Two Basic Scientists Walk into a Translational Space.

When John Schiller first joined Douglas Lowy's lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor João Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.

A Prize for Cancer Prevention.

This year's Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV).

[History of the development of screening tests for cervical cancer]. / Historia de la evolución de las pruebas de tamizaje en el cáncer cervicouterino.

Cervical cancer (CC) is one of the best known malignancies. Currently, it is accepted that the etiological factor is persistent infection with high-risk human papillomavirus (HPV). Even before the identification of its etiological factors, methods such as Pap cytology and colposcopy were developed as tools for early diagnosis on CC and its precursor lesions. At the time when such tests were being developed, they were not fully accepted by the scientific community of the time; however, as time went by, the dissemination of knowledge, and more extensive application, these tests were finally included within the international guidelines. The implementation of programs with adequate coverage and quality allowed a significant reduction in the incidence and mortality of CC. However this did not occur widely, and CC is still a public health problem in developing countries. From the epidemiological and molecular viewpoint, knowledge on HPVs laid the foundations for the development of new prevention strategies based on vaccination and molecular detection of the causal agent, currently accepted as strategies for primary and secondary prevention. It is expected that the implementation of these strategies will have a greater impact on the control on CC and other malignancies associated with HPV infection.

El cáncer cervicouterino (CaCU) es una de las neoplasias mejor conocidas; actualmente es aceptado que el factor etiológico es la infección persistente por virus de papiloma humano (VPH) de alto riesgo. Sin embargo, aun antes de que se hubiera identificado el agente etiológico, se desarrollaron métodos, como la prueba citológica de Papanicolaou y la colposcopia, como herramientas para el diagnóstico temprano del CaCU y sus lesiones precursoras. En los inicios del desarrollo de ambas pruebas, estas no fueron del todo aceptadas por la comunidad científica de la época. Con el paso del tiempo, la divulgación del conocimiento y la aplicación más extensiva, se logró la aceptación y la inclusión de dichas pruebas en un gran número de guías a nivel internacional. La implementación de programas con cobertura adecuada y de calidad dio como resultado una reducción significativa en la incidencia y mortalidad por CaCU. Sin embargo, esto no se dio de manera generalizada y en países en vías de desarrollo es aún un problema de salud pública. El conocimiento sobre los VPH, desde el punto de vista epidemiológico y molecular, sentó las bases para el desarrollo de nuevas estrategias de prevención, basadas en la vacunación y en la detección molecular del agente causal, actualmente aceptadas como estrategias para prevención primaria y secundaria. Se espera que la aplicación de dichas estrategias tenga un impacto mayor en el control del CaCU y de otras neoplasias asociadas a la infección por VPH.

Fighting against human papillomavirus: the 25-year old contribution of the University of Crete School of Medicine.

Twenty five years have passed since the first research efforts in Greece on human papillomavirus (HPV) performed by the Department of Clinical Virology at the University of Crete School of Medicine. HPV infection in the human cervix was initially evaluated in relation to the host mutational and transcriptional activation of the ras/raf genes pathway, p53 gene polymorphisms, neo-angiogenesis- related gene expression and G1/S phase transition. A series of epidemiological studies ensued, evaluating HPV infection in the ophthalmic pterygium, benign laryngeal tumors, parotid lesions, nasal polyposis, actinic keratosis, aborted material and non-genital cancers. The observed geographical variations of different HPV types within the Hellenic population indicated a higher prevalence of HPV 18 on the island of Crete compared to mainland Greece. Moreover, our research led to the investigation of the mother-to-infant HPV transmission via human breast milk and the detection of novel HPV types in juvenile recurrent respiratory papillomatosis. We also evaluated the presence of HPV in the respiratory tract of asymptomatic children and the relationship between maternal HPV infection and neonatal prematurity. Despite the introduction of the current prophylactic vaccines against HPV into clinical practice, HPV remains a challenging target for the next generation of researchers, as the war against HPV continues.

History of human papillomavirus, warts and cancer: what do we know today?

Human papillomavirus has been a cause of infection in humans for thousands of years. The history of papillomaviruses, knowledge of their causative role in benign and malignant disease, and their structural characteristics have led to the development of vaccines to prevent cervical and anogenital cancers. Many questions remain unanswered before HPV vaccines can be optimised; however, the concept of virtual eradication of cervical cancer is not impossible, and remains a realistic aspiration.

The path to developing a cervical cancer vaccine.

The path that led me to where I am today in my career as a vaccinologist was not a straight one: it was riddled with twists and turns, opportunities and obstacles and full of decisions that could have taken me down very different avenues. Working and interacting with many dedicated and brilliant scientists and taking apprenticeships to become a better and more versatile scientist have been rewarding experiences and more than once luck has come into play.

[Harald zur Hausen--a scientist with passion. Vaccine against cervical cancer]. / Harald zur Hausen--badacz z pasja. Szczepionka przeciw rakowi szyjki macicy.

The profile of Harald zur Hausen, German virologist and Nobel-Prize winner for medicine in 2008, is presented in the context of his life and scientific achievements. The studies of zur Hausen on oncogenic viruses submitted a finding that chronic infection with certain highly invasive human papilloma viruses (HPV16 and HPV18 types) causes cervix carcinoma. The discovery was a starting point to successful construction of biosynthetic preventive vaccines against this carcinoma, such as "Gardasil" and "Cervarix".

The challenge of eliminating cervical cancer in the United States: a story of politics, prudishness, and prevention.

Exciting strides in reducing the incidence of and mortality from cervical cancer have been made over the last century in the United States. The issues surrounding the implementation of the human papillomavirus vaccine are remarkably similar to the issues involved in the gradual adoption of the Pap test and initiation of cervical cancer screening beginning nearly a century ago. The following review of the reduction of cervical cancer morbidity and mortality demonstrates the importance of the interplay between basic science, clinical medicine, social mores, and public policy.

Chapter 11: HPV vaccines: commercial research & development.

We are now in the fortunate position of having two highly promising human papillomavirus (HPV) vaccines in the pipeline. Amidst the excitement of anticipating what these vaccines may be able to offer, it is worth pausing to look back at how the vaccine development story unfolded from an industrial perspective, since without the massive commitment shown by manufacturers over the last decade, without any guarantee of success, there would be no such prospect. This chapter focuses on the two HPV prophylactic vaccines, produced independently by Merck & Co., Inc. and GlaxoSmithKline (GSK), that are in advanced clinical development, and it aims to provide an insight into the key considerations for initiating the programmes in a commercial context as well as some of the research and development hurdles that needed to be surmounted to bring them to the point where efficacy has been demonstrated and the licensing process is well underway.