A biostatistician uses mathematical models to better understand brain networks, possibly leading to advanced treatments
Why are some people able to give up alcohol with ease, while others struggle for years? That's the question driving the work of biostatistician Laura Saba, PhD.
Saba is an associate professor of bioinformatics at the Skaggs School of Pharmacy and Pharmaceutical Sciences at CU Anschutz. Her lab investigates the biological mechanisms underlying diseases such as alcohol use disorder (AUD) to inform drug development, while also working to identify individuals who may benefit from specific treatments based on their genetics.
"Alcohol use disorder is a heterogeneous disease, and we still don't fully understand all the pathways involved," Saba said. "We don't even know exactly which brain regions or cell types are most important."
AUD is estimated to be about 50% heritable, meaning genetic factors play a role in developing the disease. This estimate comes from studies on twins separated by adoption and is verified by animal studies, Saba said.
As a biostatistician, Saba uses mathematical models that could lead to pharmaceutical interventions for people with AUD.
"I'm working to mathematically describe the 'nature' part - specifically, the biological link between a genetic difference and the alcohol-related phenotype we observe in the lab," she said. "Alcohol use disorder is not a 'pull yourself up by the bootstraps' type of illness, which is hard for people to understand and accept. I hope our work can help people better understand how this disease causes real and incredibly complicated physical changes in the brain.
This article is part of a CU Anschutz Newsroom series exploring addiction, a serious public health issue our doctors and researchers are working hard to address.
Examining the genetics of 'tolerance'
In the 1990s, a groundbreaking study by Marc A. Schuckit, MD, linked genetics to AUD. He followed a group of sons of individuals with AUD, beginning in childhood and tracking them over 30 years to see who developed the disorder and who did not.
An anecdote from his early work stuck out to Saba and other researchers.
"When interviewing people with alcohol use disorder, many would say things like, 'For years, I was the person who could drink 12 beers and still drive home. Alcohol didn't affect me. I had a really high tolerance,'" she said.
People who don't immediately feel the rewarding effects of alcohol tend to drink more, Saba said.
"Alcohol is a toxin, so even for people who don't feel the effects, it's still affecting their brain," she said.
The study found that people with a high tolerance are more likely to suffer negative consequences through continued use, pulling them deeper into the addiction cycle. Once people fall into the addiction cycle, they have less control of their drinking and find it hard to stop, even if it's hurting them.
The groundbreaking nature of Schuckit's study led Saba to begin studying tolerance and other traits related to AUD in 2005, collaborating with Boris Tabakoff, PhD, professor at the Institute for Behavioral Genetics at CU Boulder and Paula Hoffman, PhD, professor emerita at CU Anschutz School of Medicine.
Isolating traits of alcohol use in the lab
To better understand the role genes play in AUD presentations, Saba and her colleagues used animal models to break down measurable behaviors. They isolated behaviors and measured degrees of consciousness, motor coordination and other behavioral patterns associated with alcohol self-administration.
Early paradigms looked at choice, giving the mice an option to choose between water and alcohol. Even in passive studies, Saba noted that while they didn't often drink to intoxication, they did choose to drink alcohol. This helped her team investigate why one animal drinks more than another.
"As a statistician, this lets me track the full sequence of behaviors, measure brain traits, and compare animals with and without alcohol exposure to see where differences emerge," Saba said.
It's ongoing work. Because there's no single "alcohol use disorder gene," it's allowing her to look at genetic differences that can disrupt the brain and increase susceptibility.
Does immunity play a role in alcohol use disorder?
Tabakoff and colleagues were one of the first to propose a role for immunity in the brain related to alcohol susceptibility. It's an idea that Saba says is showing up in human studies as well.
"In the last 10 years, we're starting to gather evidence of the way your brain's immune system reacts to external stimuli - how it responds to what it sees as 'invaders' - and how this might play a key role in how susceptible someone is to alcohol use disorder," Saba said.
Heritability doesn't mean AUD is destined
Unlike some genetic diseases - such as the connection between BRCA1 and BRCA2 gene mutations and breast cancer - alcohol use disorder depends heavily on environment and behavior.
"We have to be careful when we talk about 'predisposition,' genetically-speaking. It doesn't mean someone is destined to develop alcohol use disorder, because you still have to drink for that to happen," Saba said.
Her work isn't about predicting who will drink and who won't. Instead, her team focuses on understanding networks in the brain to understand why some animals are resistant.
Finding needles in a genomic haystack
Saba and colleagues aim to identify the networks associated with resistance to AUD in the mice and rats they've studied using big data and omics approaches. They were able to identify a network associated with alcohol consumption in the two-bottle choice test, which identified some animals that loved alcohol and others that wouldn't touch it.
They identified a gene in the middle of a network that wasn't included in a gene annotation database.
"The gene didn't have a name, and we didn't know what it did, or even if the gene made a protein or acted as a regulator," she said. Working with another group, they used CRISPR-Cas9 - a gene editing tool - to remove the gene in the animal models to observe the behavior.
Rats without this unnamed gene drank more alcohol than those with it.
They also looked at how other genes changed as the result of the removal of this gene.
"We found evidence that this gene regulates how RNA is processed in cells, and this is helping us to better understand its role," Saba said.
Why lab work is important to understand AUD
It's enormous work to identify the myriad ways genes express. Saba and her colleagues continue to comb the data from the animal-based alcohol studies, contributing to the body of work happening worldwide to unravel the mysteries of AUD.
"The nature of alcohol use disorder is truly devastating - not just for the person who has it, but for their loved ones as well," she said. "Ultimately, I hope the work we're doing will go toward raising awareness and improving intervention."
