Lectures

Volta Lecture

Infectious Causes of Human Cancer

8 April 2019. 
Harald zur Hausen, German Cancer Institute
, Heidelberg.

The 2018/19 M Fraccaro lecture will be given by Harald zur Hausen of the German Cancer Institute in Heidelberg in the main University lecture hall (Aula Magna) in Strada Nuova on the 8th of April at 5.00 pm and is entitled: Infectious Causes of Human Cancer. The lecture is organised on an annual basis jointly by Collegio A Volta and Collegio Cairoli where M Fraccaro served as a College Director for nearly 35 years. The poster of the lecture can be downloaded here. H zur Hausen made seminal contributions to the discovery of infectious agents causing human cancers through his pioneering work on Human Papilloma Viruses (HPV) and their roles as  causal agents of cervical cancer and several other types of tumours. H zur Hausen's work led to the development of an HPV vaccine which is widely and successfully used in order to prevent HPV infection and thus cancer.  For this work H zur Hausen was awarded the Nobel Prize for Physiology or Medicine in 2008.


Abstract

The growth, division, and death of living cells are regulated by their genes. If these functions are out of balance, tumors can form. One reason for this may be the incorporation of virus genes into the genes of host cells. Harald zur Hausen demonstrated in 1983 that cervical cancer in humans is caused by certain types of papilloma viruses (wart viruses), the genes from which are incorporated into the host cells' DNA. This discovery made it possible to develop a vaccine against cervical cancer, which had been the second most common tumor disease in women.

Biography
From Les Prix Nobel. The Nobel Prizes 2008, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2009 (https://www.nobelprize.org/prizes/medicine/2008/hausen/biographical/)


Born in 1936, I experienced the Second World War as a child in the city of Gelsenkirchen-Buer. This area was heavily bombed, but fortunately all members of my family survived the war and post-war period. As a child I remember my own intensive interest in biology, birds, other animals and flowers and was determined at an early age to become a scientist. Since schools were closed due to the bombing raids in 1943, my elementary school training was full of gaps. When I entered “Gymnasium” at the age of 10 in 1946, during the first year these gaps were evident and created some difficulties for me. After the first year there, however, although not being the top pupil, I went to school without any major problems. In 1950 my parents moved to Northern Germany where I finished high school in 1955 with the “Abitur”.

After briefly considering whether to study biology or medicine, I opted for medicine and initiated my studies at the University of Bonn. The first two years were particularly hard, since I simultaneously decided to attend lectures and courses in biology as well. The first examination after 5 semesters (“Physikum”) was passed without any problems with remarkably good grades. This created some self-confidence for the forthcoming semesters, which I spent at the University of Hamburg for one year and the (at that time) Medical Academy in Düsseldorf. At the end of 1960 I graduated there in medicine and also finished my MD thesis.

Although I remained firmly determined to continue in science, I wanted to receive a licence to practice medicine. This required at that time two years of medical internship. It brought me for short periods of time into surgery, internal medicine and for the remaining time into gynaecology and obstetrics. The last part fascinated me tremendously, although it turned out to be physically highly demanding. When I left the hospital and started to work in Medical Microbiology and Immunology at the University of Düsseldorf, for the first and only time I had some doubts whether this was the correct decision. For a short while I considered returning to the life of a practising physician; after a couple of months, however, I became more fascinated by early experimental studies. Initially I started to work on virus-induced chromosomal modifications and at the same time received relatively solid training in diagnostic bacteriology and virology, both of them at that time in an early stage of development.

During my 3½ years in Düsseldorf, I became increasingly aware of the limitations in my scientific education and decided to search for a postdoctoral position elsewhere, preferably in the United States. I received an interesting offer from Werner and Gertrude Henle at the Children’s Hospital of Philadelphia, where Werner headed the Division of Virology. In 1964 I got married and our first son Jan Dirk arrived one year later. Within the same year we decided to accept the offer from Philadelphia; in the end of December 1965 I arrived there and started work at the beginning of 1966.

The Henle’s laboratory was deeply interested in the newly discovered Epstein-Barr virus (EBV), and the whole team was actively engaged in developing serological tests for this virus and in studying its epidemiology. They had noted early that Burkitt’s lymphoma patients developed high antibody titres against viral antigens. I felt very much compelled to work with this agent, but noted at the same time my lack of familiarity with the rapidly developing molecular biological methods. I urged Werner Henle to permit me to work with a different agent, namely adenovirus type 12, hoping that this relatively well established system would permit me to become acquainted with molecular methods. He reluctantly agreed. I started to work eagerly on the induction of specific chromosomal aberrations in adenovirus type 12-infected human cells, simultaneously studying a DNA-replication disturbance of individual chromosomes in human lymphoblastoid and lymphoma cell lines, and, to please my mentor, I demonstrated electron microscopically the presence of EBV particles directly in individual serologically antigen-positive Burkitt’s lymphoma cells. During my years in Philadelphia the immortalising function of EBV was demonstrated for human B-lymphocytes, and the role of this virus as a causative agent of infectious mononucleosis was conclusively established.

In 1968 I received an attractive offer from Eberhard Wecker, who headed the newly opened Institute for Virology at the University of Würzburg, Germany. He offered me the establishment of my own independent group and granted me his support for a quick start in the German academic system. I accepted this offer and moved with my family in March 1969 back to Germany. Here I decided to change my topics completely to EBV research. The intention was to prove that EBV DNA persists in every tumour cell of Burkitt’s lymphoma and does not establish a persistent infection there, as assumed at that time by a number of my former colleagues. With the aid of Werner Henle in Philadelphia and George Klein in Stockholm I received a large number of Burkitt’s lymphoma cell lines and tumour biopsies. The biopsies also included material from nasopharyngeal carcinomas, where serological assays also suggested an involvement of EBV infections.

The major problem, the purification of sufficient quantities of EBV DNA from a low number of spontaneously virus-producing cells, was quickly solved. By the end of 1969 I had the first data available that the non-EBVproducing Burkitt’s lymphoma cell line Raji contained multiple copies per cell of EBV DNA. Shortly thereafter it was also possible to demonstrate EBV DNA in Burkitt’s lymphoma and nasopharyngeal cancer biopsies. It seems that this was the first demonstration of persistent tumour virus DNA in human malignancies.

In nasopharyngeal carcinomas, composed of a mixture of epithelial tumour cells and lymphocytic infiltrates, it was intensively discussed whether the EBV DNA might rest in the lymphocytic infiltrates. By using in-situ hybridisations, in 1973 we were able to document the presence of EBV DNA in the epithelial tumour cells.

In 1972 I was appointed chairman of the newly established Institute of Clinical Virology in Erlangen-Nürnberg. With the move to this city I planned to change my scientific direction. Cervical cancer had long been suspected of being caused by an infectious agent. In the late 1960s Herpes simplex type 2 (HSV-2) emerged as the prime suspect based on some seroepidemiological observations. Since our previous EBV work led to the identification of EBV DNA in specific human cancers, I had asked my colleague Heinrich Schulte-Holthausen to use the same technique to search for HSV-2 sequences in cervical cancer biopsies. All attempts, however, failed.

During the previous years I had studied a large number of anecdotal reports describing malignant conversion of genital warts into squamous cell carcinomas. Since genital warts had been shown to contain typical papilloma-virus particles, this triggered the suspicion that the genital wart virus might represent the causative agent for cervical cancer. Based on this hypothesis we initiated our papillomavirus programme in Erlangen. With the aid of the local Dermatology Hospital we received a large number of wart biopsies. Viral particles could be extracted from plantar warts and in 1974 we published our first report, demonstrating a cross-hybridisation of the plantar wart virus DNA with some warts, but by far not with all of them. Genital warts and cervical cancer biopsies were negative. This was our first hint that there exist different types of papillomaviruses. In the following years our group, as well as the group around Gérard Orth in Paris, were able to identify the plurality of the human papillomavirus family by isolating a steadily increasing number of novel types.

In 1977 I was appointed as chairman of the Institute of Virology of the University of Freiburg, Germany. Most members of my group in Erlangen joined me in moving to Freiburg. Here we continued intensively our studies on human papillomaviruses.Late in 1979 my co-workers Lutz Gissmann and Ethel-Michele de Villiers successfully isolated and cloned the first DNA from genital warts, HPV-6. It was initially disappointing not to detect this DNA in cervical cancer biopsies. HPV-6 DNA, however, turned out to be helpful in isolating another closely related genital wart papillomavirus, HPV-11, initially from a laryngeal papilloma. By using HPV-11 as a probe, one out of 24 cervical cancer biopsies turned out to be positive. In addition, in other biopsies some faint bands became visible, permitting the speculation that they might represent hints of the presence of related, but different HPV types in these cancers. Two of my former students; Mathias Dürst and Michael Boshart, were asked to clone these bands. Both of them were successful. In 1983 we were able to document the isolation of HPV-16, in 1984 the isolation of HPV-18 DNA. We noted from the beginning that HPV-16 DNA was present in about 50% of cervical cancer biopsies, HPV-18 in our early experiments in slightly more than 20%, including several cervical cancer cell lines, among them the HeLa line.

Within the first two years after isolating HPVs 16 and 18 it became clear that these viruses must play an important role in cervical cancer development: viral DNA was commonly found in an integrated state, indicating the clonality of the tumour. In addition, part of the viral genome frequently became deleted in the process of integration. Two viral genes, E6 and E7, were consistently transcribed in the cancer cells. Precursor lesions of cervical cancer also contained these viruses and expressed the respective genes. Early contacts with pharmaceutical companies for the development of HPV vaccines failed, in view of a market analysis conducted by one of them which indicated that there would be no market available. Fortunately, this changed in later years.

My period in Freiburg permitted me to also work on other aspects of tumour virology: I discovered the potent activity of some phorbol esters in inducing latent Epstein-Barr virus DNA. This procedure also proved to be successful for other persistent Herpes-type viruses. In addition, I isolated a novel lymphotropic polyomavirus from African Green Monkey lymphoblasts. Up to 20% of sera from human adults also revealed neutralising antibodies to this virus. Our attempts to isolate a human correlate, however, failed. I also identified a novel adeno-associated virus, now labelled AAV-5, from my own skin scrapings. In collaboration with my colleague Jörg Schlehofer, we were also able to demonstrate that herpes simplex virus, but also other herpes-, adeno-, and vaccinia virus infections of polyoma- or papillomavirus DNA harbouring cells, resulted in amplification of the DNA of the latter. The early hypothesis that cervical cancer was caused by papillomaviruses, the successful isolation and characterisation of the two most frequent HPV types in this cancer and the subsequent steps leading to a better understanding of the mechanism of HPV-mediated carcinogenesis and eventually to the development of a preventive vaccine were cited as the prime reasons for awarding one half of the Nobel Prize for Medicine or Physiology to me in 2008.

In 1983 I was appointed as the Scientific Director of the German Cancer Research Centre (Deutsches Krebsforschungszentrum) in Heidelberg, a national research centre. Besides the major task of reorganising this research centre, I tried to maintain some time for laboratory research and continued jointly with Frank Rösl to analyse intracellular and extracellular control mechanisms preventing the activity of viral oncogenes in proliferating epithelial cells. In 2003, after 20 years, I retired from the scientific directorship of the German Cancer Research Centre. Subsequently, I kept a laboratory in the virus building of the Cancer Centre and continue up to now to act as Editor-in-Chief of the International Journal of Cancer. I started this commitment at the beginning of 2000. In retrospect, I have devoted my scientific life mainly to the question to what extent infectious agents contribute to human cancer, trusting that this will contribute to novel modes of cancer prevention, diagnosis and hopefully later on also to cancer therapy. I am of course pleased to see that at least part of this programme has been successful. I am grateful to a large number of my former co-workers, who skilfully contributed to the programme. In addition, I most gratefully acknowledge the contributions of my wife, Ethel-Michele de Villiers, who is also a scientist and tumour virologist, for her never-ending support.

Image
Cells from the uterine cervix of a patient with severe dysplasia. Image courtesy of the University of Copenhagen.

 

Photography

A basic photography course is offered to College students starting from 2018/19.  Photography is not only one of man's most effective way to capture the world that surrounds us, it is also a true art form that can convey extraordinary feelings and in depth knowledge.  The photography course will be offered by the local Photography Society in Pavia, a body that collects first class photographers with an outstanding artistic record.

 Image courtesy: https://www.webindia123.com/

 

Art

A basic drawing and painting course is offered to College students starting from 2018/19.  The College is well aware that much of its work is directed to the sciences, engineering and medicine and that, as a result, active steps should be taken in order to encourage the pursue of art, music, the humanities and social sciences in College.  The art course, together with a new photography course constitute initial steps in the process of bridging the 'two cultures' at Volta.

 

 

 

Italian

In the academic year 2018/19 the College introduced the first Italian language course. This course had been long in the making because College is aware that  the University Centro linguistico offers a range of courses in Italian language.  However, a number of foreign students living and working in College have explained that the time and cost of the official courses offered bby Centro linguistico do not allow a number of them to participate, hence the College decision to offer a course of Italian language (B1 level) and culture. 

 

 

 

Regeneration of the Epidermis

9th April 2018.
Michele De Luca, University of Modena
.

The 2017/18 M Fraccaro Lecture, organised an nually by Collegio Cairoli and Collegio Volta will be given at 5.00 pm on 9th April 2018 in the main University lecture hall (Aula Magna) by Prof M De Luca at the University of Modena. 

Lecture
The lecture entitled: Life-saving regeneration of the entire human epidermis by transgenic stem cells and will illustrate ground-breaking progress in curing a child with a life-threatening skis disease (Junctional epidermolysis bullosa, genetic disease caused by mutations in genes encodingthe basement membrane component laminin 5). The approach pursued by Prof M De Luca and his collaborators involved correction of the faulty gene in skin stem cells in culture followed by propagation and implantation of the cells with the corrected gene to enable the growth of the entire body skin. The results of this study were published in November 2017 in the journal Nature and the article is available here for downloading. All College students are warmly invited to attend this important lecture.  The poster of the lecture can be downloaded here.  The lecture will be followed by refreshments at Collegio Cairoli.

Biography
Michele De Luca has dedicated most of his scientific activities to translational medicine. He is recognised as leading scientist in human squamous epithelial stem cell biology aimed at the development of epithelial stem cell-mediated cell therapy and gene therapy. Following on early work on the use of human epidermal stem cell cultures in life-saving treatment of massive full-thickness burns and in repigmentation of stable vitiligo and piebaldism by keratinocyte/melanocyte co-colture (reviewed in Regen. Med. 2006), Michele De Luca and his historic collaborator Graziella Pellegrini, were first to establish human urethral stem cell culture aimed at urethral regeneration in posterior hypospadias (N. Engl. J. Med. 1990). They then developed human limbal stem cell culture (J. Cell Biol. 1999) for corneal regeneration in patients with severe limbal stem cell deficiency (Lancet 1997; N. Engl. J. Med 2010; Regen. Med. 2013). This treatment leads to recovery of normal vision and is now used worldwide. In February 2015 such cultures were formally approved as an Advanced Therapy Medicinal Product by EMA, which registered them under the name of Holoclar. Holoclar is the first stem cell-based therapy approved in Europe and EMA has indicated it amongst the most relevant achiements in the field in the last 20 years. They have characterised molecular mechanisms regulating long term proliferative potential, clonal evolution and self-renewal of epithelial stem cells. In particular, they shed light on the role of p63 (different isoforms) and c/EBPδ in regulating the proliferative potential and the self-renewal of human corneal stem cells, respectively (PNAS 2001, 2005; J. Cell Biol. 2007). Notably, their work demonstrated that the clinical success of limbal stem cultures is dependent on a discrete number of stem cells identified as holoclones expressing the ΔNα isoform of p63 (N. Engl. J. Med.  2010, TMM 2011, Regen. Med. 2013). Michele De Luca and Pellegrini are also pioneering ex-vivo epithelial stem cell-mediated gene therapy for genetic skin diseases. He coordinated the first successful clinical trial to treat junctional epidermolysis bullosa (JEB) (Nat. Med. 2006; Stem Cell Rep. 2014; J. Invest. Dermatol, 2017; Nature, 2017). JEB is a severe, often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving JEB patients develop chronic skin and mucosa wounds, which impair their quality of life and lead to skin cancer. De Luca has recently reported life-saving regeneration of the entire, fully functional, epidermis on a 7-year-old child suffering from a devastating, life-threatening form of JEB (Nature, 2017). Using integrations as clonal genetic marks, he has shown that the vast majority of epidermal TA progenitors are progressively lost within a few months after grafting and the regenerated epidermis is indeed sustained only by a limited number of long-lasting, self-renewing stem cells. This notion argues against a model positing the existence of a population of equipotent epidermal progenitors that directly generate differentiated cells during the lifetime of the animal and fosters a model where specific stem cells persist during the lifetime of the human and contribute to both renewal and repair by giving rise to pools of progenitors that persist for various periods of time, replenish differentiated cells and make short-term contribution to wound healing (Nature, 2017). Based on this notion and on the corneal data (N. Engl. J. Med 2010) De Luca and Pellegrini established that the essential feature of any cultured epithelial grafts is the presence (and preservation) of an adequate number of holoclone-forming cells. Their work thus provides a blueprint that can be applied to other stem cell-mediated ex vivo cell and gene therapies (see N&V Nature 2010). Michele De Luca is internationally recognised for his experience in stem cell therapy and contributed to two reports by the International Society for Stem Cell Research, dealing with new guidelines for responsible translational stem cells research (Cell Stem Cell 2008, 2009).

Image: human keratinocytes in culture. Courtesy of CellnTec.

Spanish

Volta plans to offer a Spanish Language Course at a single level: Diplomas de Español como Lengua Extranjera (DELE) level B2 to College students (DELE tests can be taken at a number of Sopanish cultural Institutes (Instituti Cervantes) across the world. The closest to Collegio Volta is the Instituto Cervantes in Milan.  Following the pattern of College English, French adn German language Course, the Spanish Course under planning will involve 60 hours of teaching from mid November until late April arranged in 30 sessions of 2 hours each (two sessions per week). A poster of the Course can be downloaded here, a Course flyer can be downloaded here.

With the fall of the Spanish dictatorship in 1975 Spain has embarked in a successful journey of freedom and democracy in which Universities have played a major role. Spain hosts a number of fine Universities and Research Institutes and is a popular destination for Italian Erasmus students, not least because the Spanish life pattern is probably close enough to the Italian one.  College is detemined to implement a Spanish Course in order to ensure that Volta students moving to Spain make the best of their time of study there. 

The Course will be set at the standard required by the best Spanish Universities (the standard of language required differs at different Universities) and interested in the Course will be advised to take an online entrance test, such as the Spanish Placement Test offered by Oxford University that provides reliable and useful information about a student's entry level.

Every student at Volta is expected to study a language and currently has a choice of English (3 levels), French (1 level) and German (1 level).  Enrolment fee for all Language Courses at Volta for 2017/18 is expected to be € 100 per Course.

 

 

 

German

Volta offers a German Language Course at a single level: Deutsche Sprachprufung dur den Hocshshulzugang (DSH) level 1 to College students. The Course involves 60 hours of teaching from mid November until late April arranged in 30 sessions of 2 hours each (two sessions per week). A poster of the Course can be downloaded here, a Course flyer can be downloaded here.

Germany is the largest country in Europe. It has a superb University and Research infrastructure and is largely responsibile for the modern view that University should be engines of Research and Innovation, a concept that found implementation on a massive scale in the US. Volta wishes to encourage more students to apply for Erasmus placements and postgraduate studies and training and postdoctoral fellowships but fluency in the German language is essential for this and relatively few students of Volta currently have the level of German necessary.

College believes that the German language Course may change this. The Course is set at the standard requirement for admission of foreign students under the Erasmus scheme (DSH level 1).  Only two German Universities (Tübingen and Berlin) require DSH level 1 and College may arrange extra tuition for students who intend to apply to Tübingen and Berlin.  Students interested in the German Course are advised to take an online entrance test.  The one currently used by Volta is a brief and free German Placement Test test offered by Oxford University that provides reliable and useful information about a student's entry level.  Every student at Volta is expected to study a language and currently has a choice of English (3 levels), French (1 level) and German (1 level).


2017/18

Lecturer
Claudio Neidhöfer

Lectures
01. Lectures 01-10
02. Lectures 11-20
03. Lectures 21-30
04. Lectures 31-40
05. Attendance


 

French

Volta offers a French Language Course at a single level:  Diplôme d'Etudes en Langue Française (DELF) B2 level to College students. The Course involves 60 hours of teaching from mid November until late April arranged in 30 sessions of 2 hours each (two sessions per week). A poster of the Course can be downloaded here, a Course flyer can be downloaded here.

France is home to a wealth of Universities and 'Schools' (special Universties distinctive of the French educational system) and is a popular destination for Erasmus placements.  The level of the French Course at Volta, therefore, is set at the standard requirement set by French Universities for admission of foreign students under the Erasmus scheme or equivalent. Students interested in the French Course are advised to take an online entrance test.  The one currently used by Volta is a brief and free French Placement Test test offered by Oxford University that provides reliable and useful information about a student's entry level.

Every student at Volta is expected to study a language and currently has a choice of English (3 levels), French (1 level) and German (1 level).  Enrolment fee for all Language Courses at Volta for 2017/18 is expected to be € 100 per Course.


2017/18

Lecturer
Ingrid Ouandji


French Language 2017/18 (All Courses)

01. Lectures 01-05
02. Lectures 06-10
03. Lectures 11-15
04. Lectures 16-20
05. Attendance


 

English

Volta offers Courses in English Language at three levels.  Courses involve 60 hours of teaching from mid November until late April and are arranged in 30 sessions of 2 hours each with two sessions per week.The poster of English Courses can be downloaded here.  A flyer of the Course can be downloaded here.

The College has organised English language Courses independently in 2012/13, 2013/14 and 2014/15 and jointly with EDiSU in 2015/16 and 2016/17.  Volta offers three levels of English Courses shaped on Cambridge English.  Volta students entering the English Courses take an online test, paid by College, through Oxford University in order to be assigned to the appropriate class.  This test is used at Volta both as a placement test as well as an exit test in order to neasure progress.

The syllabus employed at Volta is Cambridge English and the teaching is structured according to the guidelines of the Common European Framework of Reference for Languages (CEFR). The aim of the English Courses at Volta is to take all Volta students to a C1 level, the one required for postgraduate studies in UK or US Universities and for employment. Students work toward the International English Language Test System (IELTS) examination.  This examination is expensive (the cost is in excess of € 200) and is accepted by Universities only if the test has been sat in the last 12 months. Thus College studens are encouraged to sit the IELTS examination only in their final year when they have reached C1 level and are in the process of applying for postgraduate training or employment.

Every student at Volta is expected to study a language and currently has a choice of English (3 levels), French (1 level) and German (1 level).  Enrolment fee for 2017/18 is expected to be € 100 per Course.

 

 

Coding

The College offers a basic Course on Computer Coding open to all students.  The Course will take place from October until mid December and will involve 16 hours of teaching arranged in eight sessions of two hours each (one session per week). The College requests that each student at Volta attends a computing Course and, under current arrangements, students can choose between this Course on Computer Coding, a Web Design Course and a LaTeX Course  There is no enrolment fee for any of the Course on computing. The poster of the Course can be downeloaded here and a Course flyer can be downloadd here.

With the breathtaking development of computing and their impact on everyday life and work, it is essential that as many people as possible master at least the basic principles and the 'alphabet' of computer coding.  The Course will offer an introduction to popular coding languages and tools (C, PHP, JavaScript, SQL), build practical examples throughout and ensure that students wishing to further their learning of computer programming will be offered the necessary tools for doing so. 


2017/18

Lecturer
Pavlo Burda 

Lectures
01. Code editor, CSS, Django administration and forms
02. Django installation, models, query sets and templates
03. Django urls, views, dynamic data in templates, extensions
04. Internet, installation, command line
05. Introduction to HTML and Phyton. Phyton installation and examples
06. Extending templates, what's next, first Django project
07. Attendance


 

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