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By Cindy Landrum<\/b>
\nPhotography by Josh Wilson<\/b><\/p>\n<\/div><\/section><\/div><\/p>\n
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Study lays groundwork for developing drugs to treat or prevent addiction in humans<\/strong><\/p>\n<\/div><\/section><\/div> To most people, fruit flies<\/span> are aggravating little pests that show up in their kitchen when they leave ripening bananas or other fruit on the counter too long.<\/span><\/p>\n But geneticist Trudy Mackay, who has directed the Clemson University Center for Human Genetics since it opened in 2018, has a much more endearing moniker for the flying insects.<\/span><\/p>\n \u201cThey are wonderful little beasties,\u201d she says.<\/span><\/p>\n And she gets them drunk, plies them with cocaine, exposes them to heavy metals and manipulates their DNA. It\u2019s all a part of her quest to discover the genetic roots of complex traits \u2014 traits that are influenced by multiple genes \u2014 that are important to human health.<\/span><\/p>\n The Center for Human Genetics is a state-of-the-art research and education facility in Self Regional Hall on the campus of the Greenwood Genetic Center in Greenwood, South Carolina. Mackay, widely recognized as a leading authority on the genetics of complex traits, is showing a visitor around the facility when she stops in the hallway at the door to what appears to be a closet.<\/span><\/p>\n It\u2019s not.<\/span><\/p>\n<\/div><\/section><\/div> Inside, there is what looks, at first glance, to be a cooler. But the air is a balmy 77 degrees. \u201cHere\u2019s where we keep the flies,\u201d Mackay says. Trays of test tubes fill the shelves. The vials hold hundreds of thousands of the common fruit fly, Drosophila melanogaster.<\/i><\/p>\n You may wonder how flying insects smaller than a grain of rice could answer questions that have puzzled geneticists for decades \u2014 how they may reveal why some people who use drugs or drink alcohol become addicted while others do not. Or unlock the secret to longevity. Or explain why a genetic disorder severely affects some members of a family but only causes minor symptoms in others.<\/span><\/p>\n Despite the stark differences in physical appearances, Drosophila melanogaster<\/i> has much more in common with humans than one would think at first glance.<\/span><\/p>\n \u201cThe remarkable thing is that 75 percent of human disease genes actually have a counterpart in the little fruit fly,\u201d says Mackay, a U.S. National Academy of Sciences member who started working with the fruit fly in graduate school. \u201cOur findings can be translated into humans.\u201d<\/span><\/p>\n<\/div><\/section><\/div> \u201cThey are wonderful little beasties.\u201d<\/strong><\/p>\n<\/div><\/section><\/div> Nearly Impossible<\/b><\/span><\/p>\n It\u2019s difficult to study <\/span>some traits in humans.<\/span><\/p>\n Take substance abuse. The National Survey on Drug Use and Health estimates that approximately 20 million people in the U.S. age 12 and over have a substance abuse problem. About 5.5 million adults reporting in that same survey used cocaine in 2019, and about 1 million people abused methamphetamine. But researchers know many more people use drugs or drink alcohol and don\u2019t become addicted. What they don\u2019t know is why.<\/span><\/p>\n \u201cWe can\u2019t give people cocaine or not. We can\u2019t give people alcohol or not,\u201d Mackay explains. \u201cScientists can do association analysis of people who abuse drugs and those who have taken them but don\u2019t become abusers. But those studies are difficult to do, and there\u2019s always going to be the complication of not being able to control the environment. People self-medicate. They typically don\u2019t do it with just one drug. Often, there\u2019s smoking and nicotine involved, and there may be more than one drug of abuse. It\u2019s a thorny problem that is almost impossible to solve in humans.\u201d<\/span><\/p>\n<\/div><\/section><\/div> Full Control<\/b><\/span><\/p>\n But controlling both genetics <\/span>and environment in fruit flies is easy, thanks partly to Mackay\u2019s decision nearly 20 years ago when she was on the faculty of North Carolina State University.<\/p>\n Her lab needed some fruit flies to use in its research, so Mackay asked Richard Lyman, one of the lab\u2019s research scientists, to go to the State Farmers Market in Raleigh during the peach season to collect some. Lyman captured over 1,000 pregnant female fruit flies. After he returned to the lab, he inbred the flies for 20 generations. The inbreeding virtually eliminated genetic variation in each of the lines.<\/span><\/p>\n Those flies were the start of the Drosophila Genetic Reference Panel, a valuable resource Mackay\u2019s lab developed for researchers from all over the world to use. The original panel of 200 lines now comprises 1,200 fly lines with fully sequenced genomes. Lyman also moved to the Clemson Center for Human Genetics to direct the Drosophila Research Core.<\/span><\/p>\n Mackay\u2019s latest collaborative research involved giving male and female flies a fixed amount of sucrose or cocaine-laced sucrose over two hours.<\/span><\/p>\n \u201cWe just dissolve the drugs in a sugar-water solution and give it to them,\u201d says Brandon Baker, who recently earned his Ph.D. in genetics at Clemson and worked in Mackay\u2019s lab both at the Center for Human Genetics and at North Carolina State University. \u201cWhen we do that, we actually can see some effects that we see in humans in the flies.\u201d<\/span><\/p>\n The flies exposed to cocaine in this experiment showed impaired locomotor activity and increased seizures.<\/p>\n It\u2019s what Mackay and her collaborators, including her husband and fellow scientist Robert Anholt, did next \u2014 and how they did it \u2014 that broke new ground.<\/span><\/p>\n They identified specific cell clusters in the fruit fly brain affected by acute cocaine exposure, a discovery that potentially lays the groundwork for the development of drugs to treat or prevent addiction in humans.<\/span><\/p>\n To assess the effects of cocaine consumption on brain gene expression, the researchers dissected the fly brains and dissociated them into single cells. Using next-generation sequencing technology, they made libraries of the expressed genes for individual cells. The study looked at nearly 89,000 cells, each of which has thousands of transcripts. Through sophisticated statistical analysis, the researchers could group them into 36 distinct cell clusters.<\/span><\/p>\n \u201cWe identified the regions of the brain which are important. Now, we can see what genes are expressed when exposed to cocaine and whether there are Federal Drug Administration-approved drugs that could be tested, perhaps first in the fly model. We\u2019ve already spotted several of these genes,\u201d Mackay says.<\/span><\/p>\n Researchers can now leverage this work to understand potential therapies, explains Mackay, the Self Family Endowed Chair in Human Genetics.<\/span><\/p>\n<\/div><\/section><\/div><\/div><\/div><\/div><\/div><\/div> First Time<\/b><\/span><\/p>\n The study marks the first time<\/span> scientists have scanned the entire brain of the fly in one comprehensive experiment to reveal new brain regions involved in the response to cocaine, says Susan Harbison, who has worked with Mackay and is now an investigator with the National Institutes of Health\u2019s National Heart, Lung and Blood Institute in Bethesda, Maryland.<\/p>\n Harbison says that before this work, the only way to identify which brain regions responded to cocaine was very laborious with no guarantee of success.<\/p>\n Wen Huang, an assistant professor in Michigan State University\u2019s Department of Animal Sciences who did postdoctoral research in Mackay\u2019s lab when she was at North Carolina State, calls the work \u201ca huge advance.\u201d<\/p>\n \u201cWithout getting to this kind of single-cell cellular detail, what you have is a very blurred picture,\u201d he says.<\/p>\n Huang compares it to somebody attending a large party and taking a picture of everybody who was there. \u201cThe pixels are pretty big. You can\u2019t really look at all the details,\u201d he says. \u201cWith this type of technology, you can look at every single cell and identify different cell types based on their gene expression. It\u2019s just like when we look at people. You can recognize them as a whole, but they have subtle details that tell them apart.\u201d<\/p>\n Additional research by Baker identified nearly 1,000 genes that were involved in variation in voluntary consumption of cocaine and methamphetamine.<\/p>\n<\/div><\/section><\/div> Against the Grain<\/b><\/span><\/p>\n Baker says when he first began researching cocaine and methamphetamine, the drug abuse research field did not readily accept fruit flies.<\/p>\n \u201cTrudy taught me it\u2019s OK to go against the grain, that it\u2019s OK not to do exactly what\u2019s popular if you have a good belief that it\u2019s going to work,\u201d he says. \u201cWe\u2019ve been able to show through our hard work that flies are an excellent system to find genes that are important.\u201d<\/p>\n Going against the grain is nothing new to Mackay.<\/p>\n \u201cWhen I worked with her,\u201d explains Harbison, \u201cI was fascinated by her idea that one could understand complex traits studying naturally occurring variants across the genome and that by applying quantitative genetics to the data, one could examine the genetic architecture of a trait holistically. Her approach differed completely from classic reductionist approaches.<\/p>\n \u201cShe\u2019s been at the forefront of the move from single-gene analysis to the elucidation of entire genetic networks influencing complex traits,\u201d Harbison continues. \u201cThe payoff has been tremendous in terms of increasing our understanding of complex trait biology.\u201d<\/p>\n<\/div><\/section><\/div> They identified specific cell clusters in the fruit fly brain affected by acute cocaine exposure, a discovery that potentially lays the groundwork for the development of drugs to treat or prevent addiction in humans.<\/strong><\/p>\n<\/div><\/section><\/div> Drawn to Genetics<\/b><\/span><\/p>\n Mackay\u2019s interest in the emerging field<\/span> of genetics started when she took an advanced biology class in 10th grade that included genetics, along with laboratory experiments working with Drosophila.<\/i><\/p>\n \u201cIt just fascinated me,\u201d she says. \u201cI\u2019ve always enjoyed quantitative biology, the math part of it, and anybody who likes animals gets fascinated by how they\u2019re all the same breed, but they all look different. Unlike other fields, people first studying genetics in school are fairly easily divided into two groups and two groups only: \u2018I don\u2019t get it\u2019 and \u2018I get it.\u2019 It\u2019s this great divide with no middle ground. I was in the \u2018I get it\u2019 group. It just clicked for me.\u201d<\/p>\n Her first project as an undergraduate at Dalhousie University in Canada didn\u2019t involve fruit flies. Instead, she studied Sprirorbis borealis,<\/i> an aquatic worm prevalent off the coast of Nova Scotia that decided between two kinds of seaweed as its lifetime substrate.<\/p>\n \u201cThe big question was why did they choose? Was there any genetic variation to it? Indeed, there was, but it was the 1970s and there was no way to figure out anything other than they were genetically different because we had no genetics in non-model organisms,\u201d she says.<\/p>\n Mackay decided the more purely genetic questions drew her in, so she picked the fruit fly as her research vehicle.<\/p>\n She moved to Edinburgh, Scotland, to pursue her Ph.D. at the University of Edinburgh. \u201cEdinburgh was, and still is, the best place to go for quantitative genetics,\u201d she says.<\/p>\n There, she worked with Alan Robertson, one of the leading researchers in the field. She put fruit flies in either constant or variable environments and tracked their genetic variation over time.<\/p>\n After spending time on the faculty at Edinburgh, Mackay took the faculty position at North Carolina State in 1987.<\/p>\n<\/div><\/section><\/div><\/div><\/div><\/div><\/div><\/div> Love of Horses<\/b><\/span><\/p>\n She soon met Anholt. <\/span>Neither research nor fruit flies brought them together. Instead, it was their mutual love for horses.<\/p>\n A friend asked if she wanted to go on her first fox hunt. \u201cI really wasn\u2019t interested in hurting a poor fox,\u201d she says. After getting assurances they wouldn\u2019t actually catch anything, Mackay agreed to go on the fox hunt at the Red Mountain Hunt Club in Rougemont, North Carolina.<\/p>\n \u201cTrudy was riding a horse. My horse was lame, so I was serving champagne at the start of the hunt,\u201d Anholt recalls.<\/p>\n They later discovered they were both scientists. Eventually, Mackay convinced Anholt, a faculty member at Duke University whose research centered around olfactory behavior, to work with the Drosophila<\/i> model.<\/p>\n They did their first experiments together at the kitchen table. \u201cI brought odor solutions home. She brought fruit flies home, and we developed an assay to measure behavior to odorants on the kitchen table,\u201d Anholt says.<\/p>\n While at North Carolina State, Mackay\u2019s interest in identifying the genes affecting complex traits continued, and she did the first genotype-phenotype association studies in flies, looking at the relationship between genes and their observable characteristics.<\/span><\/p>\n \u201cThose first studies showed that it is much more complex than anyone realized,\u201d Mackay says.<\/span><\/p>\n That\u2019s why they developed the Drosophila Genetic Reference Panel.<\/span><\/p>\n \u201cIn the next phase of our work, we just went to town measuring practically everything we could think of, from sensitivity and resistance to alcohol, lead, cadmium and paraquat, all these different environmental stressors,\u201d says Mackay. \u201cI was interested in lifespan, starvation resistance. Robert was interested in olfactory behavior. We also wanted to figure out the underlying molecular networks, not just one gene at a time but how they interact together. That\u2019s what started us down the RNA sequencing path that culminates today with single-cell RNA sequencing.\u201d<\/span><\/p>\n<\/div><\/section><\/div> The Center for Human Genetics has already done complete genome sequencing of three patients with rare but undiagnosed genetic disorders and their parents. Two of the three now have diagnoses, and they\u2019re still working on the third.<\/strong><\/p>\n<\/div><\/section><\/div> Advancing Human Genetics<\/b><\/span><\/p>\n When they moved to Clemson <\/span>and the Center for Human Genetics, Mackay and Anholt officially combined their labs.<\/p>\n \u201cI tell people Trudy is the brains, and I\u2019m the cheerleader,\u201d Anholt says.<\/p>\n They are continuing their research into complex traits, including substance abuse and lifespan.<\/p>\n \u201cWe have lines of flies that live twice as long as the average fly, and we want to know why,\u201d Mackay says.<\/p>\n The National Institutes of Health recently awarded Clemson $10.6 million to establish the Center of Biomedical Research Excellence in Human Genetics in collaboration with the Greenwood Genetic Center. Mackay, Anholt and Richard Steet, the Greenwood Genetic Center\u2019s director of research, will direct the effort, which is the NIH\u2019s first center specifically focused on human genetics.<\/p>\n The center will cover common disorders, such as cardiovascular disease, cancer and neurodegenerative diseases as well as very rare genetic disorders.<\/p>\n The Center for Human Genetics has already done complete genome sequencing of three patients with rare but undiagnosed genetic disorders and their parents. Two of the three now have diagnoses, and they\u2019re still working on the third.<\/p>\n \u201cIn one case we solved, the patient had the very first variant ever discovered in that gene,\u201d she says, adding that knowing what the gene is and having a diagnosis could eventually lead to a treatment. \u201cThat may be the most exciting thing we\u2019ve done since we\u2019ve been here.\u201d<\/p>\n New discoveries excite Mackay as much now as they did when she started her career:<\/span><\/p>\n \u201cWe love our jobs because every day is different. We never know what we\u2019re going to find out, what challenges we\u2019re going to meet and what new results we will have. It\u2019s really exciting, like going into the unknown. I think any scientist would say the same thing.\u201d<\/span><\/p>\n When Mackay\u2019s students come to her and tell her they got a result they don\u2019t understand, she tells them that\u2019s the beginning of something exciting.<\/span><\/p>\n \u201cIt\u2019s not science if you know what you\u2019re going to find before you do it. You ask the question, and Mother Nature gives you the answer. You have to go with it because, unless you made a mistake, it\u2019s the answer,\u201d she says. \u201cIt may not be what you expect, but you\u2019re going to learn something new.<\/p>\n \u201cThat\u2019s the beginning of something exciting. The unexpected can lead to the biggest discoveries.\u201d<\/span><\/p>\n<\/div><\/section><\/div> Cindy Landrum<\/b> is a senior science writer in the College of Science.<\/span><\/p>\n<\/div><\/section><\/p><\/div>
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Study lays groundwork for developing drugs to treat or prevent addiction in humans<\/p>\n","protected":false},"author":13,"featured_media":24143,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[4],"tags":[563,1197,1201,1365,1437,2730,3093],"coauthors":[],"class_list":["post-24135","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-features","tag-center-for-human-genetics","tag-fall-2021","tag-fall-2021-features","tag-genetics","tag-greenwood-genetic-center","tag-stem","tag-trudy-mackay"],"jetpack_featured_media_url":"https:\/\/clemson.world\/archive\/wp-content\/uploads\/sites\/3\/2021\/09\/Mackay_Fly-Test-Tubes.jpg","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/posts\/24135","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/comments?post=24135"}],"version-history":[{"count":0,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/posts\/24135\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/media\/24143"}],"wp:attachment":[{"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/media?parent=24135"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/categories?post=24135"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/tags?post=24135"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/clemson.world\/archive\/wp-json\/wp\/v2\/coauthors?post=24135"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}