The birth and development of biomedical research in Lisbon (Dactilografado - s/data)


The birth and development of biomedical research in Lisbon

(publicado em português em DAVID-FERREIRA, José Francisco, "Nascimento e consolidação da investigação biomédica em Lisboa", In Constantino Sakellarides e Manuel Valente Alves (eds.), Lisboa, Saúde e Inovação. Do Renascimento aos dias de hoje. Lisboa, Saúde e Inovação, Editora Gradiva, 2008, pp. 205-212.

O texto "Advento e Consolidação da Investigação Bio-médica em Portugal. Contribuição da escola de Histologia de Lisboa" é uma versão mais extensa destes dois)



J. F. David-Ferreira
Medical physician and emeritus professor of the Faculdade de Medicina da Universidade de Lisboa

Scientific medicine, like all modern science, was born and developed in Europe. It was a long and slow process that started to gather momentum during the 16th century.

Vesalius' (1514-1564) De Humani Corporis Fabrica, published in 1543, revolutionised medical teaching at the time and is now considered one of the cornerstones of medical literature. Past misconceptions and errors were put right and anatomy took its place as an essential university subject in the training of physicians and surgeons.

After Vesalius, the 17th and 18th centuries saw great progress throughout Europe. It is important here to highlight the works of Harvey (1578-1657), Malpighi (1628-1694) and Morgagni's (1682-1771) for their influential contributions to the advancement of medical science and research.

Harvey's work Exercitatio Anatomica de Motu Cordis et sanguinis in animalibus, published in 1628, leads the way in the investigation of the functional significance of anatomical structures. This marks the beginning of physiology, which would later go on to earn its own place in medical teaching.

Use of the microscope made it possible for Malpighi to venture into new territory with his work in microscopic anatomy, enabling him to describe the thin structure of several organs (lungs, kidney, spleen, skin). He also discovered blood capillaries, thus solving one of Harvey's pending enigmas.

Morgagni's treatise De sedibus et causis morborum. Per anatomem indagatis, published in 1761, starts to take a look at characterising the anatomical changes seen in different pathological states. It's a cornerstone in pathological anatomy and clinical medicine and was to shape medical thinking. It marks the end of dogmatic medicine and the humour theory held by Hippocrates (450-380 BC) and Galen (131-200).

All this progress was marked by the emergence of new subject areas that, by earning a place in medical teaching, ensured their rapid development.
The first half of the 19th century was a particularly productive time: new knowledge and theories changed what was known about the organisation of "living matter" and the nature of disease. Bichat's (1771-1801) tissue theory in his Traité des membranes, published in 1800, is a founding paper in histology, a subject that was to evolve with further use of the microscope.

Schwann (1810-1882) and Schleiden's (1806-1881) demonstration that organisms are made up of cells is one of the foundations of cell theory (1839) and is a prelude to Virchow's (1821-1902) work on cellular pathology. The latter's work not only completes cell theory with his well-known aphorism «onmis cellula et cellula», but also reinforces the whole basis of anatomical and clinical medicine.

Still in the 19th century, S. R. Cajal's (1852-1934) neurone theory and Pasteur (1822-1895) and Koch's (1848-1910) discoveries further develop biomedical science and put an end to the idea of spontaneous generation, promoting instead the germ theory of disease. This is microbiology's greatest triumph, making it the discipline with the biggest and fastest impact on the health of the population.

Two other big theories were announced around the same period, this time without the aid of the microscope: Mendel's (1822-1884) genetic theory of inheritance published in 1855, one of the most important discoveries of the century, and Darwin's (1800-1882) principle of natural selection published in 1859.

Nearly all the conceptual advances and practical successes in biomedical science in the 19th century were the result of successive improvements made to the microscope and the advancement of the techniques used to observe and study cells, tissues and microorganisms. The microscope in its different stages of development, was the instrument that most contributed to the advent of scientific medicine in the 19th century and to its consolidation in the 20th century.

Portugal saw the introduction of microscopy to teaching and its use in medicine relatively late on. Costa Simões (1819-1913) from the Universidade de Coimbra promoted its use and included it in his teaching and May Figueira (1829-1913) from the Escola Médico-Cirúrgica de Lisboa (School of Medicine and Surgery in Lisbon) furthered its use in medical practice.
They both studied medicine under Jerónimo José de Melo (1794-?) at the Universidade de Coimbra and it was he who aroused their interest in microscopy. They travelled and worked abroad (France and England) in order to widen their knowledge and perfect their technique.

May Figueira travelled to Brussels after graduating from Coimbra in 1855 and got his doctorate there. He then went to Paris, which at the time was one of the main medical centres in Europe, and studied under the renowned microscopist Charles Robin at the Collège de France.
On his return to Lisbon of particular note are his contributions to the study of liver pathology in yellow fever, his role as a consultant in tumour pathology and his discovery of pulmonary aspergillosis. In 1859, he became part of the teaching staff of the Escola Médica-Cirúrgica where he lectured in anatomy for one year and clinical medicine for twenty. From the time of his return, May Figueira was always an advocate of laboratory medicine. He held two open courses on microscopy, one in 1863 and the other in 1864, which helped promote its use in medicine despite strong scepticism and criticism of the courses. Miguel Bombarda (1829-1910), then a lecturer in general physiology and histology at the Escola Médica-Cirúrgica continued May Figueira's efforts at the Gabinete de Estudos Histológicos do Hospital de Rilhafoles (Centre for Histological studies in Rilhafoles Hospital), where he was also a director.

Marck Athias (1875-1946), an experienced histologist who studied in Paris at one of the most renowned medical institutes of the time, run by Mathias Duval, and graduated with a thesis on "The histogenesis of the cerebral cortex", was put in charge of the centre's technical department.

The Escola Médica-Cirúrgica de Lisboa, founded in 1836, underwent major changes at the end of the century. A number of lecturers, including Miguel Bombarda and Francisco Gentil (1878-1964), took advantage of the autonomy that the school enjoyed and embarked on a program of self-improvement, which had far reaching consequences on their academic achievements.
Student admissions became more demanding, the curriculum was updated, new subjects were introduced, and lecturers could only apply to teach on one specific subject in an area where they possessed good qualifications.

Bacteriology's successes at the end of the 19th century and the hope which they engendered justified the priority which was now being given to bacteriological investigations and allowed more funds to be allocated to creating laboratories and bacteriological institutes all over Europe.

One such was established in Portugal, the Real Instituto Bacteriológico (Royal Institute of Bacteriology), of which Câmara Pestana (1863-1899) was appointed director. He had started his career as a histology lab technician and at the time of the appointment was in charge of the small bacteriology laboratory in Lisbon.

The 19th century also saw drastic changes in university teaching throughout Europe. In accordance with the idea in place at the University of Berlin, members of staff were now asked to not only transmit knowledge but to also discover new science through research at their university or associated research institutes. Following the Republican revolution of 5th October 1910, the changes that were beginning to be implemented at the Escola Médico-Cirúrgica were helped by the establishment of the Lisbon and Oporto universities and the education reform of 1910. This marked the beginning of the period in which the celebrated generation of 1911 first started to earn acclaim.

Due to pressure from those who were the most aware that the country was scientifically behind the rest of Europe, the Faculdade de Medicina da Universidade de Lisboa (Faculty of Medicine of Lisbon University) was based on the model in place at the University of Berlin, where each subject had a research centre associated to it. Despite having been founded before the University of Lisbon, the Câmara Pestana institute was the first centre to serve that purpose. Later on, after the Faculty had moved to the new Campo Santana building, its offices became known as Institutes.

Marck Athias was appointed head of the Instituto de Fisiologia e Química Fisiológica (Institute of Physiology and Physiological Chemistry) while his assistant, Augustino Celestino da Costa, was appointed to the Instituto de Histologia e Embriologia (Institute of Histology and Embryology). The latter remained in this job until he was made professor emeritus and appointed head of the Escola de Histologia de Lisboa.

Of all the institutes founded after the establishment of the Universidade de Lisboa in 1911 and the transfer of the Escola Médico-Cirúrgica1 to the new faculty building, it was that of Histology and Embryology which remained the most consistently faithful to the ideas behind its foundation. Looking at its evolution up to the end of the century, three periods can be distinguished, each corresponding to a different director: the Institute's founder, A. Celestino da Costa was in charge from 1911 to 1954, during which time the Institute resided in the Faculty building at Campo Santana. From 1954 to 1974 M.J. Xavier Morato (1906-1988) was at the head and from 1974 to 1999 the Institute was run by J. F. David-Ferreira. The last two directors oversaw the Institute at its new location in the Hospital Santa Maria.

When Celestino da Costa and his colleagues began their research, the era of morphological histology was coming to an end. Now the problem was trying to understand the function of the cellular structures that had been observed. This is what Celestino da Costa and his colleagues focused their research on, always bearing in mind the aphorism that "structure is a plastic representation of function".

The institute of histology attracted large numbers of students and doctors, mainly because histology, just like physiology, is a subject area closely related to several medical specialties. The knowledge gained there about the histophysiology of organs and systems was essential for medical training or research for a thesis paper.

Ever since its establishment the Instituto de Histologia e Embriologia was funded by government agencies (Instituto de Alta Cultura, Instituto Nacional de Investigação Científica e Tecnológica, and more recently the Fundação para a Ciência e Tecnologia) whose job was to help the development of science by providing subsidies for financing, new equipment, training and travel grants.

During Celestino da Costa's directorship, the Instituto de Histologia contained the headquarters of the Centro de Estudos Endocrinológicos (Centre for Endocrine Studies), a part of the cultural institute. The centre endorsed a research program into the histophysiology of endocrine glands, an area that was to have a large impact on medicine. Not only did it allow greater numbers of people to train and qualify as physicians and medical lecturers, but it also contributed to the establishment and recognition of endocrinology as a medical speciality.

Besides the histological and embryological work which he carried out at his institute, Celestino da Costa also did some research at the Bento Rocha Cabral institute for scientific investigation, a private institute he belonged to and which possessed means his institute didn't, for example equipment that was necessary for tissue culture.

After his death in 1954, the Instituto de Histologia, now under Xavier Morato, became known as the Centro de Estudos Histológicos Augusto Celestino da Costa (Centre for Histological Studies), in homage to its founder. It was still subsidised by the Cultural Institute, but its research program was broadened with the addition of new lines of investigation.

The new director's strategy was to introduce laboratory techniques which would create new leads in the research projects already under way and perhaps be able to apply them in practice to public health. Three areas were chosen to start work on: 1) electronic microscopy, shown by many publications to be of great importance in microbiology and ultrasctructural cytology; 2) embryonic organ culture for experimental embryology projects and later on for the study of the effects of physical, toxic and pharmacological agents on embryonic development; 3) cytogenetics, where caryotyping became the method of choice for diagnosing congenital diseases. This was an ambitious program, but one which could potentially be of great scientific and medical interest.

With the new electronic microscopy, citogenetics and organ culture labs set up, the institute was able to keep up and even contribute to research carried out at other European biomedical centres in these three areas, even if in other areas it still lagged behind.

All the research assistants and collaborators who participated in these projects were studying towards a doctorate.
The Calouste Gulbenkian Foundation was established as a foundation in 1956, and began its patronage work with astonishing rapidity. A year or less after it was set up, it was already giving out scholarships and subsidizing several institutions. Xavier Morato didn't waste any time in asking the then head of the Foundation, Azeredo Perdigão, for funding to set up the electronic microscopy laboratory at his institute. His arguments behind the request were the importance of developing new technologies in biomedical research and the fact that a researcher had already been appointed and was ready to oversee the technical running of the laboratory.

In September 1956, when I was at the First Regional Electronic Microscopy congress in Stockholm, I received a telegram from Xavier Morato informing me that the Foundation's Administrative Council had discussed his case and agreed to subsidise his project. It was this aid that allowed the laboratory to be established.

The Calouste Gulbenkian Electronic Microscopy laboratory began to be set up in 1957 and was inaugurated, fully operational, in 1958.

From then on the institute began several research projects, both on their own and in collaboration with researchers from other institutes. They also held conferences to divulge electronic microscopy techniques and their applications, and organised hundreds of demonstrations for students and visitors.

David-Ferreira resigned in 1964 due to disagreements on strategy between him and the director. He was replaced by two former interns, first Lille Falcão and later Nascimento Ferreira. From 1979 to 1999 the institute underwent extensive renovation and consolidation of their scientific activity.

After the institutional crisis caused by the revolution, the teaching system had to be reorganised. David-Ferreira, at the time head of the Cellular Biology laboratory of the Gulbenkian Institute of Science (IGC), was invited by the faculty's committee to be a lecturer in biological medicine4, with a curriculum aimed at the scientific training of future doctors.

The creation of a new subject led to a reorganisation of the teaching staff. Assistants were taken on who were training or had trained at the IGC labs and Oeiras Advanced Study Institute, one of the centres where the most advanced cellular and molecular biology techniques were being used.
Once these new assistants arrived the institute had to be reorganised. This was an ambitious project considering the funding and resources needed to adapt the facilities and acquire the new equipment that would be essential for them to carry out their work.

This was all made easier in the 80s with a subsidy from the Gulbenkian (once again) to replace all the electronic microscopy equipment that was outdated, and a second subsidy from the Faculty's Directing Committee to set up another molecular biology laboratory.

This was the "light at the end of the tunnel" they needed, but the real breakthrough came with the launch of the Science Program – considered the jackpot amongst the Portuguese scientific community.
The quality of the work carried out at the IGC and the Instituto de Histologia by the new generation of lecturer/researchers from the Faculdade de Medicina de Lisboa, was crucial to presenting a strong application to the Science Program's competition set up in 1989 for the creation and funding of new research units.

The Instituto de Histologia's initial limitations had been overcome and it now had the required conditions and qualifications to put together a proposal.
The Gabinete de Apoio à Investigação Científica (Scientific Research Support Office) (GAPIC) and the Lisbon University Foundation put forward the idea of creating a Centro de Biologia e Patologia Molecular (Biology and Molecular Pathology Centre) (CEBIP), thus combining some of the Faculty's active departments. The committee charged with making the decision went over the proposal but only approved it for the Instituto de Histologia e Embriologia.

CEBIP was initially made up of three units, each formed by a separate team of researchers led by a unit chief. The three original units were: molecular and cellular biology, cellular immunology and cutaneous biology and pathology. Extra funding later on in 1997, allowed a new unit to be created - Developmental Biology, under the leadership of Domingos Henrique. CEBIP's scientific work focused initially on four ideas:

1) Supramolecular organization of the nucleus. (M. Carmo Fonseca);
2) Distribution and interaction of the cytoskeleton and extracellular matrix (J. F. David-Ferreira);
3) Cellular immunology in immunodeficiency and immunopharmacology (Rui Victorino);
4) Cellular and molecular interactions in human skin (F. Guerra-Rodrigo).

The research projects already underway, some of which had been started at the Gulbenkian Institute of Science, carried on and were enhanced with the arrival of new researchers, interns and grant recipients as a result of more grants, such as Praxis, becoming available. Therefore more and more people were working at CEBIP and taking part in various biomedical groups.

We should mention at this point the shrewd initiative taken by the University's Scientific Council to create biomedical doctorates that allowed non-medical graduates to participate in the university's scientific work. The number of PhD candidates increased significantly due to the resulting wider range of disciplines.
In order to meet demands, the facilities had to be renovated and new labs were created.

Among the new equipment, one important item for the success and progression of the research was a confocal transmission microscope. M. Carmo Fonseca, who oversaw its installation, made sure it functioned properly and provided any necessary improvements, had already worked with one and organized courses to divulge its uses.
Although the confocal microscope still had a few flaws with regard to resolution, it overcame one of the biggest limitations of the normal microscope – it allowed the observation of live cells and had the added advantage that the materials to be observed could be prepared faster.

Research papers published by CEBIP in renowned international journals and the number of projects submitted to and approved by national and European competitions gave it well-deserved promotion and earned it excellent results in all the evaluations it underwent.
In 1999, Decree-Law nº 125/99 instituted "associated laboratories" which opened new horizons for the centres created by the Science Program.
The approval of CEBIP's application to become an associated laboratory was the beginning of the establishment of the do Instituto de Medicina Molecular (Institute of Molecular Medicine) (IMM), a project that had lain dormant since 1998 and that was made possible by the association of some of the University's research centres and units.

The establishment of the IMM in November 2001 represented the culmination of a process whose goal was to give the Faculdade de Medicina the means, both instrumental and human, to introduce, apply and develop modern cellular and molecular biology techniques and promote their usage in biomedical research. A collective effort carried out over decades and whose success reflects the quality of the teaching and the sophisticated techniques employed at the Faculty.

The Faculdade de Medicina da Universidade de Lisboa has always distinguished itself by its scientific work, as much in basic sciences as in clinical sciences, taking a place at the forefront of national health sciences ever since it was established. The creation of the IMM and its installation in the Egas Moniz5 building, allowed a new cycle of progress to begin in which the most modern scientific tools were used to advance biomedical knowledge and introduce advanced diagnostic and therapeutic techniques. This is the post-genomic era of medicine, made possible by the great discoveries of the 20th century.



1. The new building for the Escola Médico-Cirúrgica de Lisboa, long called for to replace the rundown installations that were currently being used next to the São José Hospital, was finished in 1907, a condition that had been imposed by Miguel Bombarda so that the V International Congress of Medicine, of which he was secretary general, could be held there. The work was completed on the eve of the inauguration of the congress, but the Faculdade de Medicina da Universidade de Lisboa (FMUL) only moved in in 1911.

2. I was introduced to histology in my first year at FMUL. My tutor was Luís H. Dias Amado (1901-1981), one of Celestino da Costa's first assistants, expelled from the University under Salazar's fascist regime. Not resigned to his situation, Dias Amado organised evening histology classes for a group of colleagues at his clinical analysis laboratory on Rua Castilho. In my third year I continued my training with Celestino da Costa as an intern at the Histology institute.

3. The Instituto Científico Bento Rocha Cabral (Scientific Institute) was founded in 1923 with the help of a donation from its patron, a great benefactor who made his fortune in Brazil and left a legacy in his will for the establishment and upkeep of a scientific research centre named after him in the building where he lived after his return from Brazil. The physiological chemistry lecturer from the Faculdade de Medicina pioneered the institute, and Simões Raposo, Lopo de Carvalho, Ferreira de Mira and Celestino da Costa all worked there in its initial period (1925).

4. I accepted the post of part time biological medicine lecturer after getting permission from Azeredo Perdigão and having heard that Xavier Morato who had been reconciled with students and colleagues was thrilled by my acceptance.

5. Egas Moniz building. The Faculty's board had been asking for a new building next to the Hospital Santa Maria since 1986 to hold the second year classes, a multidisciplinary laboratory, the physiopathology, hygiene and epidemiology departments and an annexed health centre. The first proposal was made and approved in 1985, but the construction work of the Instituto de Ciências Fisiológicas (Physiological Sciences Institute) as it was called at the time, was only started ten years later. The initial project was then redesigned to take into account the new circumstances, namely that the Instituto de Histologia and CEBIP's installations were already over crowded as a result of their development.



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