One of the most intractable obstacles in treating and curing cancer is the tumor’s ability to adapt to and resist treatments. Although many new and effective drugs are available, according to the National Cancer Institute, “nearly all current treatments face the same problem – for many patients, they ultimately stop working.” Northwestern University’s Chemistry of Life Processes researchers, Vadim Backman and Igal Szleifer believe they may have found an answer to this urgent problem.

Backman, Walter Dill Scott Professor of Biomedical Engineering, Biochemistry and Molecular Genetics and Medicine, the grant’s principal investigator, and co-principal investigators Szleifer, Christina Enroth-Cugell Professor of Biomedical Engineering, and Professor of Chemistry and Medicine, and Hemant K. Roy, M.D., Franz J. Inglefinger Professor of Medicine, Chief, Section of Gastroenterology, Boston University, recently received a $2 million National Science Foundation Emerging Frontiers in Research and Innovation award  to develop novel technologies that alter the  physical environment inside tumor cells to turn off their ability to adapt.

Recent technological advances have led to an important discovery that chromatin, DNA plus the regulatory proteins called histones around which DNA is wrapped, is not packed inside the nucleus in an organized fashion as once believed but is, in fact, completely disorganized.  This is a key finding from a physical scientist’s perspective.

“By magnifying DNA one million times, you find something that resembles a very little noodle packed and folded in a disorganized way within the nucleus,” says Backman.  “The length of the noodle inside the nucleus is similar to that of road from Boston to Dallas packed into the size of a typical living room. The noodle has the DNA code written on it, so it will be read differently depending on how it’s packed. Factors such as how crowded the environment is, or what kind of ions are around the genome all depend on the physical packaging of this very long polymer.”*

Revolutionary technology, such as CRISPR-cas9 have enabled physical manipulation of living systems in ways never before imagined.  Live cell imaging techniques, pioneered by Backman and others, go a step further.  For the first time, scientists can actually see in real time within seconds what happens to chromatin in vivo while cells are being treated with various agents, an important step in the evolution of this approach.

Changing the operating system

“If genes are the hardware, chromatin is the software,” says Backman. “The way nature operates, it doesn’t just change genes, it changes the way genes get expressed. That’s the software.”  Much effort has been expended on finding ways to change the genetic code, e.g. hardware, using tools like CRISPR, to alter cell behavior. Backman and Szleifer, however, are looking to change the operating system itself: the way the “DNA noodle” (the chromatin) is packed and structured inside the cell. This process dictates how the hardware is read.

Depending on how genes are packed, they can become more, or less adaptable to internal or external environmental pressures, such as drugs, injury or inflammation. When it comes to disease, that’s an important distinction.  For instance, turning off the mechanism that allows a gene to adapt to its environment, a natural consequence of evolution, is a powerful tool in fighting cancer. However, if you want to reverse tissue damage, then increasing genetic plasticity becomes beneficial.

“It’s not bad or good. It’s a dial,” says Backman.

Images of nuclear chromatin obtained with technology developed by the Backman research group. Red areas represent chromatin packing domains while the green shows labeled transcriptional factor activity (RNA-polymerase II).

Health impacts

Multiple diseases are mediated by a combination of genetic (hardware) and epigenetic (software) mechanisms.  The list includes cancer, atherosclerosis, Alzheimer’s and other neurodegenerative diseases. “These are some of the most complex disease of the 21st Century,” says Backman. “I think there’s a reason for it because they don’t involve [just] a single gene, a single molecule that goes wrong. I think eventually medicine will be able to find a way to cure most diseases where few specific genes or proteins are involved.

“What I think unites the three big ones and why we don’t have a cure for any one of them is precisely because they are so complex and involve not just one agent, one gene, but thousands of genes,” Backman says.

“There are thousands of mutations in cancer. There are thousands of genes involved in Alzheimer’s and atherosclerosis. These are very complex processes,” he says.  “I think what is required is not just to change a gene or fix a pathway; it requires changing the whole operating system within the cell and that’s what this grant will try to do.”

For now, the team will focus on developing strategies to constrain the adaptive potential of cancer cells in order to prevent the progression of pancreatic and ovarian tumors and prevent emergence of resistance to anti-cancer therapeutics. Their three-pronged approach will include the following advanced technological elements:

  • Novel nanoscale imaging methods that enable investigators to visualize changes in chromatin packing in real time in live cells;
  • Highly accurate, multi-layered models of perturbation of chromatin in response to various agents; and
  • Sophisticated screening of potential chromatin packing modulators for efficacy and specificity in blocking the evolution of tumor cell resistance to various therapies.

Line of sight collaboration

“CLP was a key collaborator on this grant,” says Backman. “The infrastructure supports this kind of activity, not just from the research perspective, but also from the administrative, outreach and broader impacts perspective.”

He describes the Institute as a “convergence facilitator” that nurtures transdisciplinary collaborations, such as the EFRI research program, which integrates imaging, molecular biology, physical genomics, computational genomics, biophysics and medicine to create a radically new approach to treating disease.

“The work within the line of sight is critical here,” Backman says, noting the ease with which he, Szleifer and other collaborators and their labs can interact with each other and access the Institute’s drug development facilities and expert staff.

“Without CLP,” says Backman, “it would have been difficult to put this program together and then to implement it now that it’s funded.”

*Paraphrase of an analogy attributed to Erez Liberman-Aiden, assistant professor of molecular and human genetics, Baylor College of Medicine”

Feature image credit: MedicalNewsToday, Cancer cells destroyed in just 3 days with new technique, 11/7/2017

by Lisa La Vallee