Programmed cell death sounds a lot like premeditated suicide. And that’s probably because it is premeditated suicide.
Santosh D’Mello, Ph.D., professor of molecular and cell biology with a joint appointment in the School of Brain and Behavioral Science, has made a career of investigating this form of suicide.
“The focus of my lab is a process called apoptosis,” D’Mello said. “Apoptosis, a suicide process in cells, is a Greek word that refers to the falling of leaves every autumn.”
But what if that program gets out of whack, allowing cell after cell to die in a never-ending chain reaction or permits cells that are set to die to live on indefinitely?
“Every cell in the body is built with a suicide program, and the suicide program lies dormant for the most part,” D’Mello explained. “But when it is beneficial for the body to get rid of the cell – for example, a cell that is infected with a virus or bacteria – that happens through this process called apoptosis. It’s called programmed cell death because it really is a highly organized and choreographed program within the cell that is activated if and when needed. Hundreds of proteins are involved in controlling this program.”
D’Mello said a lot of apoptosis occurs in our nervous systems during embryonic development – such as the sculpting of the fetus when the tissue between fingers has to be carved out.
“The brain builds itself with twice as many cells as it needs,” he said. “There is a pruning of cells that are superfluous or that don't make proper neural networks, and that is an essential part of brain development. It’s one of the last phases of brain development but a critical step.
“But we now know that although beneficial during brain development, the suicide process also can be triggered accidentally or aberrantly in neurons. This happens in certain neurological diseases, such as Alzheimer’s, Parkinson’s or Huntington’s disease, or in conditions such as ischemic stroke or traumatic brain injury. In all these cases, the body doesn’t really want to lose brain cells but the suicide process within populations of neurons is somehow triggered and cells die in large numbers. In this context, it is of no benefit. It makes a person sick and is often fatal,” D’Mello said.
“And then there is another extreme of this process where cells cannot kill themselves,” D’Mello added. “Many cancers result not from cells proliferating out of control but because cells that have served their function and normal life-span can’t kill themselves and therefore survive indefinitely. They continue to divide, generating more cells like themselves, and ultimately generate tumors.”
Many applications with implications for the future
D’Mello said that understanding how apoptosis is controlled is of interest to clinicians, and biotechnology and pharmaceutical companies, wanting to cure disorders such as cancer, stroke or neurodegenerative diseases.
D’Mello’s work focuses on neurons, the brain cells that are responsible for cognition, language, emotions, as well as the regulation of movement and the proper functioning of other organs.
“We feel that neurons will have a much more complex control of apoptosis than other cell types because neurons are part of the brain, upon which the survival of animals has depended through evolution.
“The death of a neuron, which is a cell that cannot be easily regenerated, is a serious issue. Animals, including humans, can’t afford to lose neurons accidentally,” D’Mello said. “There must be more stringent control of this process [apoptosis] in neurons as compared with other cell types in the body, simply because they are critical for the functioning of the body and cannot be replaced.”
Support for D’Mello’s research continues to flow. This summer he was awarded a $1.6-million grant by the National Institute of Neurological Disease and Stroke, an arm of the National Institutes of Health (NIH), to study chemical compounds that could be used to treat neurodegenerative diseases.
A chemical compound called GW5074 “has really amazing neuro-protective properties,” he said. “It works in tissue-culture models of neurodegeneration, that is, it prevents the degeneration of neurons in culture dishes. GW5074 is also effective in animal models of neurodegeneration, such as a mouse model of Huntington’s disease.”
“We are currently testing this compound in a model of Parkinson’s disease and our preliminary results look promising,” D’Mello said. “We hope that this compound or derivatives of it will be used in human clinical trials for disorders such as Alzheimer's or Parkinson's disease. It would be terrific to see a treatment for these devastating diseases in my scientific lifetime.”
He also has two other federal research grants: One from the Department of Defense to find out how different neurotoxins induce apoptosis and thus kill brain cells, and a second one from the NIH..
“Our assumption is that the mode by which these different neurotoxins act could have common features. If this is the case, our hope is that once we find out the common molecules that are involved in the death of neurons by different chemical neurotoxins, we can deactivate these molecules and maybe prevent neurotoxin-induced brain damage in humans in the future,” he said.
The NIH grant studies the molecules within neurons necessary for the survival of these cells. “Activating such molecules in the brains of patients with neurological diseases could prevent the aberrant loss of neurons and thus preserve neurological function,” D’Mello said.
He also is studying stem cells for possible applications.
About the students...
Like other UTD professors, D’Mello has a healthy amount of respect for the student body.
“I really think the students here are top-notch. I’ve been impressed by undergraduates, both in the classroom as well as in my lab,” he said. “I had an undergraduate a few years ago who did her honors research in my lab who single-handedly did much of the preliminary work on which a major NIH grant was based. Other undergraduates in my lab have also made huge contributions to my research program. So we really have outstanding undergraduates. I have also been most fortunate to have superb graduate students in my lab. These students can compete with the very best.”
D’Mello said that teaching here is much easier because students are actually interested in learning, maybe sometimes a little too interested.
“I think there is a little bit of an overemphasis on good grades – but overall there’s a better body of students here than any other place I have taught."
D’Mello is also impressed with the breadth of UTD’s biology department.
“There is a lot of molecular and cell biology going on here, and I can connect to more scientists with similar research interests as mine. That was one factor that brought me to UTD."
The Dallas area was another draw.
“I had lived in the Northeast long enough and my enthusiasm for cold weather had waned, so Dallas seemed like an attractive city to move to. The people in the department were friendly and energetic, and when I was considering moving from the University of Connecticut, UTD felt like a very good institution to be in,” D’Mello said.
D’Mello, who is married to Carmela and has a daughter, Anila, enjoys living in Dallas.
“Both my wife and I grew up in crowded cities -- Carmela in Naples, Italy, and I grew up in Bombay -- and we like living in big cities. We have lived in Boston, which we loved, and Pittsburgh, a smaller city but quite dense. There were a lot of people and a lot of activities going on all the time. Although Dallas does not have the same atmosphere, we live south of LBJ so that we can spend time downtown as much as possible,” he said.
D’Mello said he feels especially optimistic about the future at UTD.
“Based on how things have grown over the past few years, it certainly looks like UTD has spectacular potential. Many people like me want to be part of an organization as it is growing, in the case of UTD, to a tier-1 research institution. That’s where I think UTD is going to be in a few years. I’m excited about being part of the process."
- Updated: February 6, 2006