“You know that it will be a big change, but you really don’t have a clue about your future.”A 34-year-old postdoctoral researcher at the Telethon Institute of Genetics and Medicine in Italy at the time, Dr. Sardiello had made a discovery that would change his life forever. Eight years later, Dr. Sardiello is now the principal investigator of a lab in the Jan and Dan Duncan Neurological Research Institute (NRI) where he continues the work that had brought him and his lab to America.
Throughout his undergraduate career, Sardiello knew he wanted to be involved in some manner with biology and genetics research, but his passion was truly revealed in 2000: the year he began his doctoral studies. It was during this year that the full DNA sequence of the common fruit fly was released, which constituted the first ever complete genome of a complex organism. At the time, Sardiello was working in a lab that used fruit flies as a model, and this discovery served to spur his interest in genetics. As the golden age of genetics began, so did Sardiello’s love for the subject, leading to his completion of a PhD in Genetic and Molecular Evolution at the Telethon Institute of Genetics and Medicine. It was at this institute that his team made the discovery that would bring him to America: the function of Transcription Factor EB, colloquially known as TFEB.
Many knew of the existence of TFEB, but no one knew of its function. Dr. Sardiello and his team changed that. In 2009, they discovered that the gene is the master regulator for lysosomal biogenesis and function. In other words, TFEB works as a genetic switch that turns on the production of new lysosomes, an exciting discovery.1 Before the discovery of TFEB’s function, lysosomes were commonly known as the incinerator or the garbage can of the cell, as these organelles were thought to be essentially specialized containers that get rid of cellular waste. However, with the discovery of TFEB’s function, we now know that lysosomes have a much more active role in catabolic pathways and the maintenance of cell homeostasis. Sardiello’s groundbreaking findings were published in Science, one of the most prestigious peer reviewed journals in the scientific world. Speaking about his success, Sardiello said, “The bottom line was that there was some sort of feeling that a big change was about to come, but we didn’t have a clue what. There was just no possible measure at the time.”
Riding the success of his paper, Sardiello moved to the United States and established his own lab with the purpose of defeating the family of diseases known as Neuronal Ceroid Lipofuscinosis (NCLs). NCLs are genetic diseases caused by the malfunction of lysosomes. This malfunction causes waste to accumulate in the cell and eventually block cell function, leading to cell death. While NCLs cause cell death throughout the body, certain specialized cells such as neurons do not regenerate. Therefore, NCLs are generally neurodegenerative diseases. While there are many variants of NCLs, they all result in premature death after loss of neural functions such as sight, motor ability, and memory.
“With current technology,” Sardiello said, “the disease is incurable, since it is genetic. In order to cure a genetic disease, you have to somehow bring the correct gene into every single cell of the body.” With our current understanding of biology, this is impossible. Instead, doctors can work to treat the disease, and halt the progress of the symptoms. Essentially, his lab has found a way using TFEB to enhance the function of the lysosomes in order to fight the progress of the NCL diseases.
In addition to genetic enhancement, Sardiello is also focusing on finding drugs that will activate TFEB and thereby increase lysosomal function. To test these new methods, the Sardiello lab uses mouse models that encapsulate most of the symptoms in NCL patients. “Our current results indicate that drug therapy for NCLs is viable, and we are working to incorporate these strategies into clinical therapy,” Sardiello said. So far the lab has identified three different drugs or drug combinations that may be viable for treatment of this incurable disease.
While it might be easy to talk about NCLs and other diseases in terms of their definitions and effects, it is important to realize that behind every disease are real people and real patients. The goal of the Sardiello Lab is not just to do science and advance humanity, but also to help patients and give them hope. One such patient is a boy named Will Herndon. Will was diagnosed with NCL type 3, and his story is one of resilience, strength, and hope.
When Will was diagnosed with Batten Disease at the age of six, the doctors informed him and his family that there was little they could do. At the time, there was little to no viable research done in the field. However, despite being faced with terminal illness, Will and his parents never lost sight of what was most important: hope. While others might have given up, Missy and Wayne Herndon instead founded The Will Herndon Research Fund - also known as HOPE - in 2009, playing a large role in bringing Dr. Sardiello and his lab to the United States. Yearly, the foundation holds a fundraiser to raise awareness and money that goes towards defeating the NCL diseases. Upon its inception, the fundraiser had only a couple of hundred attendees- now, only half a decade later, thousands of like-minded people arrive each year to support Will and others with the same disease. “Failure is not an option,” Missy Herndon said forcefully during the 2016 banquet. “Not for Will, and not for any other child with Batten disease.” It was clear from the strength of her words that she believed in the science, and that she believed in the research.
“I have a newborn son,” Sardiello said, recalling the speech. “I can’t imagine going through what Missy and Wayne had to. I felt involved and I felt empathy, but most of all, I felt respect for Will’s parents. They are truly exceptional people and go far and beyond what anyone can expect of them. In face of adversity, they are tireless, they won’t stop, and their commitment is amazing.”
When one hears about science and labs, it usually brings to mind arrays of test tubes and flasks or the futuristic possibilities of science. In all of this, one tends to forget about the people behind the test bench: the scientists that conduct the experiments and uncover the next step in the collective knowledge of humanity, people like Dr. Sardiello. However, Sardiello isn’t alone in his endeavors, as he is supported by the members of his lab.
Each and every one of the researchers in Marco’s lab is an international citizen, hailing from at least four different countries in order to work towards a common cause: Parisa Lombardi from Iran, Lakshya Bajaj, Jaiprakash Sharma, and Pal Rituraj from India, Abdallah Amawi, from Jordan, and of course, Marco Sardiello and Alberto di Ronza, from Italy. Despite the vast distances in both geography and culture, the chemistry among the team was palpable, and while how they got to America varied, the conviction that they had a responsibility to help other people and defeat disease was always the same.
Humans have always been predisposed to move forwards. It is because of this propensity that humans have been able to eradicate disease and change the environments that surround us. However, behind all of our achievements lies scientific advancement, and behind it are the people that we so often forget. Science shouldn’t be detached from the humans working to advance it, but rather integrated with the men and women working to make the world a better place. Dr. Sardiello and his lab represent the constant innovation and curiosity of the research community, ideals that are validated in the courage of Will Herndon and his family. In many ways, the Sardiello lab embodies what science truly represents: humans working for something far greater than themselves.
- Sardiello, M.; Palmieri, M.; di Ronza, A.; Medina, D.L.; Valenza, M.; Alessandro, V. Science. 2009, 325, 473-477.