of my career for the last twenty years. However, when I attempted to obtain access to archival documents from pharmaceutical companies involved in the development of such drugs, both in Europe and the United States, their uniform response was that such archives were closed to individuals outside the company. At this point, although it appeared to be a formidable task, I decided to broaden my research and investigate the development of the discipline in this country. Next, I determined the extent that this investigation was needed and who would utilize the results. During the 1993 Focus on Fungal Infections meeting in Tucson, Arizona and the Conference on Candida and Candidiasis in Baltimore, Maryland, I con­ducted informal interviews with medical mycology leaders who were involved in patient care, research, and the training of future medical mycologists. I also interviewed retired leaders by phone. My initial findings were that most of these medical mycologists had a number of concerns regarding the current state and future development of the science in this country.

Since the beginning of the 1990s, the perception was that the discipline was changing rapidly and that training and research programs in medical mycol­ogy were decreasing in number and scope in the United States. On the other hand, a significant increase in the incidence and prevalence of nosoco­mial yeast and mould infections has been evident. As a result of improved management protocols, AIDS and other immunosuppressed patients live longer, but remain highly susceptible to life-threatening opportunistic fungal infections. Since it is not man­datory that physicians and other health care profes­sionals report mycotic diseases, it is difficult to compare their incidence and prevalence with that of other infectious diseases. Leaders in the field felt that additional trained personnel were essential to respond to the increased incidence and prevalence

ix

of debilitating and fatal fungal diseases. In the area of research development, the concern was that medical mycology had not made the necessary transitions at the same pace as the other branches of microbiology in the 1970s, when research moved from the whole organism to its molecular biology and genetics. Medical mycologists also became uncertain regarding the sources of funding for train­ing and research because of the significant decreases in these funds that began in the early 1980s. With these issues in mind, I conducted a historical inquiry into the development of the discipline, which pro­vided insights into why and how its development and progress had been affected during the last I 00 years.

What is the field of medical mycology? This discipline is concerned with the study of medically important fungi and fungal diseases in humans and other animals. With this description of medical mycology in mind, this book may serve as a refer­ence tool or a source of learning about the discipline for individuals who are interested or involved in the different aspects of medical mycology: patient man­agement; clinical, basic, and applied research; laboratory diagnosis; as well as education and train­ing. It will also be a reference book for medical, microbiology and medical technology students. It provides overall and detailed chronological descrip­tions of the most significant scientific, educational, and technological medical mycologic events that took place from 1894 to 1996 in the United States.

What other publications could supplement the information provided in this book? A search of the literature revealed that there are no comprehensive historical studies of the development of medical mycology in the United States. Uncovered were a few monographs and a number of obituaries regard­ing pioneer American medical mycologists and works concerning certain epochs and topics in this country and Europe. Some of these publications are chronologies that are considered summary general­izations by historians. In addition, my interviews indicated that efforts were made in the 1980s to publish a biographical book regarding medical mycology's pioneers up to 1960. However, it appears that financial difficulties precluded publication of that work. Important information was obtained

X

from several of these unpublished chapters and other historical publications cited in the list of references. In 1986, Ainsworth published his Introduction to The History of Medical Mycology and Drouhet published in 1992 a handbook on mycology that included an introductory chapter on the history of education and

training in medical mycology worldwide. These works, however, do not provide an in-depth con­sideration of any particular country or area. Appen­dix D briefly summarizes these and other related publications.

Introduction

Fungal infections occur throughout the world, but some of them are more predominant in certain geographic areas. Although fungal diseases usually are not considered to be as common as bacterial and viral diseases, they are frequently associated with severe morbidity and mortality. Among the super­ficial fungal infections, tinea pedis (athlete's foot) and pityriasis versicolor are among the world's most common diseases.

The increased frequency and severity of mycotic diseases have prompted greater research efforts in the development of antifungal drugs. However, despite those efforts, in 1996 there were only six antifungal drugs licensed in the United States for use against systemic fungal infections. Furthermore, the newer candidate drugs required further evalua­tion of their efficacy because their spectrum of effect and application in the eradication of the various mycoses remained unanswered. The need for more effective, economical, less toxic, and easier to admin­ister antifungal agents to treat systemic fungal infec­tion was clearly evident. The evaluation of new compounds and management approaches demanded more training and research programs.

It never has been easy to acquire formal training in medical mycology. The training of a medical mycologist has been considered a twentieth century innovation. As the incidence of fungal diseases increases, there is clearly a need for more and better trained individuals. Two concerns require immedi­ate attention: the replacement of the diminishing number of senior mycologists and the provision for broader based multidisciplinary training programs to better meet the new challenges ofthe 21st century. More training programs should be established at both the pre- and postdoctoral levels with molecular biology as a major component. These endeavors demand the provision of more financial support and allocation of other key resources to medical mycology in this country.

The largest portion of federal funding for health oriented research is administered through the National Institutes of Health (NIH). Kennedy's (1990) analysis of policy effects on federal support of health research revealed several negative regula­tory factors. Although appropriations for NIH grew

xi

steadily during the decade of 1980 to 1990, expendi­tures for training and research contracts decreased. Direct NIH investments in training rose slightly, but fell dramatically when discounted for inflation. Expenditures for research related to AIDS accounted for approximately 20% of the overall extramural programs, while other training and research contracts declined. As governmental sources of funding are reduced, the academic and medical communities seek more support for educa­tional and research activities from industry. These developments have led to closer collaborations between academic and corporate researchers. Due to varying economic conditions in the future, corpo­rate funding can be expected to become even more restricted and difficult to obtain.

What has been the trend for funding of medical mycological training and research? In the beginning of this century, philanthropic and private organiza­tions (e.g., the Harvard Traveling Fellowship, the College of Physicians, the Rockefeller Foundation, and the Brown-Hazen Foundation) provided grant support for training and research in medical mycol­ogy. However, those contributions were usually small and generally had ceased to exist by 1996. At that time, some fellowships and grants for medical mycol­ogy were being supported by Pfizer Inc., US Pharma­ceuticals Group and Janssen Pharmaceutica.

The purpose of this study was to investigate, in a historical context, the development of medical mycology training and research in the United States. The development of this discipline has been assessed within the context of scientific progress, as demon­strated by the creativity and scholarly contributions from training, research, and technological activities directed toward the control of fungal diseases. The study covers the historically significant, as well as decisive educational, scientific and technological events that have guided the development of medical mycology in this country since the late 1800s. It includes key figures who led the field and the effect of their ideas and visions on the evolution of the discipline. However, the scope of this book does not include two important fungal pathogens, Paracocci­dioides brasiliensis and Pneumocystis carinii. The former is important in those areas of Latin America

xii

where it is endemic, and the latter was considered phylogenetically closely related to fungi only in the late 1980s.

Narrative description was the first phase of this study and it involved the critical evaluation of documents to uncover significant facts. The narra­tive description was accompanied by an analysis of the causes of historical events that actually took place during those first 100 years, some reasons for related human behavior, and the perceived impact on the development of the discipline in the United States from the late 1880s into the 1990s.

The process of choosing what is considered sig­nificant in historical research is called the method of selection by historians. For the present study, the selection involved the filtering of the facts that explained the causation of the events relevant to what was important to the development of the discipline. It was performed according to factual data and the social value being assessed, which was defined as the control of fungal diseases.

This study analyzed changes in the foci of training and research, the composition of groups, the institu­tions that resulted (scientific societies, research groups), and past and present leaders. Both the uniqueness and the commonness of the events were investigated. The commonness allowed the grouping of related events or the categorization of the events by the identification of similar features. The major contributions of past and current medical mycology leaders also were evaluated by themselves (if alive) and others through the questionnaire. The groupi~g and the identification of unique characteristics sug­gested problems, helped categorize the data, and stimulated the formulation of conclusions. These analyses also helped to explain new directions in which the discipline was moving.

The use of concepts helps historians to avoid erroneous or oversimplified causative explanations. Two concepts, defined as the abstract ideas that refer either to a class of phenomenon or to certain characteristics that phenomena have in common, were used to generate data on the influence of an individual on the direction and career of others. One concept was the formal training connection, with special attention to the influence of major professors on students in their masters and doctoral programs in medical mycology. The other concept was either informal training and mentorship, or a combination of both, where the influence was not connected with a formal degree, but was regarded by the respondent

as vital for his/her career and development as a mycologist. "Training Trees", Appendix B were then created to reflect the genealogy of the discipline. They provide a model to display the information gathered on the training and education of medical mycologists in the United States.

A number of data sources were examined for relationships between specific contributions and the knowledge derived and disseminated. For the scien­tific contribution sections, the data collection focused on selected published papers of significant scientific and technological events. Such sources are usually considered secondary sources in historical studies, but they are regarded in this book as direct records of the era in which they were published. More than 2000 scientific articles were examined, the selected ones are listed in the references. The criteria used to select the articles focused on first contributions such as: the first description of a fungal disease or fungal pathogen, pertinent mile­stone publications from outside the United States, the development of antifungal agents and their evaluation, the establishment of therapeutic regi­mens, the resolution of taxonomic issues, useful laboratory diagnostic tests, important technological inventions, trends or events that changed the direc­tion of the discipline, and discoveries that led to meaningful future research breakthroughs. No reviews or books will be found among the references because only articles describing original discoveries were used as data sources. However, important medical mycology books were reviewed and an annotated list is included under Appendix C.

Other primary sources comprised materials such as the minutes and bulletins of the Medical Mycolo­gical Society of the Americas (MMSA), archival material from the American Society for Microbiol­ogists (ASM), and the personal files of medical mycologists. The latter sources included correspon­dence pertaining to their research and training experiences and their curriculum vitaes. The first training and research programs in medical mycol­ogy originated at Columbia University and Duke University. The Duke University archival materials were not available, however, a training grant propo­sal describing this training and research program since its establishment was provided by Thomas Mitchell. Archival material from Columbia Univer­sity that related to medical mycology was obtained from Margarita Silva-Hutner. The available unpub­lished chapters on the history of Medical Mycology

at Tulane University and biographies of early leaders as well as numerous obituaries were examined and listed under References. The unpublished chapters are archival documents of the MMSA and were provided by Morris Gordon.

Oral history has been used as a primary source in other historical studies. This primary information source represents living resources or participants. Thirty-seven medical mycologists were carefully selected and interviewed to obtain their views and accounts of their work. This oral history helped to support other documents and provided useful in­depth perceptions of un-published information regarding the impact of training on the field.

Questionnaires are valid data sources in historical research and have been used previously to determine the degree of involvement in training and research activities. This study included an open-ended, infor­mal questionnaire that was answered by 100 of the 275 medical mycologists listed as members of MMSA living in this country and by 11 of the 36 physicians listed in 1993-94 as members of the National Institute of Allergy and Infectious Dis­eases, Mycoses Study Group (NIAID-MSG). The questionnaire provided invaluable information regarding the institutions where medical mycolo­gists have received formal or informal training ("Training Trees", Appendix B). It also contained questions concerning the availability of funding, the current state of the science, and the changes deemed necessary for further advancement of medical mycology. In addition, the perceptions of the respondents regarding important contributions and contributors to the development of the discipline in this country were provided (Tables 3 and 4). A summary of the analysis of the questionnaire is attached (Appendix A). The "Trees" were displayed during the 1995 and 1996 MMSA annual meetings and were reviewed and revised as necessary. How­ever, this genealogical listing should not be consid­ered exhaustive as it only reflects the information the author obtained from her efforts as noted.

I conceptualized the development of medical mycology into five periods, or "eras", according to changes in direction resulting from various scientific and educational contributions: (a) the "Era of Dis­covery", 1894 to 1919, (b) the "Formative Years", 1920 to 1949, (c) the "Advent of Antifungal and Immunosuppressive Therapies", 1950 to 1969, (d) the "Years of Expansion, 1970 to 1979 and (e) the "Era of Transition", 1980 to 1996. This book is

xiii

structured around these eras as the following chap­ters discuss the origin and the development of medical mycology in the United States. The impor­tant milestone events that span these eras have been summarized in a table at the end of this Introduction under the title, "Developmental Eras in the History of Medical Mycology in the United States, 1894 to 1996".

Chapter I

Historically many fungi had been known before their role in animal and human diseases was dis­covered between 1835 and 1841. These early dis­coveries led to other important studies, both in Europe and Latin America, from that period into the early 1900s. Chapter I describes in detail those original contributions to medical mycology, or its "roots".

Chapter II

The "Era of Discovery" explores the key figures and their first descriptions of important mycotic diseases in the United States from the 1894 to 1919. The recognition of fungi as etiologic agents of systemic diseases by physicians, who were not trained as medical mycologists, marked the beginning of the discipline in this country. But, historical studies of key figures from related sciences during this period, considered the golden era of microbiology, have not acknowledged the value of these contributions to the study of infectious diseases. Even today the impor­tance of fungal diseases in public health is over­looked. The intent of this book is to assess the impact of those early medical mycology discoveries.

In 1987, Kass divided the history of the specialty of infectious diseases in this country into three broad phases. His first phase is the "colonial era" when "every physician was necessarily an infectious dis­ease specialist" (p. 745). The second phase encom­passes the years of the first discoveries of the microbial causes of disease. The third phase began with the advent of specific chemotherapeutic treat­ment after World War II, the era of the antibiotics. Kass' second phase closely corresponds to the origin of medical mycology in the United States. This book's "Era of Discovery" also corresponds with K.S. Warren's (1990) first developmental period for tropical medicine, which he considered a product of the colonization of the tropics.

xiv

Chapter III

This chapter describes the beginning of medical mycology training programs and the establishment of research laboratories during the formative years of the discipline from 1920 to 1949. Key pioneers during this era provided more logical classification systems that improved the scientific investigation of human fungal pathogens. Their epidemiologic stu­dies facilitated the differentiation between infection and disease, thereby improving the understanding of the natural history of systemic mycoses. Beginning in the late 1920s, continuing throughout the 1930s, World War II, and the late 1940s, leaders in the field trained the second generation of medical mycolo­gists and ensured that medical mycology continued its development in this country as a distinctive field of medicine.

Chapter IV

Chapter IV deals with the third developmental era, the "Advent of Antifungal and Immunosuppressive Therapies", which began with the discovery of nystatin in 1950 and amphotericin B several years later. This era corresponds with Kass' (1987) third phase in the development of the specialty of infec­tious diseases. That phase began with the advent of specific chemotherapeutic treatments after World War II, the era of antibiotics. However, the "Advent of Antifungal and Immunosuppressive Therapies" is a more complex period in medical mycology. This period encompasses the initiation of renal trans­plantation in conjunction with the use of immuno­suppressive therapy for oncology patients and to avoid organ rejection.

Chapter V

During the 1970s, the "Era of Expansion", the direction of medical mycology's development chan­ged as a consequence of the increased incidence of mycoses in immunosuppressed patients and impor­tant advances in technology. With the commitment of sizable new revenue sources, the discipline saw new centers and programs established, as well as a major emphasis in educating and training the "third generation" of molecular-based medical mycolo­gists. In terms of commitment of resources and the number of scientists dedicated to the field, this era is considered the high water mark period to date for

medical mycology in the United States. Built on the 1950s and 1960s, rapid advances in transportation and communication occurred during the 1970s, as well as public acceptance in utilizing them, a trend that escalated in the 1980s and 1990s. The latest technological discoveries and the experts behind them became more accessible. All of these events directly impacted the discipline.

Chapter VI

This chapter deals with the "Era of Transition" between 1980 and 1996 when the much higher incidence of human mycoses, because of the AIDS pandemic, again brought major changes to the discipline. During this era, research in molecular biology, cellular immunity, and genetics was either initiated or intensified and DNA-based diagnostic tests and epidemiologic tools were developed. Recent developments within the discipline of micro­biology have often resulted from discoveries using molecular tools and the knowledge that DNA is a repository of genetic information. A large number of microbiologists as well as medical mycologists reor­iented their research direction from the microbiolo­gic aspects of fungal molecular models to their cellular functions. In 1986, Beeson compared these scientific developments to the "golden age of micro­biology" in the late 1800s when bacteria were recognized as etiologic agents of disease. During that era, the fundamental phenomena of immunity also were recognized. The invention of the micro­scope played an important role in the earlier devel­opment of these microbiologic disciplines, but has had limited importance in contemporary times. The impact of these advances and how medical mycol­ogy has kept abreast with technology, as have related sciences, is accessed in this chapter. Another sig­nificant trend of this era was the retirement and death of numerous leaders in the field. Coupled with the major reductions in governmental and founda­tion funds, the result was a major shift in leadership and a much stronger emphasis on collaborative research.

Chapter VII

This chapter summarizes the five developmental eras of medical mycology in the United States and provides specific conclusions drawn from this his­torical study.

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ing

and

the

decl

ine

and

clos

ing

of

esta

blis

hed

trai

ning

pro

gram

s (b

) L

eade

rs r

etir

ed o

r di

ed b

ut w

ere

not

repl

aced

at

thei

r in

stit

utio

ns

(c)

Res

earc

hers

bec

ame

mor

e sp

ecia

lized

, fo

cusi

ng o

n sp

ecif

ic a

spec

ts o

f fun

gal

dise

ases

(d

) L

eade

rshi

p tr

ansi

tion

to

new

and

col

labo

rati

ve g

roup

s fo

rmed

with

sci

entis

ts f

rom

oth

er m

edic

al d

isci

plin

es

(e)

Init

iati

on a

nd e

xpan

sion

of b

asic

res

earc

h in

mol

ecul

ar b

iolo

gy a

nd g

enet

ics

and

expa

nsio

n o

f oth

er s

tudi

es f

unde

d m

ostl

y by

NIH

(f

) A

ppli

cati

on o

f D

NA

-bas

ed m

etho

dolo

gies

res

ulte

d in

acc

urat

e an

d ra

pid

diag

nost

ic l

abor

ator

y te

sts

and

relia

ble

epid

emio

logi

c to

ols

(g)

Pro

visi

on o

f sta

ndar

ds fo

r an

tifu

ngal

sus

cept

ibil

ity

test

ing

and

esta

blis

hmen

t o

f bet

ter

ther

apeu

tic

regi

men

s fo

r ce

rtai

n sy

stem

ic d

isea

ses

in p

atie

nts

with

or

wit

hout

AID

S s

uppo

rted

by

phar

mac

euti

cal

and

corp

orat

e fu

nds

Ada

pted

fro

m E

spin

el-I

ngro

ff,

Clin

Mic

robi

ol R

ev 1

996;

9:

235-

272.

:;j