In the Lloyd and McCullough laboratories, unexpected discoveries open pathways for potential treatments for diseases associated with DNA damage.
In 1928, Alexander Fleming, a Scottish bacteriologist studying bacterial infections and their treatments, made a most fortuitous discovery. Returning to his lab after a vacation, Fleming noticed mold growing in Petri dishes containing Staphylococcus bacteria. Fleming observed that the bacteria around the mold were dying. Based on his observations, Fleming hypothesized that the mold was producing something that inhibited the growth of the bacteria. The name of that remarkable mold was Penicillium. A decade later, scientists at Oxford University succeeded in isolating and producing penicillin in large quantities. Antibiotics had arrived, ushering in a new era of medical care.
At its most fundamental level, science is the systematic study of the unknown. Scientists are explorers striking out in the darkness. Discovery begins with observing natural phenomena, collecting and analyzing data drawn from observation, and formulating and testing hypotheses. Most reasoned, evidence-based hypotheses are only best guesses until demonstrated valid or invalid through rigorous laboratory experimentation.
Sometimes, as in the case of Fleming, exploration leads to unexpected discoveries with paradigm-shifting implications for society.
At the Oregon Institute of Occupational Health Sciences (OccHealthSci), researchers are studying molecules with unique attributes that could lead to novel treatments for liver and skin cancers, metabolic diseases such as obesity and diabetes, and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease.
Professors Stephen Lloyd and Amanda McCullough are trained in molecular biology and biochemistry. Lloyd and McCullough are experts in DNA damage and repair mechanisms at OccHealthSci. Think of DNA as the instruction manual for building and operating living things—a blueprint that tells life how to form and function. Environmental factors such as exposure to UV radiation or toxic compounds can damage DNA, altering its instructions in ways that lead to disease and potentially death. Life, however, has evolved intra-cellular enzymes to repair damaged DNA.
In their laboratories, Drs. Lloyd and McCullough study the mechanisms by which these repair molecules function and the biological implications that result when those functions are compromised. Specifically, Lloyd and McCullough have concentrated their efforts on two enzymes, NIEL1 and OGG1 that aid cells in surviving DNA damage caused by oxidative stress, including multiple types of cancer.
Lloyd’s and McCullough’s research has contributed much to our understanding of the relationships between the OGG1 and NEIL1 repair enzymes and the genesis of environmentally driven DNA damage and certain types of cancer. Although the original impetus to initiate studies on these repair enzymes was with applications relating to cancer, their work also led to unexpected discoveries with implications far from cancer, including inflammation, obesity, and neurodegeneration.
Since their research teams knew OGG1 and NEIL1 played a role in repairing DNA damage that could lead to cancer, they devised an experimental strategy to test the hypothesis that mice deficient in these enzymes would have increased cancer rates.
“The surprising observation from that experiment was that although some mice developed cancer, the overall finding was that mice with enzyme deficiencies got fat, developed fatty liver disease, and became insulin resistant. They had what we collectively call ‘metabolic syndrome,’” Lloyd said.
The team’s observations set in motion not only an unexpected pivot for their laboratories but also launched new fields of investigation of the critical role of DNA repair in many diseases. In addition to genetic changes leading to cancer, the team was now looking at DNA repair and metabolic health.
The researchers began studying OGG1 and NEIL1 repair enzymes in mitochondrial DNA. Mitochondria are cellular power plants that convert chemical energy from food into energy cells can use. In studies in mice, the research team found that supplementing the amount of repair enzymes in their mitochondria supercharged their metabolism, such that mice on diets containing 60% fat gained little weight. Their livers were pristine.
The next step was to develop molecules that were capable of stimulating the activity of OGG1 in the mitochondrial compartment of the cell. That work yielded similarly positive outcomes and resulted in a patent application covering the molecule’s design and potential applications.
After the research teams filed their patent applications, a group of individuals formerly employed by a major pharmaceutical company made contact. These individuals were interested in the team’s discovery and had done similar work with the repair enzymes. Their focus, according to Lloyd, was on the potential for using drugs to enhance OGG1 DNA repair capacity to address neurodegenerative disorders associated with mitochondrial DNA damage, such as ALS, Alzheimer’s, and Parkinson’s diseases.
The group formed a biotech company, Luciole Pharmaceuticals, and licensed Lloyd’s and McCullough’s technology from Oregon Health and Science University. Luciole focuses on discovering and developing small molecule activators of OGG1 to accelerate the repair of damage to mitochondrial DNA and the development of neurodegenerative disease, obesity, and metabolic syndrome. Drs. Lloyd and McCullough are co-founders of the company.
“One of the rare privileges of working in basic research is having the opportunity to apply your work to practical matters,” Lloyd said. “We followed the science, leading us to an unexpected but important discovery.”
As with all discovery and innovation, much work still needs to be done. The DNA repair enzymes studied in the Lloyd-McCullough Lab at OccHealthSci may yield more surprising results with important implications for understanding and ultimately treating diseases associated with DNA damage. And while Lloyd continues following the science where it leads, the team at Luciole is hard at work leveraging the discoveries to develop solutions to some of the most vexing issues in modern medicine.