Searching for Cures – Professor Niall Howlett

Life is an injurious thing: Everyday our bodies’ are bombarded by harmful radiation and exposed to toxic substances that damage the DNA of our cells. If left to accumulate, this damage can result in cellular dysfunctions including cancerous growth. Luckily, the normal human body is extremely effective in repairing these DNA injuries. However, in the case of patients suffering from a rare inherited disease called Fanconi anemia, these DNA repair mechanisms appear to be broken.

Fanconi anemia, or FA, is a recessive, genetic disorder resulting in physical growth abnormalities, bone marrow failure, and an increased susceptibility to cancer. Although major progress in bone marrow transplant techniques has extended the life expectancies of many patients into their early 30s, few other treatments are currently available. As Cell and Molecular Biology Professor Niall Howlett explains, “This is a recessive disease, so both parents are usually completely healthy on their own, but suddenly, they end up with this extremely sick child and very few treatment options.”

Motivated by the patients, their families, and the clinicians he meets at annual FA Research Fund meetings, Professor Howlett focuses his research on two FA proteins that are directly involved in DNA repair: FANCD2 and FANCI. These proteins undergo a process called ubiquitination which essentially tags the proteins for DNA damage repair and assists in moving them to the appropriate areas of a cell’s nucleus. Unfortunately, this ubiquitination mechanism isn’t working in over 90% of FA patients.

“If we can figure out what these proteins really do, how they are regulated, maybe we can intervene in some of these patients where clearly this process is broken,” stated Howlett.

Going above and beyond: Back in 2007, when Dr. Howlett first started research at URI, these two FA proteins were classified as orphans. In other words, not a single domain, or section of a protein’s sequence, had been linked with a purpose or function. However, through the hard work and determination of his laboratory team, Dr. Howlett has successfully identified at least three protein domains and has contributed in a major way to our understanding of how these proteins work.

Under Howlett’s guidance, a full lab including one post doc, five graduate students, and two undergrads, continually conducts experiments to keep the discovery ball rolling. Research procedures such as western blotting, fluorescence microscopy, and liquid chromatography-mass spectrometry are employed to collect data on the molecular functions of these proteins. “Pretty much everyone does everything within the lab,” said Howlett. “The idea is that hopefully when people graduate they have a strong portfolio of skills. I find that’s really important for job prospects. I want my students to be exposed to as much as possible.”

Outside of the laboratory, Dr. Howlett remains dedicated to ensuring students receive a well-rounded education. Through his two courses in introductory biochemistry and cancer biology, Howlett presents topics such as DNA repair, chromosome stability, and cancer chemotherapy to over 280 undergraduates.

“It’s all about trying to keep them awake,” says Howlett. “The core information, which admittedly can be a bit dry, is absolutely essential, you have to have a good grasp of it. But the key is to try to apply it to real world situations. For instance, we cannot understand cancer without fully comprehending the fundamental process of DNA replication,” he added.

Here, in Dr. Howlett’s world, research and teaching are intrinsically linked- a benefit felt by both the students and the professor.

Finding Clues to Other Diseases: The reach of Dr. Howlett’s discoveries doesn’t stop at his students or potential FA treatments. Rather, his research may offer key information to the understanding of more common diseases such as hereditary breast and ovarian cancer. In fact, it was the diagnostic test for FA that first suggested the link between these diseases back in 2002.

To test for FA, a laboratory exposes a sample of the patient’s blood to a DNA damaging agent and specifically looks for radial chromosome formations –a branching pattern formed by multiple chromosomes attempting to fix one another (see image 1). These radial chromosome formations indicate an unsuccessful attempt at DNA repair. Surprisingly, when cell lines from individuals with hereditary breast or ovarian cancer – caused by mutation of the BRCA1 or BRCA2 genes – underwent this same FA test, similar, high levels of radial chromosome formations were observed. This discovery indicated that the genes and proteins underlying these seemingly distinct diseases might function together. Further studies have verified this relationship. In other words, if we can figure out the molecular mechanisms by which the FA proteins operate, we will be able to gain insight into the underlying molecular processes of more common diseases.

Another disease link with FA involves PTEN, the second most widely mutated gene in cancer. Among cases of glioblastoma (brain cancer), endometrial cancer, and prostate cancer, close to 50% of patients have mutated PTEN. According to Howlett, this suggests PTEN has massive influence on cancer in general and it makes the interactions of the FA and PTEN proteins that much more important.

“If we can figure out how the FA and PTEN proteins interact and function together, not only will we be able to help FA patients but we’ve got this huge cohort of cancer patients that may also end up benefiting from this research,” explained Howlett.