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
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 email@example.com.