Investigator Spotlight: October 2015
Antonio Toniolo, PhD
Dr. Toniolo is an nPOD investigator at the University of Insubria Medical School in Barese, Italy. Dr. Toniolo joined nPOD in 2011.
- Tell us about your education and background – where are you from, where did you go to school?
I don’t remember a single classmate or friend with diabetes during all my school years in Central Italy. This says how rare diabetes was in the young about 50 years ago. I met the first insulin-dependent diabetic when I moved to Sardinia as Professor of Microbiology. Sardinia is an island that shares the world’s highest incidence of type 1 diabetes with Finland. The diabetic girl was hard-working and graduated on time. Later on, she became a neurologist. I got my MD degree from the Medical School at the University of Pisa, where I had a two-year clinical residency. In the evening, instead of clinical wards, I attended the Laboratory of Medical Microbiology and worked with cell cultures and mice. Later, I started studying bacteriology, virology and immunology, and acquired the basic criteria for diagnosing infectious diseases. I also had interests in Veterinary Microbiology (there was a vast array of viruses, bacteria and parasites from different animal species), Neurophysiology (the lab next to mine, where physiologists were designing their own instruments for recording electric signals from animal brain and neuron cultures), and Pharmacology (ligand-receptor interactions). Thus, my early years exposed me to different areas of experimental medicine and brought me away from clinical work. I chose to study Microbiology since I wished to understand what causes a disease. At that time, my studies were focused on the interference of viruses with the immune response- a niche that became popular as “virus-induced immunodeficiency” when AIDS made its appearance. In 1977, I received a Board Certification in Medical Microbiology that was extended to Europe and Switzerland. Upon publishing papers of some impact, I was awarded an international fellowship of the International Fogarty Center and a position at the National Institutes of Health in Bethesda, Maryland.
- Where do you currently work and what is your position? What does a “day in the life” look like for you?
At the National Institute of Health (NIH), I started working in the Laboratory of Abner Louis Notkins, who was studying diabetes in mice, and had just found a specific diabetogenic enterovirus in a child with fulminant diabetes (coxsackie B4). The atmosphere was frantic. Many qualified researchers populated the lab: experts in pathology, immunology, electron microscopy, virology, basic endocrinology all allowed me to familiarize with different areas of knowledge. We learned about experimental diabetes, mouse genetics, organ-specific autoimmunity, detection of autoantibodies, hormone levels and more. In the meantime, we kept close contact with leaders in picornavirus and reovirus research. Ji-Won Yoon (from Korea) succeeded in isolating two different clones of the encephalomyocarditis virus: the B- (non-diabetogenic) and the D- (diabetogenic) variant of the virus. Experiments became much simpler than when mice were inoculated with a mixture of virus variants- it was enough to inoculate the D clone in susceptible mice to acquire beta cell destruction and hyperglycemia in a short time. The model, however, didn’t reproduce type 1 diabetes in humans, since autoantibodies were not produced and the incubation time was short. However, the virus allowed us to demonstrate the synergistic activity of chemicals and viruses that caused diabetes. To better simulate the human disease, we moved to a different model: infection by reoviruses (a group of RNA agents explored by the outstanding virologist Bernard Fields). We associated reovirus infection of neonatal mice with the production of autoantibodies against beta cells, pituitary cells and thyroid. Thus, the reovirus caused diabetes, growth stunting and thyroid disorders. An entirely new area of research was unlocked: the role of virus infections in endocrine disorders. Family reasons forced me to return to Italy. In a basic lab, I resumed experiments with mice because human and technical resources were inadequate, funds were scanty and prospects were uncertain. My return from the US was a debacle: the only possibility was to re-start diabetes studies based on friendships with my pediatric endocrinology colleagues. We tried to isolate viruses from children with type 1 at clinical onset. Partial evidence for infectious events was obtained in cell culture, but molecular tools were not available for identifying the viral agents that we thought might be associated with type 1.
- Why diabetes? How did you get involved in diabetes and/or what made you want to work in diabetes research?
In 1985, I was promoted to Professor of Medical Microbiology with clinical appointment and served at four different Italian Medical Schools. Currently, I am in Varese, North-Western Italy. I teach at the University of Insubria, work as a clinical microbiologist for an 800-bed hospital, plan research, and supervise the team and external collaborators. Efforts against diabetes began with a donation from a family with a diabetic child. Later, a substantial grant was obtained from an International Attorney (also diabetic). As a result, scientific collaborations flourished, the VIDIS group (led by Keith Taylor and Heikki Hyoty) opened new horizons, and the nPOD and JDRF organizations came to the rescue. My day, including Saturdays, starts early in the morning. Priority is given to clinical work, then University duties, then diabetes team research. Technical help is scanty and the bureaucracy is oppressive. Researchers need to do administrative work and have to respect countless rules. Fortunately, my lab is close to Milan and Switzerland. Thus, I have contacts with the San Raffaele Hospital and the Swiss Institute for Biomedicine led by Antonio Lanzavecchia.
- Tell us about your research.
The history of medicine is full of breakthrough discoveries that have revolutionized ways to treat incurable diseases. The identification of Helicobacter pylori infection as a major cause of gastric ulcer, stomach cancer and lymphoma is one spectacular example. Thus, establishing clear links between microbial agents and a disease has always been followed by the development of effective cures and preventive measures. Our studies aim at solving an issue overlooked by medical research: we are looking for one or more viruses that trigger diabetes (among other possible environmental factors). Enteroviruses are prominent candidates. Identification of the “diabetogenic enterovirus types” that may have hit children in the early phases of diabetes is dependent on having methods both sensitive and specific enough to detect more than 100 different virus types. If we find any of these viruses to be associated with diabetes, it could open up diagnostic assays, possible cures or a preventive vaccine. Over the last few years, evidence emerged that “chronic” enterovirus infections can exist in humans. These infections are caused by “mutated viruses” that produce clinically silent infections. Unfortunately, these viruses are difficult to detect using conventional methods. We set up novel tests for detecting enteroviruses in pediatric Italian patients and in specimens provided by nPOD. For us, nPOD studies are particularly exciting due to the international cooperation with scientists of different backgrounds (such as histopathology, electron microscopy, immunology, proteomics, genomics and virology). Additionally, our results are shared through an IT platform open to investigators. This approach is innovative and is expected to accelerate progress since conclusions are derived from multiple points of view. Studies of Italian children and adolescents showed that, at clinical onset, an enterovirus is present in the majority of type 1 cases. We also found that cases are geographically and temporally clustered, and that enteroviruses are sometimes also present in siblings and parents.
- What are your thoughts on the progress being made in T1D research as a whole?A multidisciplinary approach is needed to understand disorders with multiple causal determinants. The anti-infectious immune response plays a key role. This theme deals with the “hygiene hypothesis,” or the fact that – upon implementing advanced hygienic conditions – the population is progressively less exposed to infectious agents. Thus, “herd immunity” is reduced. This may explain, in part, differences in the incidence rate of type 1 diabetes among different countries. Recently, large serologic studies in Northern Europe pointed to a particular enterovirus as a possible cause of diabetes, and studies in Norway indicated that enteroviruses are present within the pancreas of newly-diagnosed diabetics. Thus, our understanding of the origin of diabetes is progressing at unprecedented speed.
- Why is diabetes research so important?
Type 1 diabetes is the most prevalent chronic disease of the youth and is the result of a progressive process in which the immune system contributes to destroying pancreatic beta cells. Though the introduction of insulin as a treatment is one of the most significant achievements of modern medicine, the disease is far from conquered. Diabetic children and adolescents also face many potential complications, such as blindness, neuropathy, kidney insufficiency and cardiovascular disease. Any areas of type 1 diabetes research (etiology, biomarkers for early diagnosis, optimized treatment regimens, beta cell transplant, artificial pancreas, and prevention of complications) are vital. The major goal of the nPOD-Virus Group is to find ways to prevent the disease by identifying infectious agents that might play a causative role.
- Do you have anything extra you would like to share? Is there anyone to thank or acknowledge?
Research is costly. This is not due just to technology and reagents, but to the intelligence, time and talented hands type 1 research requires. Type 1 researchers face years of training, need to be disciplined and must endure repeated failure. In science, success is only temporary: success opens new questions. However, if you keep an eye on the ultimate goal, you will eventually learn to appreciate even small steps forward. The scientist understands how a lot of work can bring you just a bit closer to the purpose of the project. In this sense, collaborative research is of utmost importance- it encourages single participants while everybody is being fertilized by the results of colleagues. All scientists should read “Endurance” by Sir Ernest Shackleton, a report on his unfortunate mission to the South Pole and how he brought back his crew to England. They should also remember Jonas Salk, who said “you never have an idea of what you might accomplish. All you have to do is pursue a question and see where it leads.” Likewise, Craig Venter became motivated in science after returning from the Vietnam War. In short, he wanted to make his life worth living. My great mentor and friend, Robert Gallo, had extraordinary advances in immunology and virology. As a young medical student, he saw his sister die of leukemia. He isolated novel human retroviruses that cause leukemia and AIDS, set up diagnostic tests and opened the way to therapy. My National Institutes of Health mentor, Abner Notkins, is still fond of immunology, viruses, diabetes and neuroscience after 50 years of investigation. His clear mind, skill in designing experiments, attention to detail and writing style are a joy when I visit NIH. I recall a special Saturday morning in Bethesda. He asked my friend, Takashi Onodera, and myself to meet him to write a paper on virus-induced autoimmunity, a problem we had been confronting for two years. We started frenziedly writing the paper on a playground table and the article was completed within six hours. One month later, the paper was accepted by the Journal of Experimental Medicine without any corrections. Finally, a thought to Keith Taylor, physician and diabetic himself, who led a group of virus-oriented diabetologists until his death in 2012. His enthusiasm and guidance were contagious: young people form the UK, the US Scandinavia, European Countries, Japan and Australia entered the field and are now part of the JDRF nPOD organization.
- When you’re not working, what do you like to do for fun?
My anxieties include unsuccessful experiments, lack of funds and disheartened collaborators. Good results of an experiment are reassuring me at times of distress. Aside from professional duties – before being hit by a car while taking care of people in a huge highway accident – I enjoyed skiing and riding my fast Laverda bike. I also loved taking pictures, something I’m still practicing. Consultations and phone calls of parents with diabetic children keep me happy and confident at the end of the day.