Running with Scissors

Jamie Gagnon

One could argue that the age of genomes is divided between before CRISPR-Cas9 and after CRISPR-Cas9 (commonly referred to as just “CRISPR”). As a Harvard post-doc studying the genes involved in embryo development, James (Jamie) Gagnon remembers in 2012 that “pivotal moment” when these “really nice pair of scissors now easy to make” came on the scene.

“Before CRISPR,” says Gagnon whose interest early on had been more in engineering than biology, “we were all using the earlier generation of genome editing tools. Even so, we were able to determine that after making a mutation in a cell, when it divided, the change that had been made was inherited.”

The new “scissors” rapidly scaled up genome editing, allowing researchers to more easily alter DNA sequences and modify gene function. At the time CRISPR was inspiring others to move from the research model of smaller organisms like the c. elegans, a transparent worm made up of approximately 1,000 cells, to much larger ones like zebrafish. “The power of genetics,” Gagnon says, “is that zebrafish are now genetically accessible model of all vertebrates, including humans which share 70 percent of genes with fish.”

Zebrafish Research subjects

The impulse for Gagnon’s current work in vertebrate lineage and cell fate choice happened in Northern Maine, during a winter-mountaineering trip with his friend and fellow researcher Aaron McKenna whom he met while they were undergraduates at Worcester Polytechnic Institute in Massachusetts. There in the wilds, not far from Vermont where Gagnon grew up, ensued an extended conversation between the two which started to form a deeply complex but exciting research question.

“If we want to study how embryos grow, we have to do it in a living animal,” Gagnon remembers acknowledging to McKenna. “We knew we needed to do it [research] in live animals, complete and whole. I couldn’t shut up about it for several days,” he says, smiling. “Everyone was mutating genes.” It seems that at the time, and perhaps still to this day, ‘Let’s break a gene and see if you’re right about what it does’, was pro forma.

Zebrafish Scale

Instead, the developmental biologist (Gagnon) and the computational researcher (McKenna) decided to pick up where others had ended (and published), using technology in a creative way to mark cells with a genetic barcode that could later be used to trace the lineage of cells. The two were suddenly using data sets of CRISPR-scissor mutations to figure out how cells actually developed in zebrafish.

Still, the prevailing question for Gagnon the researcher is how does biology build an animal with millions of cells, all sharing information and all shape-shifting at the same time? And how does science then best go about studying that?

How does science turn chaos and cacophony into a symphony that is the marvel of a living organism?

A symphony orchestra isn’t a bad metaphor for the edge of science that Gagnon and his lab and colleagues find themselves standing at. (It helps, perhaps, that his wife Nikki, a trained studio artist, works at the Utah Symphony | Utah Opera.) “For thirty years,” says Gagnon, people have been deciphering the genome code … one of the worst computer codes ever written.” Just how bad is bad? Imagine three billion letters in one long line with no punctuation or formatting.

The Gagnon Lab

Perhaps it’s the engineer in him, but to get at that unwieldy code, he sees his task as finding additional tools to regulate CRISPR activity. These tools include doing base-editing and using self-targeting guide RNAs to facilitate cells themselves making a record of what they’re doing, what they’re listening to, as it were, as they play their own “score” of development. “We want to turn the single, really good sharp knife of CRISPR,” he explains “into a Swiss Army knife” to figure out the score of an organism’s symphonic work.

The micro-scissors of CRISPR that appear to have issued a sea change in genomic studies, he hopes, can be used to “force cells to make notes along the way” of their own developmental journey. “Every time the oboe plays,” he says, returning to the metaphor, “we want the player [the cell] to make a record and journal entry on it.”

Illustration by The Gagnon Lab

“In early embryos, there are multiple languages or instruments being used by a finite number of cells to communicate with other cells and to build an animal,” he continues. To which language/instrument does a cell “listen” to, and what choices (expression) does it make as a result?

In a sense Jamie Gagnon is no longer just trying to “decode” the genome, but to use CRISPR to make a version, readable to humans, of what cells are doing in real time and how. In short he’s looking for the creation of a cell-generated Ninth Symphony, a complex but coordinated record of how development occurred that a Beethoven would be proud to conduct.

It may be dangerous to run with scissors, something parents routinely warn their children of, but it turns out that a really good pair of them can do more than the obvious: they can inspire other technologies that promise to bend the arc of science towards even greater aspirations.

 

by David Pace

- First Published in OurDNA Magazine, Fall 2019

TreeTop Barbie

When Nalini Nadkarni was a young scientist in the 1980s, she wanted to study the canopy – the part of the trees just above the forest floor to the very top branches.

But back then, people hadn't figured out a good way to easily reach the canopy so it was difficult to conduct research in the tree tops. And Nadkarni's graduate school advisors didn't really think studying the canopy was worthwhile. "That's just Tarzan and Jane stuff. You know that's just glamour stuff," Nadkarni remembers advisors telling her. "There's no science up there that you need to do."

They couldn't have been more wrong. Over the course of her career, Nadkarni's work has illuminated the unique and complex world of the forest canopy.

She helped shape our understanding of canopy soils — a type of soil that forms on the tree trunks and branches. The soil is made up of dead canopy plants and animals that decompose in place. The rich soil supports canopy-dwelling plants, insects and microorganisms that live their entire life cycles in the treetops. If the canopy soil falls to the forest floor, the soil joins the nutrient cycles of the whole forest.

She also discovered that some trees are able to grow above-ground roots from their branches and trunks. Much like below ground roots, the aerial roots can transport water and nutrients into the tree.

During Nadkarni's early work as an ecologist she began to realize something else: There weren't many women conducting canopy research.

Nadkarni was determined to change this. In the early 2000s, she and her lab colleagues came up with the idea of TreeTop Barbie, a canopy researcher version of the popular Barbie doll that could be marketed to young girls.

She pitched the idea to Mattel, the company that makes Barbie. "When I proposed this idea they said, 'We're not interested. That has no meaning to us," says Nadkarni. "We make our own Barbies."

Nadkarni decided to make them herself anyway. She thrifted old Barbies; commissioned a tailor to make the clothes for TreeTop Barbie; and she created a TreeTop Barbie field guide to canopy plants. Nadkarni sold the dolls at cost and brought TreeTop Barbie to conferences and lectures.

Her efforts landed her in the pages of The New York Times, and word eventually got back to Mattel. The owners of Barbie wanted her to shut down TreeTop Barbie due to brand infringement.

Nadkarni pushed back.

"Well you know, I know a number of journalists who would be really interested in knowing that Mattel is trying to shut down a small, brown woman who's trying to inspire young girls to go into science," she recalls telling Mattel.

Mattel relented. The company allowed her to continue her small-scale operation. By Nadkarni's count, she sold about 400 dolls over the years.

Then in 2018, more than a decade after Nadkarni started TreeTop Barbie, she got an unbelievable phone call. National Geographic had partnered with Mattel to make a series of Barbies focused on exploration and science. And they wanted Nadkarni to be an advisor.

"I thought, this is incredible. This is like full circle coming around. This is a dream come true," says Nadkarni.

For its part, Mattel is "thrilled to partner with National Geographic and Nalini," a spokesperson told NPR.

Nadkarni knows that everyone might not approve of her working with Barbie. Barbie's role in creating an unrealistic standard of beauty for young women has been debated. Nadkarni has also wrestled with how she feels about it.

"My sense is yes she's a plastic doll. Yes she's configured in all the ways that we should not be thinking of how women should be shaped," says Nadkarni. "But the fact that now there are these explorer Barbies that are being role models for little girls so that they can literally see themselves as a nature photographer, or an astrophysicist, or an entomologist or you know a tree climber... It's never perfect. But I think it's a step forward."

Nadkarni is an Emeritus Professor at The Evergreen State College, and currently is a professor in the School of Biological Sciences at the University of Utah.

 

Nalini Nadkarni's story has appeared in The Washington Post, Time Magazine, Taiwan News, News India Times, Philadelphia Inquirer, National Geographic, The Guardian, Science Friday, San Francisco Chronicle, India Today, India Times, KSL News, Salt Lake Tribune, USA Today, BBC, The Morning Journal, CNN, UNEWS, Star Tribune, National Science Foundation, Continuum, TreeHugger, and many others.

 

 

- First Published by NPR News, Fall 2019

 

Bridget Phillips

As one of the University of Utah College of Science's Ambassadors, sophomore Bridget Phillips regularly appears at College events hosting alumni and special guests, and working with faculty and staff to promote science teaching and research at the The University of Utah.

A team member in the Shapiro Lab, she works studying the genetic causes and patterns of variation in the axial skeleton of domestic pigeons.

"Because axial skeleton structure is highly conserved," she says, "understanding skeletal development in pigeons can tell us about the processes that control skeletal development in other animals as well."

A Salt Lake native, Bridget is the recipient of the Ole Jensen Scholarship this year. Because of the scholarship, she says, "I’ve been able to dedicate much more of my time to [research in the Shapiro Lab]. I greatly appreciate and deeply value the scholarship."

Dr. Jensen (BS'72), co-founder of ClearChoice Dental Implant Centers, established an endowment for undergraduate research at the School just last year. He will be at the Retreat this year to receive the 2019 Distinguished Alumni Award.

Bridget's ambition is to attend graduate school and to continue her research in genetics. "By completing a degree in Biology and a minor in mathematics, I hope to be better equipped to study immunology through genetics and bioinformatics research."

Favorite Thing About the UofU:
"I was able to start in a wonderful lab as a first-year and be able to live in Crocker Science House with other like-minded science folks."

Hero:
Thomas Hunt Morgan, who was able to show that chromosomes have a role in heredity.

Little Known Fact:
"Because all 350 breeds are capable of interbreeding to generate genetic crosses, pigeons provide a unique opportunity to identify specific genes involved in many morphological traits."

Associate V.P. for Research

The College of Science is pleased to announce the appointment of Diane Pataki, Ph.D., as the Associate Vice President for Research at the University of Utah, effective April 1st, 2019. She will continue to serve as the Associate Dean for Research in the College of Science through July 1st, 2019.

Dr. Pataki is a Professor in the School of Biological Sciences at the university. Prior to arriving in Utah in 2012, Dr. Pataki received a B.A. in environmental science at Barnard College and an M.S. and Ph.D.at the Duke University Nicholas School of Environment.

Dr. Pataki’s research work is transdisciplinary and has spanned the impacts of climate change on ecosystems, coupled human-natural processes related to urban CO2 emissions, and the role of urban landscaping and forestry in the socioecology of cities. Her lab currently studies human-environment interactions related to urban biodiversity, resource use, & landscape design, and continues to collaborate with social scientists, urban planners, landscape architects, engineers, and local stakeholders to understand the ecological and social consequences of urban landscape change.

In addition to her research, Dr. Pataki served as a faculty member at the University of California, Irvine for 8 years where she was the founding Director of the Center for Environmental Biology and the Steele Burnand Anza Borrego Desert Research Center. She has also served as a Program Director in the National Science Foundation Division of Environmental Biology and a member of the Environmental Protection Agency (EPA) Board of Scientific Counselors.

Dr. Pataki is looking forward to leading efforts across our campus to coordinate and enhance support for research proposal submissions, grantsmanship, and grants management. She will succeed Cynthia Furse, Ph.D., as the new Associate Vice President for Research. Dr. Furse will be transitioning back to full-time teaching and research on July 1st, 2019.

Please join us in thanking Dr. Furse for her exceptional service, and in welcoming Dr. Pataki in her new position.