Crystals Tell the Future of Human Disease Manal Swairjo Explores New Molecular Clues from Ancient Times

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 mswairjo@westernu.edu.