“Academia produces knowledge brilliantly. It distributes it appallingly,” Professor Dorina Buda wrote recently on LinkedIn.
The statement made me pause because it brought back two experiences from nearly a decade apart. Both involved the same molecule, peroxynitrite, a peroxy isomer of nitrate. The first occurred when I knew virtually nothing about patents. The second came after I had worked as a patent examiner at the U.S. Patent and Trademark Office and had become familiar with patent prosecution. Yet in both cases, I learned how easily scientists can focus on discovery and publication while overlooking what a discovery might become after it leaves the laboratory.
My interest in peroxynitrite arose during an extraordinary period in nitric oxide research. By the mid-1990s, nitric oxide had gone from being regarded largely as a small reactive gas to being recognized as an important biological messenger. Its roles in vascular relaxation, neurotransmission, platelet function, immune responses, and cellular signaling were changing the way scientists thought about physiology. It was also a period of intense interest from both academia and industry, with substantial investments being made to understand nitric oxide biology and to explore its possible therapeutic and technological applications.
But nitric oxide chemistry also had another side. Nitric oxide reacts rapidly with superoxide to form peroxynitrite, a much more reactive species that was being investigated for its possible involvement in oxidative injury, protein modification, lipid oxidation, nitration reactions, inflammation, and disease. Nitric oxide also reacts rapidly with oxyhemoglobin, ultimately forming nitrate and methemoglobin. In physiological terms, these two reactions illustrate very different consequences of nitric oxide chemistry: Reaction with superoxide can divert nitric oxide toward potentially damaging oxidant chemistry, whereas its rapid consumption by oxyhemoglobin helps limit the lifetime, diffusion, and vasorelaxant action of nitric oxide in the circulation.
For those of us studying this chemistry, there was also a very practical problem: Peroxynitrite was not easy to prepare reliably. I had watched a fellow postdoctoral researcher and two graduate students repeatedly struggle with one of the available methods for preparing peroxynitrite. At the time, practical methods were limited, and the approach most familiar to our laboratory involved the autoxidation of alkaline hydroxylamine followed by freeze fractionation. The method had several practical limitations, including complicated handling, high ionic strength, residual reactants, strongly alkaline conditions, and limited options for purification.
In 1995, I began thinking about whether there might be another way. The answer came from an unexpected place. A friend who could read German knew that I had experience with ozone and brought me a 1929 paper describing the reaction of ozone with azide.
That immediately raised a question in my mind: Could chemistry reported more than six decades earlier solve a contemporary biochemical problem? We investigated the reaction and found that ozone could react with sodium azide under alkaline conditions to produce stable, concentrated peroxynitrite solutions of low ionic strength that were essentially free of hydrogen peroxide. We characterized the chemistry and published the method in Free Radical Biology and Medicine.
At that stage of my career, I regarded publication as the natural conclusion of the work. There had been a problem, we had found a solution, and we had documented it and shared it with other scientists. The method was subsequently adopted by researchers at major institutions, including MIT and the University of California, Berkeley. On more than one occasion, when I met scientists at conferences, our peroxynitrite synthesis became an immediate point of recognition. The method had begun to identify me professionally before I fully appreciated what else the chemistry might become. What happened afterward changed the way I thought about that sequence.
The same chemistry acquired another meaning
On December 12, 1996, a truck carrying a heavy load of sodium azide overturned and caught fire on I-15 near Mona, Utah, producing a toxic vapor plume and prompting the evacuation of residents. The accident also raised concerns about possible contamination of the local water supply and the broader environmental consequences of a sodium azide spill. Environmental chemists investigating how sodium azide might behave and be remediated in the environment later encountered our work describing the reaction between ozone and azide and became interested in it for an entirely different reason.
We had asked whether ozone and azide could be used to make peroxynitrite, whereas the environmental chemists were interested in whether ozone could be used to destroy unwanted azide. The chemistry was the same; only the problem had changed. That was something I had never imagined when we performed the experiments. Then came another surprise.
In 1999, U.S. Patent 5,914,305 was issued to researchers at Lever Brothers Company for “Peroxynitrite Based Bleaching Systems.” The patent proposed using peroxynitrite to remove stains and soils from fabrics and other materials. It discussed methods for preparing peroxynitrite, cited work from our group, and in its experimental studies prepared peroxynitrite using sodium azide and ozone.
The inventors were not patenting our synthesis; their invention concerned the use of peroxynitrite as part of a bleaching system. What fascinated me was the difference in perspective. Biomedical scientists had been asking what peroxynitrite did to proteins, lipids, cells, and tissues, whereas industrial scientists were asking a different question: What can peroxynitrite do for us?
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I had helped develop chemistry that became useful in a direction I had never considered. Although I had been directly involved scientifically, I was largely unaware of what happened to the chemistry after publication. At that point, I knew very little about intellectual property, but that would soon change.
Years later, I knew better, but academia still came first
In November 2000, I explored an alternative career path and became a patent examiner at the U.S. Patent and Trademark Office. I underwent extensive on-the-job training and, over the course of about a year, examined dozens of patent applications, wrote numerous First Actions on the Merits, and worked with primary examiners on several applications that were allowed and subsequently issued as U.S. patents.
Working so closely with inventions affected me in a way I had not expected. Rather than drawing me away from academic research, it strengthened my desire to return to it. After about a year, I left the patent office with a much greater understanding of intellectual property and an even stronger urge to create and innovate rather than evaluate the inventions of others.
In January 2002, I returned to academia with renewed interest in research and began working on problems in mechanistic and molecular toxicology, including the chemistry and biological reactions of peroxynitrite. While working on several other research problems, I developed a homogeneous method for the synthesis of peroxynitrite solutions using isoamyl nitrite and hydrogen peroxide in an isopropyl alcohol-water system. The reaction was simple, rapid, and efficient. Under suitable conditions, peroxynitrite yields reached about 92 percent within approximately 10-12 minutes, and the method was amenable to large-scale synthesis.
By then, the broader commercial potential was also becoming apparent, as was the possibility of filing a utility patent. We showed that peroxynitrite and oxidants produced through its reaction with carbon dioxide could oxidize indigo and indigo carmine, important pollutants in textile wastewater. The work therefore suggested potential applications in textile processing, wastewater treatment, bleaching, and other industrial oxidation processes.
Although I knew that the chemistry could have intellectual-property value, my first instinct as a tenure-track academic was still to publish. I wanted to establish the scientific contribution, strengthen my academic record, earn tenure, and, most importantly, make the work available to other scientists who might find it useful. Patenting or commercialization could follow later if appropriate. At the time, that order seemed perfectly reasonable to me. In many respects, it still does. My purpose was never primarily personal or commercial gain; the broader dissemination of useful scientific knowledge mattered more.
The experience nevertheless taught me that publication and intellectual-property protection operate on different timelines. Academic science rewards disclosure, whereas intellectual property often requires protection before disclosure. The two goals need not conflict. Scientists can patent and publish, but sometimes the sequence matters enormously.
The question we are not trained to ask
Academic researchers are trained to ask whether a result is new, reproducible, scientifically important, and publishable. Those are exactly the questions we should ask.
That perspective is consistent with how I have always approached science. I value open science and the broad dissemination of scientific knowledge. Commercialization has never been my primary motivation, and I do not object when others recognize possibilities in published work and develop them further. In many ways, that is one of the purposes of publishing science.
But perhaps we should occasionally ask one more question before disclosure: What else could this become? A laboratory method might become a diagnostic tool, a biochemical observation might suggest a therapeutic strategy, and a chemical reaction developed for biomedical research might find an entirely different application in environmental technology, manufacturing, public health, or another industry.
Not every discovery should be patented. Most should not. Nor should intellectual-property considerations unnecessarily delay the communication of useful science. The issue, for me, is not choosing commercialization over open science. It is recognizing when a genuine choice exists and making that choice deliberately.
Technology-transfer offices can help, but the scientist at the bench is often the first person who recognizes that something unusual has happened. Academic incentives do not always encourage us to stop and consider the broader possibilities. Papers, grants, citations, promotion, and tenure are immediate and measurable. Translation may be slower, less certain, and far removed from the original scientific question.
My experiences with peroxynitrite taught me that the same knowledge can look very different depending on who encounters it. A biomedical scientist may see a reactive molecule, while an environmental scientist may see a remediation strategy. An industrial chemist may see a process, an entrepreneur a product, and a patent professional protectable intellectual property.
None of those perspectives diminishes the science. Nor does allowing others to pursue those possibilities diminish the contribution of the original investigators. Such efforts extend the life of the discovery.
That is why Professor Buda’s observation stayed with me. Academia is exceptionally good at creating knowledge. We may need to become equally good at recognizing where that knowledge can go.
Before sending the next manuscript, perhaps the question is not only, “Is this ready to publish?” It may also be worth asking where else the discovery could lead.
Producing knowledge is one accomplishment. Recognizing what else that knowledge can become and creating a pathway for it to get there is another. Sometimes the distance between the two is much greater than we realize.
Rao M. Uppu is professor of environmental toxicology and chemistry at Southern University and A&M College in Baton Rouge, Louisiana, where he has served since 2002. He is also an adjunct professor of chemistry and pathobiological sciences at Louisiana State University.
Trained in biochemistry, physical organic chemistry, and free radical chemistry, his research spans bioanalytical methods, biomarker discovery and validation, chemical toxicology, environmental chemistry, computational genomics, reactive intermediates, and the molecular mechanisms of disease. His scholarship is indexed on ORCID, ResearchGate, and Google Scholar.
Dr. Uppu is a Fellow of the American Association for the Advancement of Science (AAAS), the Royal Society of Chemistry (RSC), the Royal Society of Biology (RSB), the Royal Society of Medicine (RSM), the Royal Society for Public Health (RSPH), and the Academy of Toxicological Sciences (ATS).
In addition to his scientific research, he writes reflective essays on scientific culture, mentorship, peer review, ethics, and the human dimensions of academic life. He shares updates on LinkedIn.
