Research Engine

The next scientific revolution will be illuminated

The tools of bioluminescent optogenetics, or BL-OG, promise to remake the enterprise of scientific discovery

Photo courtesy of Justine Allen, Ph.D., Carney Institute for Brain Science

Bioluminescence in the mouse choroid plexus, courtesy of Manuel Gomez-Ramirez, PhD and Eric Klein

By Richard Asinof
Posted 8/15/20
New scientific advances in the development of the tools of bioluminescent optogenetics, or BL-OG, are being pioneered by a research lab run by Christopher Moore, a professor of Neuroscience at Brown University and Associate Director of the Carney Institute for Brain Science, under the philosophy of open science.
What kinds of collaborative research and educational efforts can be integrated as part of the high school science curriculum in Rhode Island, featuring BL-OG? How does BL-OG promise to enhance and to disrupt the academic research enterprise and pharmaceutical pipeline around drug discovery? How can the philosophy of “open science” be applied to the ongoing work to create a vaccine for the coronavirus, in terms of sharing knowledge across pharmaceutical platforms? What is the best way to promote the values of science and to combat calculated misinformation being purposely promoted by the Trump administration around the coronavirus around testing and transmission of the disease?
There is an old cartoon that showed a young boy coming upon a girl studying an object on a sidewalk with the caption: “It’s mine. I lost it. What is it?” The concept of “ownership” and “scarcity” are often intertwined in much of our scientific and political endeavors, unfortunately.
The art of convergence, of conversation, of breaking down existing silos, whether in decision-making in government or in science, requires a different kind of skill set around listening and participation. Dr. Doug Eby, a physician involved in primary care, once spoke at the Warren Alpert Medical School and, as part of his presentation, said that the advice he gave his providers was this: “Learn to listen in 10 different ways.”
That kind of inclusive approach to patient care – in allowing patients to be active participants in the conversation around their own care – is often the missing ingredient in other enterprises as well.
All too often, it requires making some noise to be heard, to echo what Congressman John Lewis said: “Never, ever be afraid to make some noise and get in good trouble, necessary trouble.” Not being heard is much like Langston Hughes poetic question: “What happens to a dream deferred?”
At the same time, there are those who are more than willing to exploit frustrations around not being heard to provoke anger, anxiety, and outrage, whether it be digital platforms such as Facebook or journalistic endeavors who use the emotional content to sell advertising.
In these perilous times we live in, amidst the coronavirus pandemic and its soaring death rate, the work of scientists who are willing to share their research in an Open Science platform is a healthy antidote to the forces of tyranny at work.

PROVIDENCE – There is a brilliant new scientific revolution called BL-OG – or bioluminescent optogenetics – blossoming at Brown University, under the guidance of Christopher Moore, Professor of Neuroscience and Associate Director of the Carney Institute of Brain Science.

BL-OG is a breakthrough scientific technology that marries the capability of cells to produce their own sources of light to the technology of using light to observe and control the individual firing of neurons.

Translated, instead of having to shine an intrusive laser into, say, a targeted region of the brain, BL-OG creates new molecules through which the targeted neurons can emit their own light source – luminescence similar to what is produced in nature by fireflies and plankton.

BL-OG, explained Moore, “can create precision tools for understanding how cells communicate anywhere in the body.” The development of new bioluminescent molecules and modules, such as LMO3 and the recently created LMO7, Moore continued, to take advantage in making optogenetic sensors to illuminate and target synaptic processes throughout the body.

“Basically, we’ve taken what would have been chemical transmissions in the brain, usually neurotransmitters, and we’re seeking to replace it with optical transmissions,” Moore said. “This revolution, if you will, by making things light sensitive, [means that] you don’t have to aim a laser at the spot.”

Translated, Moore and his team of collaborators are working to solve all the challenges you need to solve to use local and tuned chemical light, not externally inserted and controlled fiber optics, to drive optogenetic sensors.

In discussing the research work, Moore described it as: “We’ve made some really new bright light generators, [by taking] existing forms of light-generating modules, and adding a little amino acid protein to make sure that the light bulb is right next to the light receiver, at the molecular level.” There are awkward names now, what Moore called “license plate names,” which demonstrate exactly how new the creations are.

Translated, the research is attaching what Moore called “super bright searchlights – or whatever metaphor you want” – to the same optogenetic modules.

The scientific implications are far-reaching and novel, according to Moore. “Anyone who has ever done a drug study will tell you that one of the most frustrating results is a negative outcome,” he said. “It is doubly frustrating, if you want to see if the drug can save an animal’s life, and unless the drug does something you can measure, externally or internally, you’re never sure if it’s a true negative result, because maybe the drug didn’t get to the target – maybe it got sequestered by the liver.”

With the tool of bioluminescent optogenetics, Moore continued, “Every time the drug is activated, you are generating photons – that is the way you activate the drug. It means that you have, for free, an ‘online reporter’ of the drug having reached its target.”

One lab found that the BL-OG LMO3 molecule can improve recovery from spinal cord injury in an animal model. “That’s a really neat advance,” Moore told ConvergenceRI. “It is a genuine step forward in helping to recover from spinal damage.”

The research, Moore continued, has not yet made the leap to humans. “In concept, there is no reason why it can’t. We have a path to get there, but we’re not there yet.”

Moore said: “We do know that all of the molecules we have been using seem to be really well tolerated and safe. There is no toxicology to the drugs that we’re developing.”

If the BL-OG technology works on spinal cord repair, the hard-working Moore added, with a laugh: “We can take the day off after that.”

Another target of potential use of BL-OG tools are the neural pathways of pain in skin, according to Moore, who said he recently had discussed the possibility with Diane Lipscombe, Professor of Neuroscience and director of the Carney Institute for Brain Science, a colleague and collaborator.

Promoting ‘Open Science’ in theory and practice
Moore was recently featured in a podcast, “Once a Scientist,” created by Nick Edwards, in which Moore explained his goals as a scientist: “My goal isn’t to teach people facts,” he said. “It’s partly to teach people how to answer questions, and in equal measure, how to pose questions.”

One strategy to accomplish this, Moore suggested during the podcast, was to assign a short essay before each lecture, challenging students to answer questions about the subject without any prior knowledge – in the belief that even if his students do not intuit how nature solves a particular problem, they might develop a better understanding of the relevant parameters. [See link below to podcast, “Brown Univ. Professor Christopher Moore, on identifying heroes and building mental models.”]

An underlying ethos of Moore’s work is his advocacy of the concept and philosophy of “Open Science.”

“I strongly believe, at every level of analysis, that ‘Open Science’ – capital O, capital S – is what is likely to lead to success in the broader enterprise of discovery in science,” Moore said.

Moore’s belief rests upon the premise that sharing the progress being made as part of the scientific endeavor and making others aware of new insights as rapidly and as transparently as possible is critical to success.

“It is a philosophical commitment to, whenever possible, to share [information] as openly and transparently as rapidly as we can,” Moore said, with emphasis. “Now, there are moments in science when that is not possible, moments where it really makes sense to patent something, because if you don’t, it will never turn into the drug that can help somebody, because that is the way that [intellectual property] works.”

And, Moore continued, sometimes discretion and boundaries are required. “There are going to be moments, even when you are talking with a good friend, and you know that you are in the middle of making a discovery, and if you tell them about it, they will almost be obligated to publish a similar finding, because they work in a similar area.”

At those moments, Moore said, the commitment to sharing “doesn’t have to be everything, all the time, absolutely transparent. You can’t let the perfect be the enemy of the good.”

But those moments, Moore argued, are far more rare in science than people may realize. “I tell my students that 95 percent of the time, err on the side of talking too much about what is going on with your science, not too little.”

Further, Moore added: “If you don’t talk about what your are doing, you’re not going to get enough feedback. You really, really, really aren’t.”

Expanding the use of BL-OG as a tool
The work being done in Moore’s lab on BL-OG at Brown is actually a collaborative effort, including academic labs at partner institutions at Central Michigan University and the University of California at San Diego.

And, more than just a series of scientific research advances conducted in the laboratory, Moore explained, the proponents of BL-OG at Brown have developed outreach activities to bring the technology not just into other labs through the concept of “Open Science” but to disseminate the technology as part of a wide-ranging innovative educational curriculum targeted at undergraduates as well as at high school and grade school students, working collaboratively with science teachers.

The work is being funded in part through a National Science Foundation grant, NeuroNex 1707352, coordinated by Justine Allen, Ph.D., the program manager of the NSF NeuroNex Technology Hub at the Carney Institute for Brain Science. In addition, the effort seeks to educate students of all ages, with a special section of the website assembled by Krystal Literman, MS.

As Allen explained, because there are four labs in three locations, at Brown University, at Central Michigan University, and at the University California San Diego, it requires a system of collaborative communications much different from single-lab projects. “Our team meets via Zoom weekly to discuss research, outreach, education and administration updates,” she said.

“We are especially proud of our educational impact at the undergraduate level,” Allen told ConvergenceRI. As part of that effort, known as the “NeuroNex Undegraduate Practicum,” the program includes a weeklong, immersive experience for undergraduates from across the U.S. and Canada. To date, according to Allen, the program has trained 26 students from 21 colleges and universities during the last three years.

Another example of sharing scientific information on an Open Science platform is the development of a new collaborative organization, called Open Ephys, serving the community of scientists and researchers who work on electric physiology, an effort created by a number of grad students working in Moore’s lab. [The link is www.open-ephys.org.]

As a further example of how that kind of “open” knowledge access and transfer can translate into improving scientific endeavors, Moore said: “You don’t have to spend hundreds of thousands of dollars buying equipment. You could actually make it yourself or you could pay a lot less to buy equipment that already had “Open Design,” so you knew how to fix the equipment if you wanted to – there’s a lot of shared knowledge that is going on.”

The technology is being openly and freely shared, which is fabulous, Moore continued. “That’s very much the value of what we’re trying to do with bioluminescence. The molecules are now in, I think, a hundred different labs. Researchers are starting to publish papers using LMO3.”

Much of the information is posted on the website, bioluminescencehub.org. Detailed information about LMO7 has not been shared yet, because a paper is in progress, which should be submitted and published “quite soon,” according to Moore.

[“We should probably plan to talk again, in about three months,” Moore told ConvergenceRI, after the pending paper has been published. ConvergenceRI has covered the ongoing work by Moore on bioluminescent optogenetics beginning in August of 2015. See links below to ConvergenceRI stories, “Programming brain cells to turn their own light on and off, like fireflies,” and “New national research hub takes shape at Brown.”]

A key goal of the interactive website is to create a free, open database for anyone who is interested in using bioluminescent molecules, with what Moore described as “really easy, one-stop shopping” to go to find out what is already known, and what molecules might be useful for different research endeavors.

“We had five interns this summer, basically reading articles, analyzing them, extracting the information, putting them in the database,” Moore said. “We are starting a collaboration with a group from Harvard that already has a similar database for fluorescent proteins.”

Not limited just to academic scientists
One of the innovative approaches of expanding the universe of knowledge around BL-OG tools of scientific inquiry has been to design an educational curriculum for after-school activities at the grade-school level, which had been planned to be piloted at local schools in Providence – just before the coronavirus pandemic hit.

In response, Moore explained, the program was quickly adapted into a series of online exercises that grade school students could do at home.

“If you know any fourth-, fifth- or sixth-graders who want to do an online project, this is all on our website, and you can now just click to download it,” Moore said. “If you can’t get students excited about bioluminescence, shame on you. It is stuff that glows.”

Editor’s Note: For purposes of transparency, Sam Asinof, the son of Richard Asinof, is involved in the production of the podcast, “Once a Scientist.”

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