Recap of sixth international conference on rare and undiagnosed diseases. Pozzuoli (Naples), Italy – Telethon Institute of Genetics and Medicine. 20-21 June 2018

Recap of sixth international conference on rare and undiagnosed diseases. Pozzuoli (Naples), Italy – Telethon Institute of Genetics and Medicine. 20-21 June 2018

“Through this message I do not want to get any privileges.  All I would like to know is what I can do for my wife, my half but my all that nobody can be substituted”.
Korean man asking for help for his wife.

Not yet discovered is the gene that transformed an Olivetti typewriter (Photo 1) factory into a world class genetics center, the Telethon Institute of Genetics and Medicine (TIGEM).  Under the guidance of the National Institutes of Health (NIH) and the Undiagnosed Diagnosed Diseases International (UDNI), over 100 geneticists and scientists gathered on TIGEM’s campus in Pozzuoli, Italy for the sixth international meeting. The group is dedicated to diagnosing rare genetic diseases, and treating and findings way to prevent genetic illnesses.  At least 19 countries were represented (Photo 1: TIGEM’s previous life as Olivetti typewriter factory. Note windows to left).

Raffaele Castello, PhD, (Photo 2: Tour guide and host Raffaele Castello, PhD) the project manager for Telethon Undiagnosed Program, seemed to have the perfect demeanor for his job of hosting us. Demonstrating fleet footedness in getting the microphone around to the attendees asking question during the discussion, he was devoted to the notion that our visit would be a success. Working tirelessly to serve as our personal ambassador, he even gave a lecture about managing projects and seemed thoroughly delighted to have been chosen to oversee this conference. The only question he was asked that he could not answer was the name of the beautiful purple-flowered botanical specimens sprinkling the grounds, but he offered to find out.  Showing a photo to my wife when I made it home, she was able to identify the bush as a bougainvillea. (Photo 3: Bougainvillaes overlooking the azure sea of the Bay of Naples)

TIGEM was founded in 1994 as an outgrowth of the Telethon Foundation, an Italian charity organization, which was formed by Susanna Agnelli in 1990.  Ms. Agnelli, who, after raising six children, found her own identity and success as a politician and writer, was the granddaughter of the founder of Fiat, a car company.  In 2014, having outgrown their 1000 m² building in Naples, TIGEM relocated to the bucolic 5000 m² Pozzuoli campus. 

The buildings on TIGEM’s grounds were constructed in the style of a Roman Villa.  Built in 1954, the architect was seeking the perfect way to show respect for the worker and their comfort and was most interested in having the light and windows ideal.  Adrian Olivetti, who started the Comprensorio Olivetti, wished to “combine the needs of industrial society with the values of a traditional society.” Ironically the same progress in science and computer technology that eventually spelled the demise of the traditional typewriter is the same technology that infuses the genetic labs at TIGEM, augmenting the progress made in genetics with the same sense of humanism envisioned by Olivetti and the architect. One could easily get a sense of this just by standing in their largest lab and witnessing the west facing floor-to-ceiling window yielding a pastoral vista available to all of  the scientists working in that lab. One computer Raffaele showed us could test 300 drugs for therapeutic efficacy in an hour.  Previously it was a tedious task of three months duration.

Situated on a flattened part of the hillside, dotted with tropical flora, the campus overlooks the azure sea below and nestles against a backdrop of verdant hills.  (Photo 4: The institute nestled in the verdant  hills overlooking the azure sea)

The visionary architect designed the buildings to collect rainwater that could be used to regulate the temperature in the facilities.  The genetic scientists working away in these same venues have their own vision for the future. They have evolved from just searching for defective genes to a focus on diagnosing, treating, and prevention mission, utilizing therapeutic advances realized at TIGEM.

Adorning the wall in the entrance hall, next to the steps going to our lecture room, were five panels, each about 4 feet wide and two stories high.  Framed and covered with glass, they represented an unusual version of modern art.  Close inspection revealed this to be the DNA sequencing of a chromosome discovered in the 1990s by TIGEM scientists. (Photo 5: The 2 story panels depicting code of gene discovered at TIGEM).

Thousands of lines of code are depicted, each letter about one millimeter in height, representing the associated genome. Raffaele advised us that it would take 1509 more panels to frame the whole genome in the same manner.  What an intriguing amalgam of turning science into art.

The same view of the sea that we had during our “Coffee/Vitamin” breaks at the institute (I observed that Italian vitamins bear a striking visual resemblance to pastry), we were able to re-appreciate at Mary Lou’s Restaurant just across the street and downhill from the institute. (Photo 6: Dinner at Mary Lou’s Restaurant overlooking Bay of Naples)

The welcom was given with a Napoli-style pizza and possibly some of the local distilled grapes.  Each attendee was presented with their personal and exquisite twelve inch pizza.  Baked In the wood-fired brick oven, they had a perfect amount of scorching on the crust, which provided a lovely flavor.   Among the international conversations happening, many stole a few glances at the world cup on the lone TV in the dining room. The next evening, Mike and Helen Cederroth once again hosted us in an unforgettable wonderful gala dinner on the seafront terrace of the Maison Toledo in Pozzuoli.  For their efforts in the rare disease and undiagnosed illness community, Mikk and Helene received the EURORDIS Volunteer Black Pearl Award as “passionate and dedicated patient advocates who have contributed remarkably to the undiagnosed rare disease cause. Together they are the founders of the Wilhelm Foundation, which helps approximately 3 in 10,000 children who suffer from often fatal undiagnosed brain diseases.” Congratulations to Helene and Mikk from the UDNI members for their well-deserved award.

There are practical benefits to these conferences. Kenjiro Kosaki from Japan, who hosted us in November 2016, reported a 38% success rate, diagnosing 21 of 62 genetic samples sent to them from four countries in their region following the 2016 conference.

A message that seemed to come through loud and clear and repeatedly at our Naples meeting was trust and data sharing.  Great progress has been made with Phenome Central and Match Maker, enabling greater connectivity and data sharing. One tidbit Dr. Gareth Baynam shared in his talk “Considerations of Philanthropy” was that the word “undiagnosed” seemed to really resonate with and really captured the attention of the lay community.  Dr. Gahl advised us that the Internal Revenue Service (IRS) was his source of philanthropy.

Emblematic of the hard work and dedication of the physician-scientists and the trust inherently given to the geneticists working in the arena of rare and undiagnosed, Dr. Gahl shared this comment with us, seen above as an epigram. He left the slide up for us to contemplate as he went about other business.

Through this message I do not want to get any privileges.  All I would like to know is what I can do for my wife, my half but my all that nobody can be substituted.  Korean man asking for help for his wife. 

The syntax here may be a bit fractured but anyone with a heart can translate without difficulty the offered message of love, caring, and concern.

The case presentations were the most diverse and interesting that I recall of our six meetings, with some clever case names. Aurora Pujol had an authentic appearing CASE SOLVED stamp slapped on one of her power point slides, chronicling a novel hypomyelinating leukodystrophy. Some may have noticed in her last slide that all her staff members were shown with their hands positioned in the manner of the rare disease symbol. Camilo Toro titled his XMEN Return, regarding a congenital glycosylation disorder associated with a magnesium problem, EBV, and neoplasia.  Paraskevas Iatropoulos described a patient who had remained undiagnosed for 46 years, with a peculiar phenotype due to combined POC1B and TTN mutations.  Yair Anikster asked the tantalizing question in her case title: Does N=1 or 2?  She described a brother and a sister with a similar genetic deficit. She also offered few World Cup predictions. Ann Nordgren shared an unknown syndrome. She ended with a particularly interesting photograph, taken by a friend, revealing a researcher seemingly sound asleep buried in a sea of books, perhaps absorbing the potential answer via osmosis.

Lunches were buffet style in the cafeteria of the institute. I was put in mind of those businesses where people gather for meals and ideas are conceived, incubated, hatched, and nurtured over a meal. I could see many conversations unfolding among members of the UDNI attendees as they were making worldwide connections.

Paul Lasko of Canada presented a wide ranging and quite thoughtful talk. He told the most compelling story of cultural awareness and how research resonated with unanticipated downstream issues regarding indigenous populations who felt that their culture had been violated. He cited instances where researchers had obtained consent from a community to bank blood samples for one purpose but used them and provided them to others to use for different purposes, without the consent or even the knowledge of the community.  An element of distrust then developed. As often is the case in indigenous cultures, it is important to dispose of human material with appropriate ceremony.  LESSON LEARNED: Cultural awareness matters. Lasko also referenced an article from Genetics (Understanding Rare Disease Pathogenesis, by Hieter and Boycott, 2014; 198(2):443-5). The message was that there were too many publications on a limited number of genes. Was there a better way to move forward?  He also showed an original mural, created in real time by Corrina Keeling, at a meeting of Care for Rare. Once again, a nice blend of art and science coming together.

Bela Melegh reminded us that, when possible, a work up should proceed from where it had stopped rather than repeating a lot of testing, causing needless expense and time.

Shinya Yamamoto reported that his team had discovered, through a genetic screen using fruit flies, a novel gene and genetic pathway that are essential for neural stem cell division and survival. The team further showed that functional variants in humans, that were previously undiagnosed, are associated with congenital microcephaly. (Yamamoto et al., 2014 Cell, OMIM #616681) This defect came to the attention of the Zika virus researchers who contacted them last year. By utilizing this data from animal models and rare disease patients, the team discovered that a pathogenic Zika virus protein hijacked this pathway to cause microcephaly, a work that is under peer review for publication. This was introduced as an example of how undiagnosed disease research starting from a single patient combined with functional studies in a model organism can have a much broader impact on more common diseases. Born and educated in Japan as a veterinarian, Yamamoto came to Baylor for his PhD and never left. His phenotype is tall, he speaks with confidence and passion, and he sports an acquired Texas trait of wearing stylish cowboy boots.

The UDNI members voted to hold the seventh international conference on rare and undiagnosed diseases in New Delhi (India) in March 2019.

Thanks to Raffaele and the rest of the TIGEM staff for hosting a well-run meeting in such a lovely setting (Photo 7: UDNI Group in Naples).