Crystals Tell the Future of Human Disease Manal Swairjo Explores New Molecular Clues from Ancient Times
Pomona, Calif. - 09/05/2006 -- Ever since the discovery (in the early 1940's) that DNA contains the genetic code, science has been content with explaining how a certain human disease is caused by improperly coded or "sick" genes. We know that some of us are more disposed to certain diseases because we carry certain genes. Cancer is a good example. We also know that environmental pollutants, bad diet, stress, and other apparently non-genetic traits can give one of identical twins a disease, but not the other. The dichotomy stands to this day and we call it nature or nurture.
WesternU Assistant Professor of Biochemistry Manal Swairjo, Ph.D., and her team of collaborators at the University of Florida, Gainesville and at Portland State University, are currently exploring this dichotomy with molecular light. Swairjo decided to re-visit the belief that genes tell it all when she was a staff scientist the Scripps Research Institute working on the unique properties of Ribo Nucleic Acid (RNA), particularly the kind that transfers instructions from the gene to the protein, called transfer-RNA (tRNA).
"For nearly 50 years now we've taken Francis Crick's idea that "DNA makes RNA makes protein" as our central dogma in molecular biology. We viewed RNA as merely an intervening stage between the gene and the protein. We neglected RNA and even believed much of it was "junk" in our genomes. Our understanding of genes was mainly through the work their protein products did," says Manal Swairjo who joined the faculty at the College of Osteopathic Medicine of the Pacific this Fall.
Since the late 1990's, however, RNA sat in a new spotlight when molecular biologists found that it could do a lot more than play the handoff role between genes and proteins. RNA can cut itself and other RNAs, something that only proteins were believed to know how to do. A biophysicist by training and a structural biologist by choice, Swairjo explains: "RNA appears to control so many operations in the cell that one can imagine, should it malfunction, RNA can be a cause of disease. This is called translational control versus transcriptional control ascribed to genes," adds Swairjo, who obtained her doctorate in Cellular Biophysics at Boston University School of Medicine.
Translation of genetic information is how all life forms reproduce and grow. In the modern cell, tRNA the adapter molecule that links the sequence of genetic information encoded by nucleotide triplets in DNA (called codons) with the sequence of amino acids in the expressed protein. Peculiarly shaped like an "L," tRNA carries a corresponding nucleotide triplet (called an anti-codon) on one tip of the "L" and the amino acid cognate for that codon on the other.
During its lifespan in the cell, tRNA undergoes extensive processing by nuclear and cytoplasmic enzymes. Before it leaves the nucleus, the nascent tRNA transcript is trimmed and edited, loaded with the matching amino acid and - most obscurely - chemically modified. It becomes "decorated" with attached chemical groups. While ornamentations of tRNA have been known in the scientific community for decades, many mysteries remain around what they do and how they are made.
Swairjo's current work at Western University of Health Sciences focuses on defining the functions of these complex tRNA ornamentations, how are they made, and the cellular processes that link them to disease manifestation. She believes that these modifications are essential for tRNA function. "They are there to fine-tune the translation process that is inherently imperfect. In fact, it does not have to be perfect. It only has to work. That's the genius of evolution."
Evolution was indeed Swairjo's starting point. She entered the RNA field with an interest in exploring the origins of life and the early evolution of the genetic code. Her choice of systems to do that was none less than expected: ancient micro organisms that are still living on earth and that possess genomes that date back 2.5 billion years. These organisms, such as types of bacteria that live near the volcanic vents at the bottom of the Pacific Ocean, act as living fossils suitable for exploring the early stages of life on earth.
"Because the genetic code is the algorithm of translation of genetic information from nucleic acids to protein, it became clear to me that in order to understand the early evolution of the genetic code, one needs to study the course of evolution of the key molecules of the translation apparatus in the cell," explained Dr. Swairjo, who published several seminal studies in the field of molecular evolution.
"The humbling discovery from the Human Genome Project that humans had no more genes than mice or - worse yet - than a simple weed Arabidopsis led us to think about what generates complexity in biology. Could it be RNA? Then how is RNA made and transported? How is it proof-read and checked for errors? How do we start looking for RNA in the vast field of human diseases of unknown cause?" Swairjo points to recent discoveries linking maternally inherited neurodegenerative diseases with deficiencies in tRNA modifications in the cells of patients. "One can also imagine how malfunction of tRNA leads to mistranslation of proteins which in turn loose function or misfold. The effects must be very small to allow the cell to survive, that's how ancient organisms evolved. Yet, accumulatively, such translation errors can create conditions that manifest themselves in form of late-onset disease."
Swairjo's main technical expertise is in macromolecular crystallography. "We isolate the RNA or protein of interest, and we make a crystal of it. We shoot the crystal with a fine X-ray beam and measure the diffraction. With a complex mathematical operation, we can determine the structure of the crystalline molecule with high accuracy," says Swairjo who has extensive experience in training graduate students and postdoctoral fellows in X-ray crystallography.
Her work also produces some visually compelling images of protein crystals and structures. Photo slides of some of her work are demonstrative of the intuitive aspects of crystallography, "a technique that is known for its magical side," Swairjo exclaims!
Dr. Swairjo's lab has several work-study and volunteer opportunities available. She can be reached at firstname.lastname@example.org.