By GREGORY ZELLER //
From the Didn’t See That Coming File comes Stony Brook University researcher Ute Moll and the p73 gene – potentially, a master key to unlocking new treatments for chronic lung diseases.
As part of a cancer study, a team led by Moll – a professor in the SBU School of Medicine’s Department of Pathology – and research scientist Alice Nemajerova studied a family of genes including the p53, “the mother of all tumor-suppression genes,” according to Moll.
“We wanted to understand how the molecular and cellular mechanisms of p53 work in a cancer cell,” the professor told Innovate LI. “When p53 is mutated, it often produces a faulty protein at a very high level, and we were very interested in that.”
When healthy, the gene performs a policeman-like function, Moll noted, regulating cellular functions and stopping cells from turning cancerous – sometimes by slowing cellular development to allow DNA to fix itself, sometimes by thrusting cells into a “suicide program” that kills them before the cancer takes over.
But when it mutates, p53 replaces amino acids with faulty amino acids, and in doing so “not only loses its molecular-policeman function,” Moll said, “it becomes a gangster.”
“It’s now an oncogene, a cancer-causing and cancer-promoting gene,” she added.
During the course of their study, Moll and Nemajerova determined that test mice with mutated p53 genes contracted cancer faster than mice with no p53 genes at all – proof-positive that mutated p53 genes become oncogenes.
They also studied p73, a “cousin” of the p53 gene (they’re named for their molecular weight), initially focusing on the cousin’s role in cancer scenarios.
First, the researchers postulated that p73, which is genetically similar to p53, might also be a tumor suppressor, but ultimately determined p73 is an “assistant” to p53, which “calls the shots,” according to Moll.
Then, noting certain “developmental abnormalities” in test mice with either no p73 genes (known as “knockout” mice) or mutated p73 genes, the doctors refocused on p73’s specific functionality. And that’s where things got interesting for the hundreds of millions of global patients suffering from chronic obstructive pulmonary disease – the third-leading cause of human death – and related disorders such as asthma and emphysema.
The knockout mice suffered from air-passage abnormalities – particularly, the effectiveness of their cilia cells, which when healthy filter out dust, pollutants and pathogens in sinus cavities, bronchial tubes and other airways.
Harvard University, which provided the knockout mice for Moll and Nemajerova’s study, wrote off the abnormalities as an immune deficiency, according to Moll, who noted a circa-2000 Harvard study that “made a passing reference to a lot of inflammatory cells in their airways.”
But Moll wasn’t convinced.
“We found that the underlying reason (for the airway abnormalities) was not because of some immune deficiency, but because these p73 knockout airways do not produce proper cilia,” she said.
The discovery that the p73 gene is the master regulator of cells that clean the airways of mice and men was an unexpected and potentially enormous breakthrough with trillion-dollar potential. Moll and Nemajerova have revealed their findings in a paper published by Genes & Development, which is managed by Cold Spring Harbor Laboratory Press and is, according to Moll, regarded among the top biological journals because of its focus on science, as opposed to commercialization.
In the paper, titled “TAp73 is a Central Transcriptional Regulator of Airway Muticiliogenesis,” the colleagues note that gene-engineered mice lacking the entire p73 gene or TAp73, a homologous version of the gene, suffered from chronic respiratory tract infections due to profound defects in ciliogenesis – the building of a cell’s primary cilia.
The science is extremely dense, though the potential of Moll and Nemajerova’s discovery is clear: Air pollution, increasing smoking prevalence in developing nations and other factors contribute to the more than 330 million global cases of COPD, running up an estimated $2.1 trillion in healthcare costs, according to SBU.
While any sort of commercialization related to the discovery is far off, Moll said the breakthrough is a big step toward classifying p73 as a “disease gene,” an unprecedented designation for p53’s cousin. The findings also open the door to large-scale population-based studies of people with chronic lung diseases.
The immediate goal is not to cure COPD and related conditions, Moll noted, but to improve treatment protocols – including the development of early-warning systems that can spare at-risk patients before pulmonary disorders set in.
“We could be looking at a COPD susceptibility test,” she said. “Potentially, we could mass-sequence p73 genes to pick out those that are functionally defective … so those people, if they live in a high-pollution environment, can be the first to get out of that environment.”
Even a potential gene-therapy-based COPD cure is not out of the question, the professor added, though that’s “well down the line.”
“That’s years away,” Moll said. “But for the susceptibility thing, we believe there is very high potential. At least, we’re talking about a test to mass-screen people, identify those with the faulty version of the gene and get them out of a certain environment because they are high-risk.”