A Ladder to the Protein Moon

by Monica Slinkard

Since the announced completion of the human genome project in April 2003, the scientific community has been working to decipher the meaning of the approximately 24,000 genes in the human genome. In case you don’t remember from high school biology (or chemistry), genes are specific sets of DNA unique to every single organism, and the code contained in a person’s DNA is part of what makes them who they are, for better or for worse.

But when it comes to understanding the exact ways in which DNA differences define unique characteristics of a person at the cellular level, in the way cells function and malfunction, even the most learned academics agree that the science of genomics has a very long way to go.

Dr. Liskin Swint-Kruse, an ASA member and a professor of biochemistry at the University of Kansas Medical Center, has high hopes. Really high — Liskin compares the quest for mastering genomics to the challenge of putting a man on the moon at the turn of the century (the last century). To an early 1900’s stargazer, the impossibility of walking on the dark side of a glowing orb in space is a fitting comparison to the distance scientists must travel before they unlock the subtleties of how DNA works.

The fact is, after decades of work, the functions of ~98% of the human genome are still poorly understood, and even for the ~2% of the genome that codes for the amino acid sequences of proteins, understanding is limited. Amino acids are the building blocks of proteins, which are the molecules that perform many of the functions in every living cell. Each DNA gene specifies a precise combination of amino acids, which in turn gives each protein a specific shape.  Each unique protein shape allows it to bond to specific molecules or carry out a specialized task. Although the ability to “read” amino acid sequences from DNA sequences is robust, there is still a huge gap in understanding as to when polymorphisms (changes in gene and protein sequences alter a protein’s function.

For any given protein, some amino acids are essential to maintain the integrity of the protein’s structure and function, and most research has focused on studying amino acids that have this critical impact. In general, these amino acids do not tolerate polymorphisms well — for example, a mutation could cause a genetic disease. However, other regions of the protein can tolerate polymorphisms. Some of these “nonconserved” amino acids have little biological effect, whereas changes at other nonconserved amino acids can give rise to important functional variation (and ultimately, unique individuals).

Several algorithms have been written that attempt to identify important amino acid positions. Unfortunately, the algorithms require several assumptions about proteins that are not yet confirmed by — or sometimes do not agree with — actual experiments.

According to Liskin and colleagues at KUMC, one possible resource to identify the functionally-important amino acid positions is to compare the amino acid sequence of related proteins (homologs) that are found within and between different species. These protein “families” have similar sequences of amino acids and similar gross structures and functions, but each protein in the family differs at the nonconserved amino acid positions and can have a unique variation of the common function. The algorithms were created within the realm of working knowledge regarding protein structure and function, but some of the current working knowledge is based on limited experimental data.

The goal of Liskin’s research is to fill this gap.  Using a protein family common to bioinformatics studies, her group has engineered synthetic family members that allow systematic experimental studies of amino acid changes. Using these proteins, they have demonstrated that many more amino acid positions have biologically significant roles than previously thought. For example, Liskin’s team demonstrated that amino acids don’t have to be in direct contact with a binding partner to make a large functional contribution, and that “conservative” changes between chemically-similar amino acids can have a much bigger impact on protein function than expected. These results reveal the imperfect assumptions underlying interpretation of genetic change — as is often the case with God’s creation, little of what we take for granted is actually insignificant.

Liskin’s work is exciting, but it highlights how the scientific community is just beginning to comprehend the complexitiesandnuance that arise from variations in DNA sequence. Liskin notes that when she presents her breakthrough research at conferences, scientific colleagues are sometimes discouraged by the reality that we are still far from fully understanding protein function. Given the complexity, some colleagues have even suggested that we will never be able to predict the functional outcomes for many amino acid changes.

Then again, if everyone had listened to the naysayers of space travel, there wouldn’t be an American flag on the moon right now.

This  research may not be as visibly heroic as moon-walking, but it is of great importance to doctors, biological engineers, and other scientists who want to both understand how genomic changes evolve new protein functions here on earth, to use genomic differences to improve medical diagnostics, and to engineer new protein functions for biotechnology.

In Liskin’s spare time, she shares her passion for science at her children’s schools and at her church. She runs hands-on science activities at “Science Night” at her kids’ elementary school and leads discussions for an international women’s education organization. She encourages children to pursue the delight of science in the religious context at her United Methodist church by developing various activities (which she would be happy to share with anyone interested), which bring Bible teachings to light through science. Liskin shares, “I hope the kids will feel that science and religion have always been integrated in their lives and not be pushed into the ‘either-or’ position.”

If you have more questions for Liskin, you can reach her at lswint-kruse@kumc.edu

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