CARRIE WAGER, PHD’00, RECIPIENT OF CHEMISTRY’S 2020 DISTINGUISHED ALUMNI AWARD, HAS ALWAYS VALUED TEAMWORK WHETHER ON THE SOCCER PITCH OR IN THE LAB.

While studying at the U, she researched total synthesis of natural products in Gary Keck’s lab and played on an intramural soccer team where she met her husband.

Wager is a chemistry midfielder in her career, driven to cover a lot of ground by her passion for working in a fast-paced, team environment. After graduating from the U, she spent 17 years at Pfizer as Senior Principal Scientist, Director of Business Planning, Chief of Staff for Pfizer Medical, and Medical Strategy Lead in Oncology. Then she earned her MBA from MIT in 2017 before joining Ascidian Therapeutics. “I really found the place where my heart belongs, and that’s working in startups,” she says. “In those situations, it’s pretty high risk, but also high reward. The strength of the team is critical, and I really enjoy that part. I’ve always been into team sports. I love having a phenomenal team that I work with.”

EXON-EDITING IS THE NAME OF THE GAME

Carrie Wager

The team Wager currently works with at Ascidian is taking a new approach to gene therapy, influenced by the organisms that the company is named after. Wager says, “We were inspired by what happens with sea squirts or ascidians because they re-engineer the transcriptome. They start as creatures that are free-floating … but then they become these structures after they re-engineer their transcriptome and are fixed on the bottom [of the ocean].” As sea squirts (Ascidiacea) mature, they self-edit their messenger RNA to change the proteins that are expressed and, ultimately, their structure.

Ascidian’s strategy for fixing genetic diseases in humans is different from other existing methods of gene therapy because it works by editing RNA through a process that is already inherent to the cell. “DNA is transcribed into RNA in the nucleus,” Wager explains. “It’s initially transcribed into pre-messenger RNA (pre-mRNA) and pre-mRNA becomes mature RNA, which leaves the nucleus. But the process of going from pre-mRNA to mature RNA is the excision or the cutting out of introns.” The splicesome is the enzyme responsible for removing the introns and leaving the exons which are then joined to form the mature strand of RNA.

Ascidian designs molecules to target mutant exons and replace them with a wild-type version. “We use these molecules that are packaged in an adeno-associated virus to gain entry into the nucleus. Then those molecules are built to bind to specific locations in messenger RNA. … The spliceosome machinery comes along and flips-in our healthy exon that’s packaged in our molecules and removes the mutant components. Then that [corrected RNA] continues on outside of the nucleus into the ribosomes, and you generate the healthy protein.”

The procedure or process can sound convoluted and dicey–like a wellplaced strike by Spain’s Olga Carmona during the final of the recent FIFA Women’s World Cup. But the stakes are just as high (and even higher for its beneficiaries) for Wager and her team whose exon editing method has many advantages over other gene therapies. Since only the RNA is being edited, risks associated with DNA editing are reduced. Harnessing a natural cellular process prevents the need for bacterial enzymes, which pose an immunological threat, to be introduced to the cell.

The most impactful benefit is the amount of editing that can be done at one time. For example, Ascidian is currently focused on addressing Stargardt’s disease, a genetic retinal disease that causes blindness and stems from mutations in the ABCA4 gene which codes for the protein involved in clearing vitamin A from the retina. Without the healthy protein, toxic compounds begin to accumulate in the eye, destroying cells and impairing central vision function.

Rather than doing “point mutations or small base insertion,” Wager uses technology that replaces whole exons. “We can swap out up to 4,000 nucleotides. So that allows you to make a difference in diseases that have really big gene sizes and genes that have high mutational variants. With one drug we can cover the majority of patients.” If Ascidian’s exon editing idea passes human trials and FDA approval, the treatment is something any ophthalmologist could do during a half-day clinic.

No Magic Bullet

While RNA exon editing is an exciting new strategy for tackling genetic disease, that’s not to say that other tools like CRISPRCas9 aren’t useful. “I’ve been in drug discovery for twenty-three years now,” says Wager. “I don’t think that there is one type of way to ameliorate disease. [T]here’s lots of different ways. They all have their niche.”

In this way, the multi-faceted dynamic of the fight against genetic diseases mirrors that of the startup culture where Wager excels. “When you find a place where it’s not just that you enjoy what you’re doing, but you thrive, that’s what the startup environment for me is [with] super intelligent people [who are] super motivated to make a difference in patients’ lives.”

Each scientist brings something different to the startup, and Wager’s expertise along with her technical skills which she attributes to her time at the U makes her a valuable addition to the team. Through her training she “learned how to exquisitely design and execute research problems in this [startup] environment… .”

“I truly believe that my graduate training here [the U] has set me up to be able to do whatever I want. … I’ve had a bunch of twists and turns [in] my career… I didn’t stay in one kind of role for more than five years. The U just teaches you skills that carry over in everyday life and in your career, and I really am grateful for how we were set up [early] to do research.”

The extensive application of Wager’s education is a testament to the quality of the chemistry department’s graduate program, successfully preparing students for careers in academia, industry, and beyond. The Distinguished Alumni Award celebrates Wager’s impressive career since her time at the U, but really, she’s just getting started in her match against genetic disease. <

Industrial chemist Ziggy Uibel performs at high octane.

Occasionally, one stumbles upon someone who convinces you, through a combination of training, tenacity and enthusiasm on an existential level, that they could do or be anything in this life.

Such is the case with Rory “Ziggy” Uibel, PhD ’03 who recently provided for a select group of non-chemists a tour of Process Instruments, Inc. Founded by Lee Smith, Process Instruments (PI) has pioneered Raman spectroscopy analysis for process control, primarily for refinery and petrochemical plants at sites that can be environmentally extreme, from arctic to desert and from tropical climates to off-shore locations.

If that sounds arcane, it becomes clearly grounded and articulated by the tour guide who leads an X Games-style stunt-double life as an extreme athlete. Even so, he’s categorically in his element as a chemist at the office and shop located in Research Park southeast of the University of Utah.

Uibel moves about the floor of PI with the wild-eyed energy of a kid in a candy shop. He might as well be on inline skates or skiing, two pastimes of his as a younger man. He is fond of picking up a dense spectrograph housed in something to the uninitiated that looks like kryptonite casing and dropping it with a satisfying thud on the bench to show how shockproof his product is.

It needs to be. A Raman analyzer uses a laser to excite a molecular vibration of molecules where a tiny portion of the incident radiation is shifted to a longer wavelength and produces a Stokes Raman scattering band. The wavelength-shifted Raman bands provide a structural fingerprint by which molecules in a sample can be identified. Process Instruments manufactures Raman instruments for not only extreme environments but for the rough handling of petroleum engineers. Its featured, online process monitoring provides updates in real time of up to seventeen different process streams per machine.

“We think of ourselves as more of an information company than an instrument company.” says Uibel. “A refinery with our real time information will be able to optimize stream blends and reduce giveaway of more expensive components,” such as octane.

PI’s optically fast spectrometer and low loss sequential optical multiplexer are paired with a set of fiber optic cables for exciting the sample and collecting the Raman scattering. At PI, the analysis and the machinery – from computers to the cooling apparatus and from the laser probes to the fiber optic conduits – can all be monitored and maintained remotely. Equipment includes back-up components and, if needed, are repaired or replaced on demand, by calling a certain mobile phone number at the other end of which is none other than Uibel (“Hi. This is Ziggy!”) who arranges to assess the situation and then often travels personally to the site to provide service.

This kind of customer service is legendary in the sector and has garnered the loyalty of clients who also benefit from rent-to-own set-ups that would otherwise run them $500,000. Most clients see a return on investment within two-to-four months, says Uibel with a grin. From a modest shop of five employees beginning in 1993, Process Instruments has grown to a staff of 16 and currently boasts a share of 20% of all U.S. refineries and 6% of the worldwide market.

But it isn’t just nerd-out technology that Ziggy’s team offers; it’s clearly encased in business acumen that is innovative and relentlessly hands-on with clients. “We are working on reaching approximately 60% total penetration with many of the individual refineries having multiple (5-10) instruments. The demand for instrumentation within the refinery markets has kept us quite busy and with the limited spare time we do have to continue to work on additional applications for our Raman instruments.”

Those applications are numerous — and always expanding. Petroleum products vary broadly from state to state, and nation to nation based on regulations related to clean air and other considerations. In addition to offering gasoline solutions such as reducing octane loss and the “giveaway” of Reid vapor pressure, (a common measure of and generic term for gasoline volatility), PI helps optimize jet and diesel fuel. The company also provides upstream solutions which optimize crude oil and offshore solutions. More than a dozen streams of samples can be analyzed with a single instrument/system. 

Uibel is also keen to talk about applications outside the fuel industry, including pharmacology packaging (using a unique Raman spectrometer to analyze each pill, for example) as well as food production and distribution. The petroleum industry may be the “low hanging fruit,” says Uibel, but the company’s Raman analyzers are also being used in tracing ppm sulfate detection in offshore waterflooding streams and direct determination of olefin concentrations in motor gasoline (US Patent No.7,973,926). Blood testing is already being done with handheld Ramen systems.

Bowling with brio on Grandeur Peak.

A Canadian by birth, Uibel has pretty much always had a dual life: one in the lab and one on the streets and the slopes where his athleticism really shines. In fact, chemistry did not appeal to him at all when he was an undergraduate at the University of Washington in Seattle. Instead, he was infatuated with aeronautics and while taking general chemistry courses researching a pressure sensitive paint for wind tunnel applications using a porphyrin molecule (water-soluble, nitrogenous biological pigment) Uibel worked with NASA and Boeing developing the paint and over time his interests shifted from aeronautics to spectroscopy.

Uibel wanted to continue his studies in spectroscopy for this purpose, and after asking around, discovered that Joel Harris’s name was at the top of everyone’s list. He decided that the University of Utah would be the ideal location for his graduate career. “I can easily say that coming to the U of U was one of the best decisions of my life,” he remarks.

That’s saying a lot, considering what Uibel’s life (and times) looks like these days, even as he’s entered middle age. What started as a seasonal gig as a “liftee” at Snowbird turned into a full “gap year” between his bachelor’s and graduate school at the U. Between skiing in the winter and rock climbing all summer near Elko, Nevada, he actually thought he would eventually find himself in a classroom teaching. That changed after earning his doctorate in analytical chemistry and landing a job at PI to design, assemble, test, calibrate and install Raman analyzers.

If this sounds like intensive work, it is. But Uibel is an intense man, and it seems to fit not only his inherent brio but also to play out and build on his activities outside of work. A globetrotter with clients from Canada to Singapore, and from Australia to off the coast of South America, Uibel has racked up a million-plus airline miles in no time (and without knowing he’d done so). This is an unassuming man who had to fetch his business card when asked what title he had at PI. (Turns out it’s Applications Manager or, maybe, Vice President of Technology.)

That’s not to say Uibel is a shrinking violet. As a youth he competed on MTV Sports as a stunt model. He recently completed the Rage Triathlon in the Lake Mead National Recreation Area, and he doesn’t stop at donning the Lycra for the swimming, bicycling and running competitions; he’s famous for summiting Grandeur Peak in Salt Lake Valley not once in a single day but a whopping five times (31 miles). The Peak has a special place in Uibel’s heart. Following the discovery of “misplaced” brick in his backpack compliments of his jokester friends, he started carrying a bowling ball and pins to the summit during the winter and bowling in carved-out lanes of snow “with an automatic return” (i.e., uphill). Stand-by participants who happen to be on-hand are awarded a tag for their backpacks emblazoned with “I Striked out on Grandeur Peak.”

“We try not to do it in the summer,” says Uibel. “Don’t want a bowling ball landing downhill on Interstate 80.”

Bowling on a mountain peak in the dead of winter? Why not? It’s consistent with Ziggy Uibel who has gone from his ambitions to be an aeronaut, a teacher, an academic and researcher, and purveyor of stunt double-inspired antics to, these days, an industrial chemist using the latest technologies and techniques to advance everything from petroleum refining to blood testing.