UCLA Graduate Student Noelle Mitchell (left) and Dr. Kyungae Yang of Columbia are lead authors of a new paper that builds on the long-term collaboration of their two research groups. One cold day in October 2016, Anne Andrews, UCLA professor of chemistry & biochemistry and psychiatry, found herself in Jyväskylä, Finland. An expert in developing biosensors used to understand brain function and psychiatric disorders, Andrews was scheduled to speak at a nanoscience conference.
Despite the three flights it took to get to this remote university near the arctic circle and the already minimal sunlight, the trip proved to be more worthwhile than anticipated. In fact, it became the catalyst for a seven-year research collaboration that is still going strong, with an impactful new paper recently published in Science.
What is this research about and why does collaboration play a key role? Consider DNA and RNA, the macromolecules that play central roles in biology by passing on genetic information. We now know that RNA can also regulate gene expression via riboswitches. These short segments of RNA recognize small molecules such as nutrients. Small molecule binding causes a change in the 3-dimensional structure of the RNA that alters protein translation. The discovery that bacteria could use riboswitches to differentiate closely related small molecules and use conformation changes to transmit information expanded on the natural functions of RNA.
Discovered in 1990, aptamers, which are artificial RNA and DNA, were thought to be the next big thing. “People hoped we would soon discover aptamers that bind to small molecules for all kinds of applications, from nanotechnology to diagnostic tools, to fighting diseases,” said Andrews. But identifying the right sequence…that has the right structure…to bind to the right molecule can be akin to finding a needle in a haystack.
This has been, until now, the challenge of using aptamers in most applications. And this is also where the collaboration aspect of this story comes into play.
Milan Stojanović, professor of medicine, biomedical engineering, and systems biology at Columbia University, is one of the world’s experts on identifying aptamers. He had never heard of Andrews until the day, seven years ago, when he got a call out of the blue. While at that conference in Finland, another speaker remarked that they had been trying, unsuccessfully, to develop an aptamer sensor for dopamine. Despite their failure, they thought Andrews might be interested in a colleague of theirs, Stojanović. Perhaps the two of them could solve the problem. Andrews called Stojanović shortly after arriving back in Los Angeles.
“Our work is a perfect example of how collaboration can push science forward in ways we can never do as individuals.”
Milan Stojanović
Since that day, the two researchers have combined their expertise in various aspects of chemistry to become one of the leading teams focused on aptamer biosensors. Just a few years into their work together, using Stojanović’s knowledge of aptamers and Andrews’ experience with transistors for biosensing, they had already designed novel sensors for tracking neurotransmitters. Not long after came implantable devices for use in the brain. Next was a wearable device that could measure cortisol levels during stress in real-time, non-invasively, through human sweat. With these successes, the true potential of aptamers was being realized.
But their most recent work may be the most important yet. Led by Dr. Kyungae Yang at Columbia, the team developed a generalizable approach that for the first time can lead to new aptamers for small molecules that were intractable targets in the past.
The Columbia investigators first identified 23 new aptamers for a variety of small molecules, including neurotransmitters and amino acids – an extraordinary feat in and of itself. These new aptamers were combined with 4 other aptamers they had already identified. Using this massive collection of aptamers and small molecule targets, which were related to one another by a change in a single part of each target, the researchers calculated the thermodynamics of binding of the aptamer/molecule pairings. “By analyzing this large and unprecedented database we were able to see exactly what parts of molecules were causing challenges,” said Yang.
Using Stojanović’s knowledge of organic chemistry, Yang’s experience and intuition in aptamer isolations, and thermodynamics data collected by Yang and UCLA chemistry & biochemistry graduate student Noelle Mitchell, the researchers theorized that aptamers could be discovered for any small molecule important in biosensing, medicine, or health and wellness. To test their ideas, they deconstructed two difficult small molecules–leucine, a key amino acid, and voriconazole, an important antibiotic with a narrow therapeutic dosing window. Using their “retrosynthetic approach”, a method inspired byorganic synthesis, and several new strategies for stepwise aptamer selections, leucine and voriconazole aptamers were at last identified. This success underscored the power of the team’s methods and insights.
Together, Stojanović, Yang, and Andrews have not only advanced this field of study opening new possibilities for the future, they have laid the foundations for the next generation of scientists.
This achievement should not be understated. The team has identified many new aptamers and developed an approach that aims to bring the true potential of artificial RNA and DNA to fruition – 33 years after aptamers were first discovered. “This represents an important step in a long-awaited aptamer revolution – one that might finally allow us to design new generations of treatments and devices for all kinds of challenges humankind faces,” said Mitchell.
The fact that the first and second authors of this paper are a senior scientist working with Stojanović and a student of Andrews speaks to the true impact of collaboration. Together, Stojanović, Yang, and Andrews have not only advanced this field of study opening new possibilities for the future, they have laid the foundations for the next generation of scientists that includes Mitchell and many others with whom they have worked that are continuing this research far into the future.
Like many great collaborators, Andrews and Stojanović are also friends. Andrews credits Stojanović with playing an indispensable role in enabling them to win a prestigious $8 million NIH Director’s Transformative Research Award in 2017. “He inspired and encouraged me to apply for the award and really held my hand through what was a new process for me during a stressful time – that’s not something just anyone would do,” she said. “In fact, that grant was instrumental in enabling our collaboration to push this area of research forward.”
Scientific collaborations indeed provide a unique opportunity to bring people from different backgrounds together in more ways than one. “My father was the son of Croatian immigrants – my given name is actually Milasincic,” said Andrews. “Milan comes from Serbia. One might often hear that Croatians and Serbians have a history of not always getting along, so it has been really amusing to stress that science has a way of erasing not only interdisciplinary, but also geopolitical barriers.”
Of course, for two such passionate research groups, the work is never done. The next steps are to build on the current archive and improve their abilities to identify and utilize more aptamers. “Our work is a perfect example of how collaboration can push science forward in ways we can never do as individuals,” said Stojanović. “Each of our research groups has become better and stronger thanks to our work together.” Sometimes, the key to unlocking a new collaboration is as simple as making a new connection.