Georgia State University’s Markus Germann has worked for years on exploring how the body fixes damaged DNA — damage that, if left unrepaired, can lead to cancerous tissue. Damage he has experienced personally.
Diagnosed with oral cancer a year ago, Germann, a professor of biophysical chemistry, underwent radiation and chemotherapy for the disease. He couldn’t eat or drink normally and was extremely fatigued, but he still came into the office to check on his lab and keep things running.
“Learning about cancer first-hand was not what I wanted, but it definitely puts a different spin on things,” Germann said. “It was surprising that, despite the advances that were made, much of the treatment is similar, albeit more refined, than what was available 10 to 20 years ago. Although we have some new drugs that are less dangerous, there are still side effects. There is a pressing need for more effective and targeted drugs.”
Now in remission, Germann continues to seek the knowledge necessary for better detection and treatment for a disease that is diagnosed in more than 1.4 million people in the United States every year.
Cancer is an incredibly complex disease with even more complex molecular and cellular mechanisms.
Cells, the basic units of the human body, are intricate, with microscopic mechanisms ranging from DNA to proteins that regulate their reproduction and interaction with other cells and cellular components.
Sometimes cells reproduce in ways leading to malfunctions. Normally, the body eliminates these wayward cells, but if not, they can swiftly replicate out of control and form dangerous cancer tissues.
Germann and the rest of Georgia State’s distinguished scholars in the Georgia Cancer Coalition — part of the state’s multi-institution effort to fight the disease — explore these cellular processes and mechanisms in order to get to the roots of cancer.
These Georgia State cancer researchers are part of a larger research program, the Molecular Basis of Disease Program, which brings together faculty in biology, chemistry, mathematics and statistics, computer science, computer information systems, and physics and astronomy to study multiple diseases at the molecular level.
Examining damage: Markus Germann
At the heart of cancer is the damage caused when cells do not replicate properly or are damaged by toxins. Germann has been investigating how this damage occurs in the DNA of cells.
DNA’s double helix, resembling a kind of spiral staircase, encodes information through base pairs — made up of adenine, thymine, guanine and cytosine held together by hydrogen bonds on either side — located along the helical backbone.
Germann and his lab explore the structural dynamics of DNA in an effort to understand how the body’s enzymes recognize and repair damage. The damage can come from kinked and grooved base pairs, or mismatched pairs of code.
“In cells, multiple events of DNA damage occur daily, but considering the enormous length of the DNA, it is extremely difficult to localize the bad parts,” Germann said. “So, how do enzymes find these things?”
The damage itself may allow for enzymes to find it and repair it, but this is often inefficient, depending upon which base pairs surround the damage.
To better understand the process of recognition and repair of damage, researchers need to find out what happens between the beginning and the end of the process, Germann explained.
On the matter of preventing his own cancer, Germann, a former smoker, is quite frank. “It was stupid to smoke. It’s like shooting yourself in the foot,” he said.
Improved detection through biomarkers: Binghe Wang
Sitting in his office at Georgia State’s Natural Science Center, Binghe Wang, professor of medicinal chemistry, opens a PowerPoint presentation on his computer’s large display, showing his research “wheel of fortune,” a graphic with numerous spokes highlighting a broad range of interests, from drug discovery to disease detection methods.
One of those spokes deals with carbohydrate-based biomarkers that will help to better alert doctors to diseases like cancer.
An element in this biomarker research includes glycoproteins — proteins embedded into the membranes of cells or secreted into the blood stream with different types of sugars attached to them.
If the glycoproteins come from cancerous tissues, however, they may have abnormal patterns, helping to show the presence of cancer.
One application for research into glycoproteins includes improving a common test for prostate cancer.
The current test — the prostate specific antigen (PSA) test — is based on determining the total level of the PSAs, which are a type of glycoprotein.
Though the current test is useful, in men over age 50, Wang explained, it is estimated to miss prostate cancer about 40 percent of the time.
“That’s very high,” he said, “and it would give you a high rate of false positives as well, which causes emotional as well as financial stress.”
A new PSA test would be based on the detection of a specific glycoform of PSA and would be potentially more accurate than the current test, saving even more lives, Wang said.
Investigating cellular executioners: Irene Weber
When abnormal cells are generated, the body normally kills them through a process called apoptosis. Cancerous tissues form when this process doesn’t happen, and those abnormal cells continue to divide and multiply.
Treating and eliminating cancer means killing cancerous cells. This is done, for the most part, through radiation and chemotherapy — which can take a heavy toll during treatment.
But Irene Weber, a professor of structural biology, is looking at enzymes called caspases, which, as part of the body’s natural defenses, serve as “the executioners” of apoptosis.
“The idea is that if you can activate cell death, this provides a means for killing the abnormal cells, and thus getting rid of cancer cells,” she explained.
Specifically, Weber is examining the structure of caspases 3 and 7, which bind to other proteins and cut them up, eventually killing the cells. One problem is that the caspases cleave perhaps hundreds of proteins, and scientists don’t know exactly which proteins are cut.
“One aspect of the basic science is looking at how you can improve the recognition of their natural substrates,” Weber said. “Then we can also look at other proteins which act to block apoptosis by blocking the caspases.”
Working with colleague Julia Hilliard, a Georgia Research Alliance Eminent Scholar, Weber and her lab are looking at the molecules involved to get a three-dimensional model, which may then provide a foundation for future scientists to design molecules that will block inhibitors, helping to activate cell death in certain types of cancer.
Weber’s research is basic, but it is nevertheless valuable in the process of understanding cancer. This understanding is needed, she said, to develop new drugs.
“You’ve got to have the basic studies in chemistry to learn how to optimize the chemical structure, and you’ve got to know enough of the biology to know which areas would be the critical targets for the drugs,” she added.
Playing hide and seek: Susanna Greer
The body’s immune system is its line of defense against foreign invaders, from viruses to tumors. But often tumors find ways to hide from the immune system, making it harder for the body to attack these deadly, swiftly multiplying cells.
Susanna Greer, assistant professor of biology, is using a grant from the American Cancer Society awarded in October to further explore proteins that play a role in helping the body’s immune system detect tumors.
She is specifically focusing on two proteins, Major Histocompatibility Complex (MHC) classes 1 and 2, which are in every cell of the body with the exception of red blood cells.
Each plays a similar role in triggering the immune system’s response. Once alerted, the immune system starts an inflammatory response to clear out the infection — as it would with any foreign body, Greer explained.
MHC Class 2 alerts the immune system to proteins shed by tumor cells, allowing the immune system to attack tumor cells. The problem is that tumors are good at turning off these proteins that sound the warning.
The epigenetic code used to regulate the cell surface expression of MHC proteins is complex. Greer and her lab are exploring how this code is translated to regulate the production of MHC Class 2 and other inflammatory proteins.
“The more we find out about how these proteins are transcribed and translated, in addition to how you can turn on transcription and turn it off, the more we can understand how we might be able to make tumors more visible to the immune system,” Greer said.
New imaging techniques and technologies: Zhen Huang
In one hand, Zhen Huang, professor of biochemistry and chemistry, holds a model of DNA’s signature double helix structure. In the other, he holds a vial containing a tiny microchip no bigger than a pencil eraser.
That little chip — able to analyze genes — holds great promise, not only to better detect cancerous anomalies, but also to rapidly detect pathogens that could cause pandemics.
“With this RNA microchip, we can analyze a large number of genes in the future,” Huang said. “The advantages are that there is much more rapidness and sensitivity than the current technology, as well as a significantly reduced cost.”
Imaging genes, structures and their anomalies by invisible X-rays or visible light is Huang’s research passion. The two overarching methods Huang uses to look at DNA genetic material and RNA (a genetic product of DNA) and thus better understand the anomalies that exist with cancer, are through X-rays and something called chemiluminescence, which uses chemicals and enzymes to help show genetic expression patterns directly.
“In order to make a proper pair of gloves for a set of hands, you need to measure dimensions of the hands,” Huang offered as an analogy.
If scientists know the shape and structure of DNA and RNA, scientists can design drugs to bind to the molecules in question — inhibiting the expression and progression of a disease, thus killing it off — whether it’s cancer, HIV or any other viruses.
The RNA microchip Huang has developed with his colleagues uses chemiluminescence to examine RNA and DNA on a tiny surface. Huang hopes that the novel RNA microchip will someday lead to greater and quicker automation of the detection process than is currently achieved by established strategies.
“Our ultimate goal is to design and construct a portable device the size of a camera, so that you can bring one with you, or it can be personalized to quickly analyze what’s going on in food, water, earth and air,” Huang said.
Foundations for the future
The reality of cancer, as well as of research into the disease, is that there is no magic bullet that will miraculously end the disease.
Cells, not to mention the DNA and RNA responsible for their reproduction and protein generation, are so incredibly complex that no single researcher could possibly find all the answers to the questions about how they become cancerous, reproduce, metastasize and die.
Through the support of the Georgia Cancer Coalition and other entities like the American Cancer Society, the National Institutes of Health and the National Science Foundation, Georgia State researchers and their global colleagues seek to further understand cancer cells and, hopefully, improve methods of detection and destruction.
“It’s overwhelming in a way, because in my lifetime, we may not solve all of the answers,” Greer said. “I think we’ll make a difference, but it’s incredibly complex.
“The good news is that there are many people working on answering these questions. And every year, we become better and better, because the technologies available become much better in allowing you to find answers.”
Georgia State’s Distinguished Cancer Scholars
Georgia State University’s Georgia Cancer Coalition Distinguished Cancer Clinicians and Scientists work to not only find new treatment and detection methods for cancer, but to prevent it.
The Georgia Cancer Coalition brings together government agencies, academic institutions, civic groups, corporations and health care organizations to help strengthen cancer prevention, research and treatment with a goal of making Georgia one of the nation’s top states for cancer care.
In addition to Germann, Greer, Huang, Wang and Weber, the university’s 10 Cancer Coalition scholars include:
• Michael Eriksen, director of the Georgia State Institute of Public Health, tobacco control
• Robert Harrison, professor of computer science, cancer bioinformatics
• Zhi-Ren Liu, professor of biology, gene regulation
• Yujun Zheng, assistant professor of chemistry, biochemistry
• Donald Hamelberg, assistant professor of chemistry, aberrant cellular processes in cancer