From Molecules to Medicine
The brainchild of one of The University of Texas at Dallas’ most distinguished chemistry professors has been a profitable business since its founding in 1995, with global reach that produces specialized chemical compounds for the pharmaceutical industry and researchers worldwide. The Plano, Texas, company – Macrocyclics Inc. – has remained a catalyst for innovation while employing UT Dallas alumni and providing hands-on training to students.
But the story of Macrocyclics began more than two decades earlier in a modest chemistry lab at a very young, sparsely populated UT Dallas. In 1972 Dr. A. Dean Sherry arrived on campus on the heels of completing a National Institutes of Health (NIH) postdoctoral fellowship at New Mexico State University. He was just the fourth faculty member in UTD’s chemistry department. Over the years, he established himself as a trailblazer in designing molecules for use in medical imaging. As his body of published work on chemicals called macrocyclic ligands expanded, so also did his academic career – and professional reputation.
By the mid-1990s, Sherry’s innovative chemical synthesis methods were considered so pioneering that researchers from around the world sought him out, eager to get their hands on his unique compounds.
“This was in the early days of the internet, and we had rudimentary email, so I began getting messages from researchers in Europe and around the country asking if I could send a small quantity of a particular compound for their research,” Sherry said. “I didn’t have a production lab, but I told them I would be happy to share details in how to prepare the compounds in their own labs. But, even with a detailed recipe, many did not have enough synthetic experience to prepare useful materials.”
And so, the idea for Macrocyclics was born.
Public investment in university research benefits not only the shareholders but also society. By fueling economic development and by enabling scientists to continue pushing boundaries, that investment yields discoveries that change the world. UT Dallas’ first startup company – Macrocyclics – illustrates this transformative impact.
The Chemistry
One of the key characters in the story of Macrocyclics is chemistry itself. A short primer shows why the company’s materials are in such high demand and illuminates their impact on medicine.
A molecule capable of binding tightly to a metal ion is called a chelate. Chelates come in various shapes, but macrocyclic chelates contain an interior ringlike structure where the metal resides. Some macrocyclic chelates occur in nature, while many others have been synthesized in labs.
Chelates play a vital role in nuclear medicine and medical imaging by binding tightly to a metal ion that otherwise might be toxic in tissues. One example of an imaging tool used in nuclear medicine is positron emission tomography, or PET scans. This imaging technology introduces small amounts of radioactive metals – carried by chelates – into a patient’s body to track cellular and metabolic activities that help doctors detect and diagnose disease. Chelated metal ion complexes are also widely used as contrast agents in MRI exams.
An active area of development by both academic and industry researchers is to use the unique chemical composition and structure of macrocyclic ligands for medical use. In their cavity, they carry a payload of metallic radiotherapeutic compounds that can kill cancer cells on contact, while the outside molecular structure can be designed to bind to a specific protein that ensures precise delivery to only diseased tissue.
“Metals have properties that we can exploit to obtain different types of images in the body and to kill diseased cells,” Sherry said. “Chelating agents carry metals to various places in the body while protecting it from the metal being deposited just anywhere. We only want these drugs in the body for a short time, and by binding the metal to the chelate, it can be naturally filtered from the body.”
The distinctive chemistry of the macrocyclic molecules – custom-designed scaffolds that ferry both a targeting agent and a cancer-killing payload – makes the catalog of Macrocyclics’ products attractive to companies that spend millions of dollars developing targeting agents and therapeutic drugs.
“There’s only one other company in the world that I’m aware of that makes anything similar to ours,” Sherry said. “That’s why we’ve been so successful.”
In the Beginning
The genesis of the company was much different from the process of starting a university spinoff today. There were no patents, no licensing agreements, no investors – just Sherry’s desire to share his materials with other researchers around the world. Macrocyclics began licensing UTD technology in 1998.
In the beginning, Sherry’s solution for managing the increasing number of requests for his macrocyclic chelates was to set up a website to take orders. But he had another problem.
“I went to Bob Lovitt, who was the vice president for business affairs at UTD at the time, and told him I can’t just be making these molecules in my chemistry lab in [Lloyd V.] Berkner Hall,” Sherry recalled. “He said, ‘Well, we’ve got these old buildings on the north side of campus that have been there forever.’ [Today they are located between a parking garage and the administration building.] So, he agreed to allow us to install a chemical hood there, but it was difficult because it wasn’t a great environment; it was just an old shack.
“That’s where Macrocyclics started.”
Sherry hired his postdoctoral researchers to prepare samples on the weekends for shipment. One of the first products was thulium DOTP, which is used in medical imaging to track biological processes based on different sodium levels inside and outside cells.
It wasn’t long before Big Pharma came knocking.
“We were at an American Chemical Society meeting presenting a poster with a new type of macrocyclic chelate on it, and we were approached by representatives from DuPont’s pharmaceutical division,” Sherry said. “They had been trying to make this same molecule in their labs. They asked us to make 100 milligrams and ship it to them. So, we did; they liked it, and they kept ordering more.”
The orders brought in a significant amount of money, especially for a fledgling company that had been funded through the U.S. Small Business Innovation Research (SBIR) program, NIH grants and revenue from a few catalog products.
The large commercial order required larger-scale equipment, so Macrocyclics moved off campus to a small warehouse facility just west of UTD. Sherry hired students to help with production.
With an entrepreneurial spirit, Sherry found an inexpensive way to outfit the new lab. Perot Systems Corp. had recently purchased Atlantic Richfield Co.’s (ARCO) 1 million-square-foot campus near UTD.
“I’ll never forget how we did this with very little money,” Sherry said. “Those ARCO buildings were filled with equipment that was just going to be thrown away. I knew some people there and asked if I could buy some of it. So, I went up there, walked around and bought five fume hoods, some lab benches and some desks, and I paid about $4,000 for the whole thing.”
The Acquisition
As Macrocyclics continued to expand its product line, the company moved to an even larger facility just north of UT Southwestern Medical Center, where Sherry was also a professor of radiology beginning in 1990.
One of those new collaborators was Dr. Garry Kiefer, a chemist at Dow Chemical Co. in Freeport, Texas, where he led the development of new radiopharmaceuticals and chelation technologies.
“Dean [Sherry] and I were working in the same field, but he was at the top of the ladder, while I was kind of new,” Kiefer said. “I cold-called him one day and asked him for some ideas on what we were doing. We connected, started collaborating, and when I retired from Dow in 2005, he asked me if I wanted to come to Dallas.”
Kiefer joined Macrocyclics that year as CEO and director of research. He has also worked with Sherry and his graduate students as a UTD research professor in chemistry.
In 2009 the company was approached by representatives from Orano Med to manufacture a chelating agent for use in its upcoming clinical trial of a radioactive lead-based drug to treat cancer.
“They needed a lot of specific information about our chelates in order to submit their therapy to the Food and Drug Administration for approval,” Kiefer said. “We could create documentation about our product, but it was proprietary, and Orano Med wouldn’t be able to see it directly. We told them the only way we could do that is if they bought our company. So, they did, in 2011.”
Orano Med is a medical subsidiary of an international conglomerate that uses nuclear materials for a variety of applications. Orano Med is developing cancer treatments that exploit the unique properties of an isotope of lead called lead-212, specifically, alpha particle therapy.
“Alpha particle therapy is very powerful,” Sherry said. “If you can get one alpha particle near a cancer cell, the cell is dead. You also need a targeting agent so that the radioactive material goes only to the cancer. The idea for alpha particle therapy has been around for a long time, and many people have tried with many failures. It takes the right combination of technologies, a trifecta of components to come together – targeting agents that go directly to cancer cells, chelates and radioactive isotopes.
“That’s why Orano Med originally needed Macrocyclics. They needed a macrocyclic chelate to hang on to their radioactive lead, and that’s what we do. We’re really good at this.”
As Orano Med has grown, Macrocyclics has grown alongside it, retaining the name in part because Macrocyclics has brand recognition throughout the world. In 2016 Macrocyclics moved into a new facility constructed by Orano in East Plano – just 6 miles from the UT Dallas lab where the company started.
Growing Talent
In 2010 UTD alumnus Federico Rojas MS’06, PhD’08 joined Macrocyclics as a principal scientist. A native of Costa Rica, he completed a postdoctoral fellowship focusing on MRI contrast agents at UT Southwestern. At Macrocyclics, he supervises the production of catalog products, develops synthesis processes for custom products and serves as radiation safety officer.
“In the 1990s, there was a batch of students from Costa Rica who went to UTD for graduate school, and one of them stopped by my university there to talk with us about coming to UTD,” Rojas said. “I was studying business at the time, but I switched to chemistry and came to Dallas.”
Duke Halloran MBA’22, MS’22 received his undergraduate degree in chemistry from the University of Arkansas and was hired as a chemist by Macrocyclics in 2016.
“Working in this lab is such an exciting experience,” Halloran said. “We’re constantly trying to do something new or improved, even if we’ve made the same products for decades. As a chemist here, you’re constantly applying fundamental science, using all kinds of cool equipment. It’s very hands-on, very challenging and very rewarding.”
Halloran recently made the switch from the lab to the front office. He graduated from the executive MBA program in the Naveen Jindal School of Management and added a master’s degree in supply chain management, both in May 2022.
Training Future Scientists
Macrocyclics recently initiated a summer internship program for UT Dallas students.
“Macrocyclics needs new chemists, and we can train them for careers, whether they join our company or go elsewhere where they can advance the field,” Halloran said.
Isaac Quinonez, a chemistry senior at UT Dallas, spent last summer as the company’s first intern. A first-generation college student from South Dallas, Quinonez participated in UTD’s Academic Bridge Program before he began his freshman year. He said that during the first week of his internship, he was tasked with making a catalog compound. His product proved to be 99% pure.
“I never saw anyone pick something up as quickly as Isaac did,” Kiefer said.
Under the supervision of Rojas, Quinonez manufactured catalog products – using state-of-the-industry lab equipment – and investigated potentially new chemical compounds.
“I didn’t know I would be doing this much chemistry as an intern, but this is an environment that nurtures your growth,” Quinonez said. “Working here has taught me that even if no one has done it before, that doesn’t mean you can’t do it yourself.”
This spring, Quinonez is participating in the Green Fellows program, which allows UT Dallas undergraduates to conduct laboratory research at UT Southwestern.
Undergraduates at UT Dallas are encouraged to participate in research opportunities on campus, but only a limited number can be accommodated. Sherry said that because the science at Macrocyclics involves chemistry, physics, biology and other technical areas, their internship should be attractive to any science major.
“Some students want to go off and start a company and develop something new; others want to go to med school, and you’re never going to change their mind,” Sherry said. “But for students who don’t have a clue about what they want to do with the rest of their lives, having more opportunities like this at local companies while they’re attending school just opens their minds to new possibilities of future careers.”
The Legacy
Sherry retired from UT Dallas in the summer of 2022, after 50 years on the faculty. While he is no longer active in the day-to-day operations of the company he founded, his pride in its success goes beyond revenues.
“Macrocyclics became well-known, and we would ship to academic labs and companies all around the world,” Sherry said. “I would often go to international scientific conferences, and someone would come up to me and say, ‘Dean, I can’t tell you how much Macrocyclics has influenced my ability to get things done.’ And that makes me feel really good.
“In academics today we talk about one’s impact on science, all these so-called quantitative measures, like journal impact factors. I tell people that starting Macrocyclics has had a bigger impact on science than anything I have ever written. You can take any of my scientific articles – and I have close to 500 publications – and they all have some impact, but nothing like Macrocyclics. Because it’s been a catalytic event – you put materials into the hands of 100 people, they’re going to do 100 different things with them.
“It’s really been amazing to me to see the impact that Macrocyclics, this tiny little company that started on the UTD campus, has had in the nuclear medicine world. It’s stunning.”
A Lifetime of Science
When Dr. Dean Sherry retired last summer, he had held a Cecil H. and Ida Green Distinguished Chair in Systems Biology at UT Dallas since 2005. In March he was named chair emeritus. At UT Southwestern, Sherry also was named professor emeritus in the Advanced Imaging Research Center – a joint research facility with UTD, UT Arlington and UT Southwestern – for which he served as the founding director until 2019. At UT Dallas, Sherry headed the Department of Chemistry from 1979 to 1990 and was interim dean of the School of Natural Sciences and Mathematics in 2020.
Sherry has mentored more than 100 graduate students and postdoctoral researchers, and he initiated the Green Fellows program. Since the program began 18 years ago, 296 students have become Green Fellows. An inventor on 34 patents, Sherry has received numerous honors for his contributions to science. In December 2022, he was named a fellow of the National Academy of Inventors. His research over the past 50 years has been supported by the NIH, The Welch Foundation, the Cancer Prevention & Research Institute of Texas, and other public and private sources.
In 2022 Sherry and his wife, Dr. Cynthia Sherry BS’78, made a $100,000 gift that established the Dean and Cindy Sherry Professorship in Chemistry, an endowment that will support the chemistry and biochemistry research-enhancing activities of the professorship holder.
