The Butantan Institute: History and Future Perspectives

Abstract

The Butantan Institute, as one of Brazil's most prestigious scientific institutions, generates new knowledge through scientific research, develops and produces immunobiological and biopharmacological products of interest to public health, educates and trains human resources in the areas of science and technology, and seeks to stimulate scientific knowledge and understanding among the general population. With 113 years of existence marked by numerous technological advances directed towards public health issues, the Butantan Institute is considered one of the major scientific centers in the world.

Full text

Historical Profiles and Perspectives
The Butantan Institute: History and Future Perspectives
Marcelo De Franco*, Jorge Kalil
Instituto Butantan, Sa
˜o Paulo, Sa
˜o Paulo, Brazil
The Butantan Institute, as one of
Brazil’s most prestigious scientific institu-
tions, generates new knowledge through
scientific research, develops and produces
immunobiological and biopharmacologi-
cal products of interest to public health,
educates and trains human resources in
the areas of science and technology, and
seeks to stimulate scientific knowledge and
understanding among the general popula-
tion. With 113 years of existence marked
by numerous technological advances di-
rected towards public health issues, the
Butantan Institute is considered one of the
major scientific centers in the world.
In 1900, a commission formed by three
respected physicians and specialists in
public health diseases: Dr. Emı
´lio Ribas,
director of health services for Sa˜o Paulo
State; Dr. Adolpho Lutz, director of the
Bacteriological Institute; and Dr. Vital
Brazil, an assistant of Dr. Lutz at the
same Bacteriological Institute, proposed
the creation of a Serum Therapy Institute
in Sa˜o Paulo to be installed at Fazenda
Butantan, a locality distant from the state
capital at that time. The foundation and
direction of the Serum Therapy Institute
of Sa˜o Paulo State (the current Butantan
Institute) was assigned to Dr. Vital Brazil
Mineiro da Campanha, with the immedi-
ate responsibility of producing a serum to
be used in combating the epidemic of
bubonic plague afflicting the country at
that time [1]. The Institute was officially
established on February 23, 1901, when
Dr. Vital Brazil was designated as its first
director (Figure 1). The first vials of anti-
bubonic-plague serum were produced in
June of that same year, and the Institute
has continued its work over the years in
many different areas, becoming known as
an important producer of several anti-
ophidic serums and a groundbreaking
scientific institute [2]. In parallel, Vital
Brazil worked with snakebite accidents
and studied venom and antibody antive-
nom interactions.
The evolution of the Butantan Institute
can be summarized in four main periods.
The administration of Vital Brazil (1901 to
1927) was accompanied by large invest-
ments in staffing, scientific research, and
the construction of laboratories and an
antiserum factory—in the same international
context as Louis Pasteur’s microbiology
studies and discussions about the specificity
of antivenom antibodies. Based on the
correlation between the severity of the
bite-site inflammation and the snake genus,
Vital Brazil was the first to show that snake
venom ordinarily displayed antigenic spec-
ificity. After reading a report of Calmette’s
anti–Naja tripudians serum [3], he was able
to produce monovalent serums against the
venoms of Bothrops jararaca and Crotalus
durissus terrificus. Vital Brazil also tested
and demonstrated the inefficiency of Calm-
ette’s anti-Naja antiserum for neutralizing
Crotalus or Bothrops toxins [4]. The three
pillars of success of the Butantan Institute
have been preserved and strengthened
since its creation: research, production,
and the popularization of science.
The second phase of the Institute
(1930–1970) was greatly influenced by a
series of authoritarian governments, the
Second World War, the organization of its
pharmacology and pathophysiology labo-
ratories, and the arrival of many foreign
researchers (including Henry Slotta from
the University of Breslau, Germany, who
discovered the female hormone progester-
one and succeeded in isolating crotoxin,
the toxic protein in rattlesnake venom) [5].
The first universities and agencies pro-
moting research in Brazil (National Coun-
cil for Scientific and Technological Devel-
opment [CNPq] and Foundation for
Research Support of the State of Sa˜o
Paulo [FAPESP]) were created in the
1930s. A period of crisis later befell the
Butantan Institute between 1940 and
1960, with a lack of funding and successive
ineffective administrations. The National
Immunization Program, created by the
federal government in 1973, enabled public
producers of serums and vaccines to
organize and modernize their laboratories
and factories, and during the 1980s,
large investments were made in the
Butantan Institute and the Oswaldo
Cruz Foundation (FIOCRUZ) to achieve
self-sufficiency in the production of
vaccines and antibodies against venoms
and toxins. During this period, the
Butantan Foundation was created to
facilitate the management of public
resources, and the Biotechnology Center
was established to develop new vaccines
and serums. Two very successful devel-
opments can be cited for this period: the
development of the hepatitis B vaccine
and the modernization of the production
processes for sera against poisons and
toxins. This period also saw the initiation
of partnerships with the private sector,
including technology transfers for the
production of influenza vaccine at Sanofi
Pasteur. Regulatory frameworks for pub-
lic health were initiated in Brazil starting
in the year 2000, but public laboratories
did not adjust to these legislative man-
dates, and a scarcity of resources (due to
national and international economic crises)
handicapped the leading research and
production institutes, including the Butan-
tan Institute. A major fire in the zoological
collections building in 2010 was a huge loss
to the scientific community.
In 2011, we assumed direction of the
Institute; we then promoted a series of
governance studies and developed a mas-
ter plan for the expansion and profession-
alization of the administration of the
Institute and its Foundation in order to
better coordinate both. Our main goals
were to establish a new organizational
chart for the Institute, enhance public-
private partnerships, and intensify inter-
national exchanges.
Today, the Butantan Institute, linked to
the secretary of health of Sa˜o Paulo State,
has the mission of developing biological
Citation: De Franco M, Kalil J (2014) The Butantan Institute: History and Future Perspectives. PLoS Negl Trop
Dis 8(7): e2862. doi:10.1371/journal.pntd.0002862
Editor: Serap Aksoy, Yale School of Public Health, United States of America
Published July 3, 2014
Copyright: ß2014 De Franco, Kalil. This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
Funding: The authors have indicated that no funding was received for this work.
Competing Interests: The authors have declared that no competing interests exist.
* Email: marcelo.franco@butantan.gov.br
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products for public health, undertaking
basic and applied research, and promoting
scientific knowledge. The Institute cur-
rently provides 40% of the nationally
produced serums and vaccines that are
distributed without cost to the entire
population of the country by the Brazilian
Health Ministry (Figure 2) through the
Unified Health System (SUS).
World renowned for its studies of
poisonous animals and the venoms and
toxins they produce, the Butantan Institute
has always attracted scientific leaders who,
together with researchers and postgradu-
ate students, develop research projects in
many different areas. Isaias Raw, Antonio
Camargo, Willy Bec¸ak, Ivan Motta, Wil-
mar Dias da Silva, Luiz Trabulsi, and
Maria Siqueria, among others, have
developed projects related to vaccine
production [6–9]; the biology and system-
atic classification of serpents, arthropods,
and parasites; the biochemistry and phar-
macology of venoms and their compo-
nents; the physiopathology of venoms [10–
15]; immunology in response to exposure
to venoms and pathogenic microorgan-
isms; the genetic basis of immune respons-
es; and the cytogenetics and genetics of
poisonous animals [16], and a number of
important reviews have been published in
those fields [17–24].
The Butantan Cultural Development
Center counts among its activities intellec-
tual diffusion and research based on
education, museology, and the history of
science and public health and focuses on
projects promoting scientific discoveries
generated within the Institute, providing
material for consultation in its documen-
tation nucleus and library, and creating
museums and educational programs. The
Cultural Development Center has four
museums—Emilio Ribas, Biological, Mi-
crobiological (Figure 3), and Historical—
and is likewise responsible for coordinating
temporary and itinerant exhibitions that
attract more than 300,000 visitors each
year.
The Research and Production Centers
of the Butantan Institute include 35
scientific laboratories, a Center for Tech-
nological Innovation, a specialized hospi-
tal (Hospital Vital Brazil), three animal
facilities (one each for mammals, spiders,
and serpents), seven vaccine production
centers (including one for veterinary use),
one center for plasma fractioning, and 11
bioproduct manufacturing sites. These
research and production centers employ
approximately 191 researchers, with 420
additional master’s, doctoral, and postdoc-
toral students who undertake scientific
missions within the country and through-
out the world through the auspices of the
World Health Organization (WHO), the
Pan American Health Organization
(PAHO), the United Nations Children’s
Fund (UNICEF), and the United Nations
(UN) (Figure 4). Fully focused on the
development of scientific research and the
production of immunobiologicals used in
public health campaigns, the Butantan
Institute produces publications available
for unrestricted consultation in all of its
areas of action and offers internships as
well as extension and postgraduate courses
(MS, PhD, and MBA).The Butantan
Institute has two PhD courses: Toxinology
and Biotechnology (the latter offered in
association with the University of Sa˜o
Paulo).
Figure 1. The Butantan Institute was founded in 1901, with Vital Brazil as its first
director.
doi:10.1371/journal.pntd.0002862.g001
Figure 2. The Butantan Institute is one of the main public producers of serums and
vaccines in Brazil. Abbreviations: Bi, billion; FAP, Fundac¸a
˜o Ataulfo de Paiva; FUNED,
Ezequiel Dias Foundation; MM, millions; MOH, Ministry of Health; OPAS, Organizac¸a
˜o
Panamericana de Sau
´de; TECPAR, Institute of Technology of Parana
´.
doi:10.1371/journal.pntd.0002862.g002
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The productive complex of the Institute
has dominated the technologies required
for producing at least 12 types of serums
and seven vaccines (Figure 5) utilized by
the Brazilian Health Ministry [25] and has
been working with technology transfer
from public and private producers in
industrialized countries as well as on its
own independent production innovation
and the development of technologies for
vaccine production.
Technology transfer is a complex,
multifaceted, and delicate process that
involves not only transferring basic knowl-
edge but also techniques for quality
control and quality guarantees, the dom-
ination of regulatory processes, clinical
studies to guarantee the adequacy of the
products, and the capacity to adapt to
local conditions, all done while renovating
and updating production facilities to
international quality standards. The Bu-
tantan Institute industrial complex was
installed in 1998 and inaugurated in 2007;
it is capable of producing vaccines against
various influenza virus subtypes, such as
H1N1, swine flu, H5N1, and avian flu.
Just four years later in 2011, the Institute
delivered the first lot of vaccines against
influenza entirely produced in Brazil and
received a certificate of good production
practices from the Brazilian National
Agency of Public Health (ANVISA) in
2012. This was the first successful techno-
logical transfer completed in Brazil be-
tween Sanofi-Pasteur and the Butantan
Institute [26]. Three new agreements were
recently signed between international lab-
oratories and the Butantan Institute for the
development and production of vaccines
against human papillomavirus (HPV) and
hepatitis A with Merck Sharp & Dohme
(MSD) and against acellular pertussis with
GlaxoSmithKline (GSK) through technol-
ogy transfer.
Additionally, the Butantan Institute
independently produced a trivalent vac-
cine against diphtheria, tetanus, and
pertussis (whooping cough) as well as a
vaccine against hepatitis B in the 1980s
[25].
A number of international agencies
have demonstrated interest in Brazil in
terms of producing and furnishing vac-
cines, with demand from Colombia and
some African countries for technology
transfers and collaboration agreements to
produce Butantan antiserums. Additional-
ly, researchers from the Butantan Institute
are working through grants provided by
financing agencies (FAPESP, Coordina-
tion for the Improvement of Higher
Education Personnel (CAPES), CNPq,
the Brazilian Development Bank
(BNDES), and the Fulbright Foundation)
on various projects in cooperation with
scientists from various international insti-
tutions [27].
The technical competency of the Bu-
tantan Institute and its investments in
upgrading its production facilities to both
national and international standards (the
Food and Drug Administration [FDA],
WHO, and ANVISA) has stimulated
interest in partnerships with international
universities and other institutes dedicated
to public health. Examples of these
partnerships and developing projects in-
clude collaboration with the National
Institute of Health (NIH), for the production
of vaccines against rotavirus and the dengue
virus; the Boston Children’s Hospital at the
Harvard Medical School, for developing a
vaccine against pneumococcus; the Sabin
Figure 3. The Butantan Institute Cultural Center—Microbiology Museum.
doi:10.1371/journal.pntd.0002862.g003
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Institute and George Washington Universi-
ty, for developing a vaccine against schisto-
somiasis (the parasites Necator and Schistoso-
ma); and the Infectious Diseases Research
Institute in Seattle and the University of
Washington, for developing a vaccine
against canine leishmaniasis.
The prestige of the Butantan Institute in
the area of toxins produced by animals
and microorganisms was decisive in its
hosting of one of the Centers for Research,
Innovation and Diffusion supported by
FAPESP since 2002—the Center of Ap-
plied Toxinology. This program was
developed to fund institutions with proven
capacity in attaining world-class research
levels. The initial program was quite
successful, and FAPESP approved a new
challenge in 2013—the Center for Re-
search in Toxins, Immune Responses, and
Cellular Signaling—that would concentrate
on studies concerning the biochemical,
molecular, and cellular action mecha-
nisms of toxins demonstrating therapeu-
tic potential, with the objective of
establishing proof of concept based on
the analyses of molecular signaling net-
works. Strategic planning calls for the
results of these research projects to be
transferred to industry through processes
mediated by the Technology Innovation
Office of the Butantan Institute.
The Butantan Institute is currently pro-
posing the creation of the Butantan Institute
for Biotechnological Innovation (IIBB) to
use its accumulated technical-scientific
experience in an institutional manage-
ment system designed to promote agility
in the administration of innovation. An
international committee composed of
renowned scientists is currently being
formed that will analyze all of the
research lines of the Institute and, togeth-
er with the directory, propose a strategic
plan for the next ten years and reorganize
all of the research groups in the IIBB that
are involved in research and develop-
ment. This is one of the Institute’s most
important programs for the future, as it is
designed to promote interactions with
private partners for the development of
its discoveries and innovations and the
incorporation of new products into ac-
tions directed toward public health. This
Figure 4. Scientific research and development laboratory at the Butantan Institute.
doi:10.1371/journal.pntd.0002862.g004
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program proposes a new juridical model
(special autarchy) for the Institute, de-
signed to achieve autonomous adminis-
trative governance, combining Institute
and Foundation to promote scientific
research, technological development, and
the production of vaccines and immuno-
biologicals in Brazil.
Our greatest efforts will always be
directed towards maintaining the highest
levels of excellence in research, develop-
ment, and the production of vaccines and
serums and guaranteeing the position of
the Butantan Institute as a bridge between
research and production so that Brazil will
stay at the forefront of progress in public
health considerations.
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