Genetic diseases can be cured using synthetically-produced proteins and knowing how a pathogen’s proteins bind to DNA can help create these cures. In 2009, Prof. Adam Bogdanove, plant pathology and plant-microbe biology, and his research team at Iowa State University, discovered “a mechanism by which bacterial proteins specifically recognize DNA targets,” a discovery that allowed him to be named one of nine runner-ups for Science Magazine’s “Biggest Scientific Breakthroughs of 2012.”
The biggest breakthrough of the year, according to Science Magazine, was the discovery of the Higgs Boson.
Bogdanove’s research involves studying how bacterial plant pathogens – microorganisms that cause diseases in a host – inject proteins called “transcription activator-like effectors” into plant cells during the infection process. According to Bogdanove, the proteins are then transferred into the nucleus, at which point “they find sequences in the genome that are specific to each individual effector.”
Basically, proteins are strings of amino acids, each of which have a specific shape, analogous to Lego blocks.
According to Bogdanove, just as Lego blocks need to fit perfectly in order to stay firmly attached, each individual protein also latches onto a location in the genome that happens to fit its specific shape perfectly. These TAL effector proteins can activate the expression of certain genes and ultimately alter the host cell’s biology.
The implications of activating genes are significant. Every cell in the body contains the same genome, so why is the functionality of a hair follicle cell different than the functionality of a kidney cell? Each type of cell activates a different set of genes, so by altering the activation of genes, the functions of a specific cell could be completely distorted. TAL effectors, for example, distort the plant cell function in ways that benefit the pathogen.
Additionally, Bogdanove notes that “there are circadian rhythms to our gene expression.” These cycles cause the pathogen to secrete hormones into our blood streams which make control sleepy-ness or hunger, as well as many other functions. By altering the activation of genes, these cycles could be disrupted.
Bogdanove was also involved in discovering that “at least one class of pathogens have figured out how to alter gene expression in plant cells to benefit the pathogen.”
One example of these pathogens is Bacterial Blight of Rice. During infection, the bacteria inject a TAL effector, which activates a certain gene in rice which encodes a protein that transports sucrose.
“The pathogen teases the cell into secreting sugar into the apoplast, or extracellular space,” Bogdanove said. This sugar secretion becomes food source for the pathogen.
Bogdanove’s largest discovery, however, was the determination of exactly how TAL effector proteins recognize where to bind in the genome. Within each sequence of 34 amino acids in a TAL effector, Bogdanove noticed that the only different amino acids are the 12th and 13th spots.
Using a computational method, Bogdanove and his team discovered that “the way these proteins recognize the sequence of DNA bases to bind to is exactly the 12th and 13th amino acids, which are different in every amino acid sequence within a protein.”
They hypothesized that each set of those two amino acids calls out a single nucleotide in the DNA. By pulling out just the 12th and 13th amino acid positions of each sequence, only the specific sequences are encoded which allow the protein to know where to bind to in the genome.
The most important result of Bogdanove’s discovery that amino acid sequences in proteins are the same except at the 12th and 13th positions is that researchers can now create a protein that binds to a particular DNA sequence. Unlike how pathogens harm the host, scientists can now find proteins that could bind to certain locations of the genome in order to benefit the host.
Another important application of Bogdanove’s research is the determination of the functionality of certain genes. Using TAL effector proteins fused to DNA-cutting enzymes, scientists can break the genome at a certain location to target a certain gene and see the implications of disabling that specific gene.
Future research may focus on genetic disorders such as cystic fibrosis, which is caused by specific genes which can now possibly be targeted and eliminated.
Original Author: Amit Blumfield