School of Biological Sciences | College of Science

How symbiosis helps define evolution

September 4, 2024

At the School of Biological Sciences at the University of Utah, the Dale Lab, along with U biologists Sarah Bush, Dale Clayton (Clayton/Bush Lab) and Robert Weiss U Human Genetics, in addition to collaborators from the University of Illinois (Kevin Johnson) and Virginia Commonwealth University (Bret Boyd) are exploiting an amazing biological system to study the relative contributions of stochasticity, contingency and determinism to evolution.

They do this using feather-feeding lice and their symbiotic bacteria that play a critical role in supplementing their host’s overly protein-rich diet of feather keratin. Their paper “Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria” published this summer in Nature Communications.

“Keratin is a protein, and animals can’t live on protein alone,” says Dale. “The bacteria are producing B vitamins that are essential for these lice. Consequently, all feather-feeding lice have bacterial symbionts.”

The Clayton/Bush lab: Bacteriocytes in the abdomen of an adult female Columbicola columbae. Red and green colors show bacterial and louse cells, respectively. The bacteriocytes form conspicuous tissues called ovarial ampullae (oa) that are associated with developing eggs (mature oocytes: mo). Inset shows vertical transmission, with bacterial cells moving from the ovarial ampulla to the posterior pole of an oocyte through follicle cells. Credit: adapted from Fukatsu et al. 2007)

These bacteria are “endosymbiotic” which means they live (obligately) within the cells or bodies of a host animal. Remarkably, these bird lice have been collected from all over the globe, yet they have independently picked up the same species of bacteria to domesticate as vitamin “factories.” Dale recalls a question posed by the famous paleontologist Stephen Jay Gould: If we could see replays of the tape of life, taking place under near-identical conditions, would the process of evolution prove to be repeatable?

“What you have to worry about with Gould’s thought experiment,” Dale states, “is that distinct environmental conditions can induce distinct selection pressures. But since these lice are ectoparasites on birds, they’re buffered against variation in the environment and have no variation in diet. So, it’s one of the best examples of an evolutionary process that has evolved repeatedly under near-identical conditions.”

Symbiotic lifestyle

Mutations are randomly or “stochastically” generated but many do not survive the test of natural selection because they negatively impact fitness. However, upon transitioning to a symbiotic lifestyle, bacteria can withstand the mutational inactivation of many genes because those gene functions are supplanted by genes in their host. In this work, Dale and colleagues found that gene losses in the bacterial symbionts follow a decision tree-like structure that results in the minimization of their gene inventory, through the removal of redundant gene functions. In simple terms, if Gene A and B have redundant functions and the bacteria lose gene A, they are forced to maintain Gene B in order to survive (or vice versa). However, the loss of gene B might then facilitate the loss of genes X, Y and Z because the functions of those genes are uniquely dependent on gene B. Thus, cascading patterns of co-dependent gene loss and retention are initiated as a consequence of distinct stochastic losses in each symbiont genome.

“That’s the beautiful outcome of this paper,” says Dale. “It provides empirical evidence for this long-term trajectory and interplay between stochasticity, contingency and evolutionary determinism.” This has implications for the evolution of mitochondria and chloroplasts, which according to the theory of endosymbiosis, are organelles that used to be independent microbes that became symbiotic with eukaryotic cells in a similar way to these bacteria and the lice.

“Those organelles started off with big gene inventories,” Dale says. “When our cells provided them with an abundance of nutrients, they minimized their functions to retain only those that proved beneficial to their hosts, encompassing photosynthesis in the case of the chloroplast and aerobic energy generation in the case of the mitochondrion.

Notably, these very important traits originated through symbiosis and defined the evolution of plants and animals on Earth.

Cutting-edge of computational biology

The Dale Lab has a substantial focus on computational genomics and data science, catalyzed in large part by a very talented graduate student, Ian James, who obtained his bachelor’s degree in biology from the U and subsequently discovered that he had a talent for computer science. “Ian is extraordinarily creative,” says Dale. “He starts out with biological questions and crafts complex data analysis pipelines, often using machine learning approaches, to obtain answers from big sets of data, ultimately producing some really psychedelic figures.”

Graduate student Ian James engrossed in “the silicon bubble of computational biology." Credit: courtesy of Colin Dale.

In combination with collaborators in Illinois and Virginia, who also utilize cutting-edge computational techniques to understand the patterns of louse and symbiont evolution, James uses pattern recognition and association rule mining to uncover hidden relationships between variables in large datasets to detect contingency in evolution.

“The resulting approaches are really novel and uncover striking and highly supported patterns” continues Dale. “Such approaches also have great potential for understanding the etiologies of diseases such as cancer, that often arise as a consequence of gene(s) becoming damaged.”

While Dale enjoys being trapped in what he calls “the silicon bubble of computational biology,” he also recognizes that field biologists, including Bush and Clayton, play a critical role in enabling this work to come to fruition. It requires specimens collected from all over the world to provide the genetic material for the cutting-edge data science and analysis. Bush and Clayton, along with many other collaborators, have been collecting and studying bird lice for decades, yielding a gift (to science) that literally keeps on giving.

The system has been used to answer many important questions in the field of evolutionary biology and serves as a model for the understanding of co-evolutionary interactions in biology textbooks. “In this case, in the context of symbiosis, this system is actually really interesting because it’s so boring” quips Dale. “Again, it’s the lack of variation in the underlying biology that makes it an excellent candidate for this type of study. I’ve always paid attention to the aphorism stating that ‘all that glitters is not gold.’ It’s also worth noting that sometimes the gold doesn’t glitter at all.”

New bioinformatics major

August 28, 2024

Tommaso De Fernex, Chair of the Department of Mathematics. Credit: Todd Anderson

Tommaso De Fernex, chair of the Department of Mathematics at the University of Utah, has announced a new bioinformatics bachelor's degree (BS) available beginning fall semester 2024. The degree provides rigorous interdisciplinary training to help graduates thrive in rapidly growing sectors.

At the nexus of data science and life and physical sciences, bioinformatics applies intensive computational methods to analyze and understand complex biological information related to health, biotechnology, genomics and more. Through a comprehensive curriculum, undergraduates at the U will gain expertise in a variety of areas that together form an inter-disciplinary, multi-semester laboratory with rich possibilities.

“This major represents a pivotal step in keeping our students at the forefront of biotechnology,” says De Fernex. “It embodies true interdisciplinary collaboration, drawing expertise from biology, chemistry, and computer science faculties. I'm grateful for the dedication of our faculty in developing this program and for our strong partnerships with the medical campus and Utah's thriving biotechnology sector.”

The complexity of life

Another math professor at the U, Fred Adler, agrees. The “study of life” is decidedly complex, says Adler who has joint faculty appointments in biology and mathematics and is currently director of the U’s School of Biological Sciences. “Unraveling that complexity means combining the tools developed in the last century: ability to visualize and measure huge numbers of tiny things that used to be invisible, technology to store and analyze vast quantities of data, and the fundamental biological and mathematical knowledge to make sense of it all.”

Continues Adler: “A few years ago, we heard that biology is the science of the 21^st century. But with all the excitement and innovation in AI and machine learning, it might seem that this prediction was premature. We think nothing could be further from the truth.” Clearly, with the advent of biostatistical modeling, machine learning for genetics, biological data mining, computer programming and computational techniques for biomedical research, he said, “the preeminent role of biology in the sciences” has arrived.

A busy intersection

Bioinformatics is a field that intersects virtually every STEM discipline, developing and utilizing methods and software tools for understanding biological data, especially when the data sets are large and complex. Mathematics, (including statistics), biology, chemistry, physics, computer science and programming and information engineering all constellate to analyze and interpret biological data. The subsequent process of analyzing and interpreting data is referred to as computational biology.

Historically, bioinformatics and computational biology have involved the analysis of biological data, particularly DNA, RNA, and protein sequences. The field experienced explosive growth starting in the mid-1990s, driven largely by the Human Genome Project and by rapid advances in DNA sequencing technology, including at the U.

The new bioinformatics bachelor’s degree also complements the University’s storied graduate program in biomedical informatics, run by the Department of Biomedical Informatics at the Spencer Fox School of Medicine.

High-growth career field

The field of bioinformatics is experiencing rapid growth, with the U.S. Bureau of Labor Statistics projecting a 15% increase in related jobs over the next decade, outpacing many other occupations. Graduates with a bioinformatics degree can expect to find opportunities in diverse sectors, including biotechnology, pharmaceuticals, healthcare and research institutions. The interdisciplinary nature of this degree equips students with a unique skill set that combines biological knowledge with computational expertise. This blend of skills is increasingly valuable in today's data-driven economy, opening doors to a wide range of career paths and translating into higher earning potential for bioinformatics graduates.

"Students with quantitative expertise, like that offered in the new bioinformatics degree, are in high demand in the life sciences industry," says Peter Trapa, dean of the College of Science. "Recent data on U graduates highlights strong job placement and impressive salaries for graduates with such skills. This degree is designed to prepare students for success in these thriving job markets."

What students can expect

As a bioinformatics major, a student will learn from and collaborate with faculty pushing the boundaries of genomics, systems biology, biomedical informatics and more. Other universities and colleges offer a similar degree, but advantages to the U’s bioinformatics major include the following:

Hands-on research experiences in a student’s first year through the College’s celebrated Science Research Initiative
Core mathematical foundations through the renowned Department of Mathematics
Access to an R1 university with nationally ranked biomedical, health sciences and genomics programs
Internship opportunities with industry partners
Advisory support and career coaching

Concludes De Fernex, “Our bioinformatics curriculum promises a challenging yet immensely rewarding journey, equipping students for high-paying careers or further advanced studies. In today's world, where science and medicine increasingly rely on big data analysis, bioinformatics stands as a frontier of discovery.”

Students can learn more about the new bioinformatics major by visiting http://math.utah.edu/bioinformatics.

By David Pace

Scientists Find Hope in Cone Snail Venom

August 23, 2024

An international research team led by University of Utah scientists has identified a component within the venom of a predatory marine cone snail, the geography cone, that mimics a human hormone called somatostatin, which regulates the levels of blood sugar and various hormones in the body. The hormone-like toxin’s specific, long-lasting effects, which help the snail hunt its prey, could also help scientists design better drugs for people with diabetes or hormone disorders, conditions that can be serious and sometimes fatal.

The results were published Aug. 20 in the journal Nature Communications.

A blueprint for better drugs

Somatostatin acts like a brake pedal for many processes in the human body, preventing the levels of blood sugar, various hormones, and many other important molecules from rising dangerously high. The cone snail toxin, called consomatin, works similarly, the researchers found—but consomatin is more stable and specific than the human hormone, which makes it a promising blueprint for drug design.

By measuring how consomatin interacts with somatostatin’s targets in human cells in a dish, the researchers found that consomatin interacts with one of the same proteins that somatostatin does. But while somatostatin directly interacts with several proteins, consomatin only interacts with one. This fine-tuned targeting means that the cone snail toxin affects hormone levels and blood sugar levels but not the levels of many other molecules.

In fact, the cone snail toxin is more precisely targeted than the most specific synthetic drugs designed to regulate hormone levels, such as drugs that regulate growth hormone. Such drugs are an important therapy for people whose bodies overproduce growth hormones. Consomatin’s effects on blood sugar could make it dangerous to use as a therapeutic, but by studying its structure, researchers could start to design drugs for endocrine disorders that have fewer side effects.

Consomatin is more specific than top-of-the-line synthetic drugs—and it also lasts far longer in the body than the human hormone, thanks to the inclusion of an unusual amino acid that makes it difficult to break down. This is a useful feature for pharmaceutical researchers looking for ways to make drugs that will have long-lasting benefits.

Learning from cone snails

Finding better drugs by studying deadly venoms may seem unintuitive, but Helena Safavi, associate professor of biochemistry in the U’s Spencer Fox Eccles School of Medicine and the senior author on the study, explained that the toxins’ lethality is often aided by pinpoint targeting of specific molecules in the victim’s body. That same precision can be extraordinarily useful when treating disease.

“Venomous animals have, through evolution, fine-tuned venom components to hit a particular target in the prey and disrupt it,” Safavi said. “If you take one individual component out of the venom mixture and look at how it disrupts normal physiology, that pathway is often really relevant in disease.” For medicinal chemists, “it’s a bit of a shortcut.”

Among Safavi’s coauthors are faculty from the U’s School of Biological Sciences, including Baldomero Olivera and Samuel Espino. The U has been a hotspot for research into the venom’s pharmacological properties since Olivera arrived in Utah in 1970 from his native Philippines, bringing his interest in cone snails with him.

Read the full, original story by Sophia Friesen in UofU Health.
Read about Toto Olivera’s 2022 Golden Goose Award for early research in cone snails here.

Humans of the U: Nathan Patchen

August 12, 2024

In my first year, however, I had some great experiences with the university’s chemistry department and fell in love with chemistry. Since then, I have decided to double major in biochemistry and biology. My goal is to pursue an MD-PhD, so I can do both research and work with patients.

I am passionate about improving the quality of life for patients, allowing them to lead healthier and hopefully more fulfilling lives. I hope to do this by working in the field of genetics/genomics and using gene editing techniques to find new tools to combat diseases that are otherwise untreatable. Additionally, I am interested in understanding why and how we age and improving patient outcomes through this process.

These interests are reflected in the research I have been a part of on campus as an undergraduate. The prestigious research that happens at the U is one of the reasons I was drawn to the school. Though research can be frustrating, time-consuming, and tedious, I have found it to be the most enriching part of my education. The incredible opportunity to participate in the forefront of science has drastically expanded my capabilities not only as a scientist but as a person.

Recently in my lab, the principal investigator (PI) assigned me to learn how to synthesize a compound we use for our experiments in an effort to bring our costs down. It was a difficult process to optimize the protocol for our lab, but through extensive troubleshooting and consulting with other labs, I became an expert on the topic.

After months of running the process over and over again without success, my PI and I discovered the error was occurring in a step I was not in control of. We were so excited to have found the solution After correcting the problem, I was able to successfully produce the desired product. Better yet, the new method dropped the cost of our experiments from $60 per experiment to less than a cent. It is exciting that I could play such a key role in helping my lab achieve a research goal that opens realms of possibility. It feels great to be able to contribute to something larger than myself.

I have recently been recognized as a Goldwater scholar which is exciting because it is a testament to my commitment to pursue science and my desire to make an impact on the world through discovery. To me, receiving this award is a great honor, it tells me that someone believes in me, and is willing to invest in my development. It is my goal to live up to that expectation, whether it be through science, medicine, or some other field, my goal is to serve and improve the lives of others.

—Nathan Patchen, a junior in the Honors College studying biochemistry and biology and a 2024 Goldwater Scholarship recipient

This story originally appeared in @TheU.

Fueling Utah’s Booming BioTech Sector

August 12, 2024

In teaching labs through the Science Research Initiative (SRI) students learn by doing, starting their first year in the College of Science.

There has been a steady stream of articles about billion-dollar valuations for Utah startups and consistently low unemployment. Amid these headlines, there is growing recognition among analysts and policymakers in Utah that the biotechnology and life science sectors are playing a significant role in that growth. A recent report from the Kem C. Gardner Policy Institute found that the industries created $8 billion in GDP in 2022, part of a total statewide economic impact of $21.6 billion. Job growth in the sector has been particularly impressive; Utah’s 5.7% annual job growth rate significantly outpaces the national average of 3.2%. Due to these steady increases, Utah now has the highest share of statewide employment among all states nationally except Massachusetts. These jobs are also high-paying positions. Wages in the sectors average $96,000, which is 48% higher than the $65,000 average in other industries.

The University of Utah and the College of Science play an important role in this booming expansion, helping supply a sizable portion of talented employees and researchers. According to National Center for Education Statistics graduation data, the U awards roughly 37% of life science-related bachelor’s degrees and 95% of graduate degrees given by schools in the Utah System of Higher Education. Graduates from the College account for nearly two-thirds of those undergraduate degrees and over one-third of the PhDs. As they build their careers, alumni have the opportunity to take principles they learn by working with award-winning faculty and then applying them in professional settings.

“Innovation in biotechnology is touching on every aspect of our lives, from climate change and agriculture to health and wellness,” says Fred Adler, professor of mathematics and current director of the School of Biological Sciences (SBS), the largest academic unit in the College. “As discovery and innovation accelerate, so do the links between basic science and applications. In the SBS, faculty are making transformative contributions to drought-resistance crops based on fundamental discoveries in genetics, testing of drug safety based on research of animal behavior, and to neuroscience through new ways of imaging cells at the finest resolution.”

EXCELLENCE IN EDUCATION

In the School of Biological Sciences, faculty are making transformative contributions to drought-resistance crops based on fundamental discoveries in genetics. Credit: Mathew Crawley

The pipeline from the classroom, and the lab, to a successful career is most fruitful when exceptional instructors and researchers provide mentorship and guidance for students. College faculty have been recognized with a range of teaching and research awards, spanning honors like the National Medal of Science (given to three faculty members from the College of Science over the years) and MacArthur Genius Grants (four recipients) to the Rosenblatt Prize, the U’s highest honor for teaching and research (11 recipients). The College has also had 15 members elected to the National Academy of Sciences, 10 of whom are still actively teaching and pursuing research. These individual honors underscore the quality of the researchers’ academic units and are reflected in their national rankings: the SBS graduate program is ranked #13 and the Department of Chemistry comes in at #18 among public universities nationwide by U.S. News & World Report.

Chemistry and biological sciences, which educate a significant number of students that join the biotech and life science sectors, are the top-ranked programs in their fields in Utah and hold top-ten rankings among both public and private schools in the West. The two units also received over $28.4 million in external research funding during fiscal year 2023. These resources provide unique opportunities for students to learn relevant science in hands-on settings and engage in transferable research skills. Considering this impressive track record, it makes sense that life science and biotechnology-related faculty continue to garner recognitions in their fields.

Take, for example, Distinguished Professor and Thatcher President Endowed Chair of Chemistry Cynthia Burrows who won the prestigious Linus Pauling Medal Award. The Burrows Lab hosts organic, biological, analytical and inorganic chemists interested in nucleic acid chemistry, DNA sequencing technology and DNA damage. The team focuses on chemical processes that result in the formation of mutations which could lead to diseases such as cancer. Studying site-specifically modified DNA and RNA strands and DNA-protein cross-linking, Burrows and her group are widely known for expanding studies on nanopore technology to detect DNA damage. Burrows’ research in altering nucleic acid composition can provide valuable information in genetic diseases as well as manipulating the function of DNA and RNA in cells.

The Caron Lab studies the mushroom body of the Drosophila (fruit fly) to better understand how brains are developed to learn.

Another U chemist, Aaron Puri, has also drawn national attention as one of five recipients of the Simons Early Career Investigator Award in Aquatic Microbial Ecology and Evolution. The award will provide $810,000 to the Puri Lab over the next three years and, according to Puri, “will enable our research group to work at the interface of biology and chemistry to decipher the molecular details of interactions in methane-oxidizing bacterial communities.” His research looks at the molecular details of interactions in these communities, aiming to solve big problems with microscopic solutions. “These communities provide a biotic sink for the potent greenhouse gas methane,” he continues, “and are a useful system for understanding how bacteria interact with each other and their environment while performing critical ecosystem functions.”

Nearby, in the Skaggs Biology Building, is the lab of Ofer Rog, who recently won an Early Career Medal from the Genetics Society of America. Rog was recognized for work visualizing meiotic exchange between “sisters,” exploring synaptonemal complex proteins and tracking single molecules. Building on this work, the Rog Lab published a study in the Proceedings of the National Academy of Sciences in December that outlined a groundbreaking way to study the synaptonemal complex. Rog explains of the complex, “You can think of it like a zipper. The axes of the chromosomes are like the two sides of your shirt. The synaptonemal complex (SC) is kind of like the teeth of the zippers that lock onto each other and can pull and align the two sides of the shirt correctly.” Rog’s team was the first to pinpoint the exact position where the SC interacts with itself to facilitate genetic exchanges. Looking forward, unlocking the SC’s role in meiosis may lead to a stronger understanding of fertility in humans.

Another esteemed faculty member in biology is Sophie Caron, a U Presidential Scholar, who uses the Drosophila mushroom body — a computational center in the fruit fly brain — as a model system to understand how brains are developed to learn. With work described as “stunning” and “breathtaking,” Caron has built an interdisciplinary research program by drawing on computational models, species-comparative studies and various anatomical and behavioral techniques to elucidate the structural, functional and evolutionary pressures that shape the mushroom body’s learning function. In addition to her research, Caron — who was also awarded an outstanding teaching and mentorship award last year— designed and teaches an extremely popular neurobiology class (BIOL 3240), a course taken by hundreds of students.

FROM THE CLASSROOM TO THE BOARDROOM

Graduates from the College of Science also play crucial roles in Utah’s burgeoning biotechnology community. Equipped with cutting-edge knowledge learned in classrooms and research labs throughout campus, these alumni are at the forefront of research and development, contributing to significant advancements in life science fields. Their expertise not only drives the success of numerous biotech companies but also attracts substantial investment to the state. By bridging academic excellence with industry needs, alumni ensure a steady pipeline of talent that sustains the growth and dynamism of Utah’s biotechnology sector.

Tom Robbins and Amy Davis of bioMérieux.

There are many examples of these types of professional outcomes. Randy Rasmussen (PhD’98 biology) and Kirk Ririe (BS’05 chemistry) were two of three co-founders of BioFire Diagnostics. The company pioneered instruments that shortened DNA analysis techniques from hours to minutes. Using this technology, they created molecular diagnostics that now simultaneously test for multiple infectious agents, allowing healthcare professionals to get quick and accurate results from onsite instruments. In 2013 BioFire was purchased by bioMérieux, a French biotech firm, for over $450 million. The company is now one of Utah’s largest life sciences employers, with over 3,400 employees throughout its six sites. While Rasmussen and Ririe have since moved on to other projects, College of Science graduates like Amy Davis (PhD’03 biology), vice president of molecular biology, and Tom Robbins (PhD’04 mathematics), vice president of software development, continue to play significant roles in the company’s work.

Some College alumni have also found ways to share their experiences with a new generation of students. Ryan Watts (BS’00 biology) discovered a passion for research while an undergraduate. After he finished his degree, he earned a PhD from Stanford University and eventually co-founded the biotech startup Denali Therapeutics, focused on defeating neurodegeneration. The company went public in December 2017, breaking that year’s record for an initial market valuation of a biotech company. Today, Denali has over 400 employees and a market cap of over $3 billion, including a growing presence in Utah. Despite his busy schedule as CEO, Watts taught a winter semester course for five years at the U which tracked the biotechnology industry and introduced biology students to processes around drug discovery, business strategy, programming and portfolio decision-making.

Another alumnus, Berton Earnshaw (PhD’07 mathematics) used his academic experience to join the founding team of Red Brain Labs in 2012. When the machine learning-focused company was acquired by Savvysherpa in 2014, Earnshaw stayed on as a principal and senior scientist. Eventually, Earnshaw became director of data science research at Recursion Pharmaceuticals, a young clinical-stage biotech and drug discovery company based in Salt Lake City. In a succession of senior roles, Earnshaw has helped guide the company’s foundational machine learning and AI development, assisting in the company’s rapid growth to over 500 employees and an international expansion. Earnshaw started teaching courses at the U on machine learning and neural networks beginning in 2018. In 2024, he accepted a role as a senior fellow with the College of Science, in part to provide an industry perspective into the dynamic world of deep learning and AI.

LOOKING FORWARD

Berton Earnshaw, Recursion.

Unwilling to rest on its laurels, the College of Science is devoting significant resources to prepare graduates for what the Utah Department of Workforce Services deems accelerating growth in the rapidly changing fields of biotech and life sciences. The Department of Mathematics, School of Biological Sciences, and Kahlert School of Computing recently announced a new undergraduate degree in bioinformatics. New faculty hires throughout the College have included individuals with expertise in areas like data science, genomics, machine learning, gene editing and next-generation imaging techniques. More undergraduate students are participating in bioscience-related research than ever, either through the celebrated Science Research Initiative or direct placements in labs throughout campus. Together, these investments help ensure that future students will be well-prepared after they enter the workforce.

The notoriety of Utah’s burgeoning biotechnology and life sciences sectors continues to be indelibly linked to the College of Science in a feedback loop that benefits the economy, the community, and the University of Utah.

by Eliot Wilcox
Operating Manager, College of Science, University of Utah

This story is featured in Synthesis, the College of Science's annual magazine.

Ants and Trees: A Tale of Evolutionary Déjà Vu in the Rainforest

July 19, 2024

Ants are famous for their regimented and complex social behaviors. In the tropics, they are also famous for forming mutualisms with plants. Certain species of trees have conspicuous hollow swellings that house ants, often feeding the ants with specialized ant food. In return, the ants are pugnacious bodyguards, swarming out to aggressively defend the plant against enemies. Scientists have observed these mutualisms for centuries, but an enduring question is how these intriguing interactions evolved in the first place.

That remains a mystery, but new research led by University of Utah field biologist Rodolfo Probst offers insights that could broaden our understanding of ant-plant symbioses.

Published last week in the Proceedings of the Royal Society B, his research focused on an ant genus called Myrmelachista. Most Myrmelachista species nest in dead or live stems of plants, without any specialized mutualistic association. But one group of species in Central America was known to nest only in the live stems of certain species of small understory trees, in a specialized symbiosis similar to other ant-plant mutualisms. These tiny yellow ants hollow out the stems without harming the host plants, and can be found throughout Central America.

Jack Longino. Credit: Rodolfo Probst

Probst made a remarkable discovery. Using DNA sequence data to unravel their evolutionary history, he found that these nine species occurred as two clusters in different parts of the evolutionary tree. That means that this complex relationship, with all its distinctive characteristics, evolved twice from non-specialist ancestors.

His two coauthors are renowned entomologist Jack Longino, better known among U students as The Astonishing Ant Man for his expertise and vast personal collection of ant specimens kept on campus, and former U School of Biological Sciences’ postdoctoral researcher Michael Branstetter, now with U.S. Department of Agriculture’s Pollinating Insect Research Unit at Utah State University.

Probst is a postdoctoral researcher in the School of Biological Sciences and the university’s Science Research Initiative, or SRI, and was recently recognized with the Outstanding Postdoctoral Researcher Award by the College of Science. Through the SRI, Probst has involved U undergraduates in his research. For example, students accompanied Probst and Longino to Costa Rica with funding support from the U’s Wilkes Center for Climate Science & Policy.

With continuing help from SRI undergraduates, Probst is looking to conduct whole genomic sequencing to tease out the genes involved in ant-plant associations, looking “under the hood” of a phenomenon that has intrigued naturalists for centuries.

Read more about the story on ants and trees by Brian Maffly @TheU.

A Framework for Cancer Ecology and Evolution

July 17, 2024

Fred Alder. Credit: Mathew Crawley

A traditional explanation in the development of cancers, known as the somatic theory, is a paradigm focused on mutations in individual cells. In this theory a cascade of approximately six mutational changes in a single cell is the source that triggers cancer. This theory explains the rapidly increasing “power function” that describes how cancer incidence increases with age.

But this power function which lines up with cancer’s six classic hallmarks is now being challenged by a different paradigm that casts doubt on the primacy of individual cells in cancer development. It also challenges the notion that cancer marks a strict change between “normal” and aberrant tissues, particularly as the body ages.

In a paper published today in The Royal Society Interface out of the United Kingdom, “A modeling framework for cancer ecology and evolution” is explored by University of Utah mathematics professor Frederick Adler with a joint appointment in biology.

Cancer's complexity

Adler says he has struggled for a long time to come up with an alternative modeling approach for cancer that has the flexibility to capture the complexity of cancer, while standing by the dictum that cancer cells are still cells. “It involved a plane trip where I worked out an extremely complicated approximate version of the method before figuring out, on solid ground, that the exact version was thoroughly simple.”

Simple didn’t just mean elegant, but also getting results in a reasonable amount of time by optimizing code, something he can appreciate as the current Director of the busy School of Biological Sciences, one of the largest academic units at the University of Utah.

The dynamics of escape in a person with imperfect initial control. We see replacement by increasingly dark shades of gray that indicate cells that are growing faster and faster, leading to an increase in the total cell population (black line at top) above the healthy level (horizontal orange line).

Adler’s findings build on those of others that countermand the primacy of individual cells. These include observations of mutations common in non-cancerous tissues, and sometimes more common than in nearby cancers. “This implies,” the paper states, “that cancers depend on interactions with the surrounding tissue.” A second emphasis on cancer ecology and evolution is now highlighting “the ecology of nutrients, acids and physical factors and the role of cell interactions.”

“Detailed study of adults shows that few if any of their cells are ‘normal,’” says Adler. “Tissues are instead made up of lineages with ever-increasing numbers of aberrant traits, many of which promote excess growth. The vast majority of these incipient growths are contained by controls within those cells and by other cells.”

In Adler’s parsing of the ecological paradigm, senescence theory plays a critical role, focusing on the breakdown of the system of controls within and around individual cells. “[M]any cancers,” for example, “develop much later than their originating oncogenic mutations.” Furthermore, mutant cells in his models are restrained “by systems that remove their growth advantage, but which can weaken with age due to changes such as impaired intercellular communication. Remarkable data on genetic diversity in healthy tissues show that cancer-related mutations are ubiquitous, and often under positive selection despite not being associated with progression to cancer.”

Overview of CAGRM framework. Cells include an arbitrary number of potential lineages, beginning with all cells in the unmutated lineage C0 and evolving first into C1 and eventually a branching evolutionary tree of lineages here indicated collectively by Ci. There are four forms of regulation (indicated by flat-headed arrows): contact inhibition by other cells (C ), inhibition by antigrowth factor (A), depletion of growth factor (G) and depletion of resources (R). Mutualist cells can aid cell replication by suppressing antigrowth factor or by supplementing growth factor or resources.

Tracking the dual nature of cells

In the paper, Adler first presents a modeling framework which incorporates evolution, stochasticity (a measure of how random a process is, or the quality of lacking a predictable order or plan) and control and breakdown of control. Using a differential equation, the model then tracks the dual nature of individual cells as ecological competitors for resources and space.

Using this framework Adler then tested whether the ecological model of cancer initiation generates realistic age-incidence patterns similar to the somatic mutation theory. Another test was made to determine how initial defects in the control systems accelerate the process.

In this comprehensive systems view, cancer, and an incipient cancer in particular, is not an invader. “It is a set of cells,” the paper reads, “that escape the many layers of internal and tissue level regulation, and then grow to damage the host. The success of a cancer, or equivalently the failure of the regulatory system, requires that the cancer co-opts or evades the systems of control and repair.”

This model/framework, according to the author, assumes a particular structure of the control system but has capacity for “several other extensions” to make it more “realistic.” Those extensions would address, for example, cell differentiation and a clearer class of driver mutations for the genetic model of quantitative trait. Another might address why the mutualist cells in the tests maintain a constant phenotype in spite of what we know about how cells alter behavior in cancer’s presence.

Statistically, we understand that cancer emerges more frequently in older individuals. But how and why is what Adler is attempting to determine. His model, says Adler, “reproduces the rapid increase of cancer incidence with age, identifies the key aspects of control, and provides a complement to the focus on mutations that could lead to new treatment strategies.”

Fred Adler points out that the control system in the model differs greatly across species in concert with their body size and lifespan, thus revealing a paradox known as Peto’s: cancer rates are similar across organisms with a wide range of sizes and lifespan. “This robustness,” concludes the paper, “is a special case of the principle that all biological systems must be overbuilt to deal with uncertainty.” Referencing Shakespeare’s Hamlet, Adler states that this development in excess of demand exists “to survive ‘the thousand natural shocks that flesh is heir to’… This model seeks to place those shocks in the ecological and evolutionary context that makes long life possible.”

by David Pace

Read about Fred Adler's related work in modeling cancer development, specifically with breast cancer.

Journey to the Center of Biotech

July 8, 2024

Xie earned her PhD in biology from the University of Utah in 2004 and where she remained as a postdoc for several years. At the time, she never imagined herself working industry. Yet to her surprise, she amassed extensive experience in biotechnology. In her first foray from academia, she taught eighth-grade science and helped build the charter school’s AP biology program.

While she loved teaching, Xie always felt the urge to venture out and gain experience in molecular biology which she also enjoyed. As such, new technological developments in a local biotechnology startup, IDbyDNA, presented her call to action. She recalls “the startup company was pushing for a new technology that was obviously going to be the future. Now the question was, who was going to make it a reality? Why not us?”

To finally embrace the uncertainty of industry was scary, but Xie knew this was her time to act. “I can always go back to teach, but this leap of faith, if I didn’t take it, I may not have another opportunity,” she says. In fact, while learning new skills herself, she never stopped teaching and mentoring others.

Hypothesis-free Diagnostics

IDbyDNA is a local metagenomics company with an innovative algorithm that simultaneously profiles tens of thousands of microorganisms (or pathogens) in any sample by massive parallel sequencing, known as Next Generation Sequencing (NGS). Xie says this technology is fundamentally different from other available tests because it is hypothesis-free. “We’re not making any guesses, educated or not; we just treat everybody the same, and we sequence everything in there. And by analyzing the sequence in the sample, bioinformatics can tell you what it is. You don’t have to say ‘Tell me if it’s the flu.' It will tell you, ‘No, it’s not the flu, it’s something else.’”

By taking this approach to diagnosis, IDbyDNA circumvents two major problems. “The first issue is [the] diversity of the potential cause of the disease. The second issue is [one of timing as] some of the really dangerous pathogens that cause diseases such as tuberculosis, can take a long time to grow. By the time you can actually grow it and identify it, the patient's disease has progressed, and, [by then,] they might have been in the ICU for weeks.”

Hybrid Capture

Though these major concerns were sidestepped, other problems became apparent. “One problem we saw at IDbyDNA was when you get a patient sample and you start to sequence the DNA, the majority of the DNA is the host DNA because the human genome is orders of magnitude larger than the pathogen genome,” explains Xie. “Even a single human cell is going to give you much more sequencing information than the pathogen. So, you actually are not going to have the level of sensitivity you want for it to be clinically applicable.”

To bypass this problem, one can enrich the pathogen signal by selectively pulling the pathogen sequences (with complementary DNA) from the sample before analyzing. The challenge here is that the diversity of the pathogens would require extremely high complexity capturing, which means high-complexity DNA synthesis.

At IDbyDNA, Xie started as a research scientist, co-developing the Explify® clinical diagnostic platform and left as an associate director after six years. The company was eventually acquired by Illumina, a giant sequencing company.

Her next adventure in industry after IDbyDNA was as principal scientist at GenScript, a company that develops and manufactures gene synthesis products and services used by researchers in academia, pharmaceutics and biotech. Xie joined the Seattle campus because of the CustomArray technology that synthesizes millions of different DNA molecules on a semiconductor chip. This high-complexity, low-cost production of DNA became the natural extension of Xie’s earlier interest.

“When I went there [Genscript], this was pre-production, and I helped them evaluate and quantify how good they are and help them improve the product,” says Xie. Her work over nine months resulted in reduced costs and streamlined application of NGS technology in product development.

Precision Oncology

From GenScript, Xie took the position of senior director of pharma services at NeoGenomics Laboratory, a company dedicated to precision oncology. This newest endeavor is the perfect combination of her other experiences: a hypothesis-free approach applied with hybrid sequencing technology that can provide targeted therapies for cancer patients. At NeoGenomics, biopsies of tumors are sequenced and matched back to the mutation that caused them.

“Then, if the clinician needs to target the specific cancer, they can select suitable drugs that have been approved or are in clinical trials to [make a] recommendation to the patient based on the sequencing results.” This highly targeted therapy means that the patient doesn't have to suffer general chemo, Xie says. She and her team have launched several impactful tests since she joined NeoGenomics. More exciting tests are getting ready for the market.

Accelerating the pace

It took a while for Xie to leave academia, but she hasn’t looked back since. She has been dedicated to accelerating the pace in the biotech industry, making innovations at the top of the supply chain that impact research in industry and academia further down, or serving patients with state-of-the-art diagnostic technologies. While earning her PhD at the U, Xie never imagined the exciting career she would create for herself.

“[W]hat I absorbed in school was that there is no value outside academia because everything else is not as scientifically rigorous and not as innovative, not as cutting edge, not at the very boundary of human knowledge.”

But Heng Xie’s success at all levels of the biotech industry is living proof of the abundant exciting opportunities students have and a testament to the growth of science beyond academia. Her experiences showcase how rigorous research in academia impacts society through the commercialization of innovative technologies.

by Lauren Wigod

Life On Other Planets … and in a student’s mind

June 24, 2024

That’s where the Martin Horvath Lab comes in and, in particular, Mary Fairbanks BS’23. She and her team in the School of Biological Sciences at the University of Utah explore structural biology and biochemistry by researching microbes from the Lost City Hydrothermal Field, an area of marine alkaline hydrothermal vents located in the Atlantic Ocean.

As with Fairbanks, who gained hands-on experience creating experiments and directly participating in research, other lab members worked on the project as undergraduates before graduating. They include Payton Utzman BS’22 and Briggs Miller BS’22 who along with Fairbanks and graduate student Vincent Mays researched microbes that live at the bottom of the ocean where there is little oxygen and even less sunlight. Because of the lack of oxygen in the environment where these microbes thrive, the fact that researchers found GO DNA repair genes is important: it shows a need for genes that repair DNA that has been put under stress from oxygen. Their research was recently published in PLOS.

Acting like a scientist

"Working in Dr. Horvath’s lab has taught me how to be curious and be dedicated to a project,” says Fairbanks. “Being able to design my own experiments has given me the opportunity to act as a scientist. I have grown through research and it continues to expand my view of the possibilities of innovation.”

Horvath first learned that one of the GO repair genes called MutY might be present at the Lost City Hydrothermal Field from a student in his Molecular Biology of DNA Lab course, Emily Dart HBS’16. Horvath knew that Dart was working with William Brazelton, a fellow biologist who had recently collected DNA from Lost City. Searching that Lost City DNA, Dart and her teammates found genes encoding at least portions of MutY.

“Since that first analysis,” says Horvath, “the sequence technology improved, more samples from another expedition generated metagenomes with better coverage, and we now have functional tests that show these MutYs from the bottom of the ocean actually work to prevent mutations in lab strains of bacteria.” That these discoveries stemmed from basic science research by undergraduates, he says, is “something that I am very proud to celebrate!”

How life might evolve on other planets

GO DNA repair genes are advantageous even in environments without much oxygen. Since hydrothermal fields like the Lost City Hydrothermal Field are similar to the environment of early Earth, this indicates that these repair systems evolved before the Great Oxidation Event.

Fig 5. LCHF MutY chemical motifs. (A) Conservation and diversity of MutY-defining chemical motifs are depicted with a sequence logo for the 160 LCHF MutYs. These motifs are associated with biochemical functions including DNA binding, enzyme catalysis, attachment of the iron-sulfur cofactor, and recognition of the damaged OG base.

Insights like this can help develop models of how life might evolve on other planets. Planets that lack the abundance of oxygen that modern Earth has may have life evolving in a similar way to microbes that live near hydrothermal vents. Since these microbes have repair systems that deal with oxidative stress, it’s reasonable to consider that life on other planets may as well.

The group also discovered the role that these repair genes, including MutY, play in hydrothermal microbes, by associating GO DNA repair with metabolic pathways. These pathways produce oxygen as a byproduct, so MutY may play a part in fixing DNA damage caused by metabolic processes.

Life on other planets may take many different forms, and similarly, learning science also takes many forms beyond the classroom. “I’ve been encouraged to ask questions and explain findings to form a cohesive pattern that tells a story,” says Fairbanks. She credits the lab experience as helping her “see a project from start to finish. I have been able to improve my critical thinking skills and laboratory technique, as well as adapt to change.”

That adaptation to change is a good lesson to learn as empirically observed far below the surface of the ocean but also on a personal level for Fairbanks and her young researcher cohorts. Findings such as these may show how DNA-based life forms rely on fixing damage caused by oxidation, even in environments without oxygen. And they give scientists a clue as to how life may look on other planets by forming models of life in environments unlike Earth’s. But the “findings” are clearly internal as well for young, developing scientists who will never forget their time examining and interpreting data in the Horvath Lab.

As Martin Horvath intones of this research, “Life finds a way.”

As do young minds like that found embodied in Mary Fairbanks who, now headed for a career in the medical field, concludes, “I believe my experience in research will make me a more open-minded thinker.”

Bacteriophages: Nature’s bacterial killers

June 18, 2024

New research led by the University of Utah and University College London (UCL) has found that plant bacterial pathogens are able to repurpose elements of their own bacteriophages, or phages, to wipe out competing microbes. These surprise findings suggest such phage-derived elements could someday be harnessed as an alternative to antibiotics, according to Talia Karasov, an assistant professor in the U’s School of Biological Sciences.

This result was hardly what she expected to find when she embarked on this research with an international team of scientists. Microbial pathogens are all around, but only a fraction of the time do they sicken humans, other animals or plants, according to Karasov, whose primary research interest is in interactions between plants and microbial pathogens. The Karasov lab is seeking to understand the factors that lead to sickness and epidemics versus keeping the pathogens in check.

“We see that no single lineage of bacteria can dominate. We wondered whether the phages, the pathogens of our bacterial pathogens, could prevent single lineages from spreading – maybe phages were killing some strains and not others. That’s where our study started, but that’s not where it ended up,” Karasov said. “We looked in the genomes of plant bacterial pathogens to see which phages were infecting them. But it wasn’t the phage we found that was interesting. The bacteria had taken a phage and repurposed it for warfare with other bacteria, now using it to kill competing bacteria.”

A thale cress specimen collected in 1866 in Germany and preserved in a herbarium in Tubingen. Credit: Burbano lab, University College London.

Mining herbarium specimens for their microbial DNA

Burbano has pioneered the use of herbarium specimens to explore the evolution of plants and their microbial pathogens. His lab sequences the genomes of both host plants and those of the microbes associated with the plant at the time of collection more than a century ago.

For the phage research, Burbano analyzed historical specimens of Arabidopsis thaliana, a plant from the mustard family commonly called thale cress, collected in southwestern Germany, comparing them and the microbes they harbored to plants growing today in the same part of Germany. Lead author Talia Backman wonders if tailocins could help solve the impending crisis in antibiotic resistance seen in harmful bacteria that infect humans.

“We as a society are in dire need of new antibiotics, and tailocins have potential as new antimicrobial treatments,” said Backman, a graduate student in the Karasov lab. “While tailocins have been found previously in other bacterial genomes, and have been studied in lab settings, their impact and evolution in wild bacterial populations was not known. The fact that we found that these wild plant pathogens all have tailocins and these tailocins are evolving to kill neighboring bacteria shows how significant they may be in nature.”

Discover the full story behind bacteriophages and their antibiotic potential by Brian Maffly at @The U. More on this story at earth.com.

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