He may have invented one of neuroscience’s biggest advances. But you’ve never heard of him

The next revolution in medicine can only come from a new laboratory technique that makes the light-sensitive neurons. The technique, called optogenetics , is one of the biggest advances in neuroscience in decades. It has the potential to cure blindness, treat Parkinson’s disease, and relieve chronic pain. Moreover, it has become widely used to test the operation of the brains of animals in the laboratory, leading to breakthroughs in the understanding of scientific things like sleep, addiction, and feel.

So it is not surprising that the two Americans hailed as inventors of optogenetics are rock stars in the world of science. Karl Deisseroth at Stanford University and Ed Boyden at the Massachusetts Institute of Technology have collected tens of millions in grants and earned millions in prizes in recent years. They have stocked their laboratories with the best equipment and the brightest minds. They have been praised in the media and at conferences around the world. They are considered almost certain to win a Nobel prize.

There is only one problem with this story:

can only be that Zhuo-Hua Pan invented optogenetics first.

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Even many neuroscientists have never heard of Pan.

Pan, 60, is a scientific vision of Wayne State University in Detroit began his research career in their country of China. He moved to the United States in the 1980s to pursue his doctorate and never left. He wears wire-rimmed glasses on a broad nose smile framed by the direct lines of her cheeks. His colleagues describe him as a pure scientist :. Modesta, dedicated, careful

Pan was driven by a desire to cure blindness. In the 2000s, he imagined that by putting a light-sensitive protein in the eye could restore vision in blind -. Compensating death of rods and cones performing other cells sensitive to light

that was the germ of the idea of ​​ optogenetics – taking a protein that converts light into the and put electrical activity in neurons. Thus, scientists might shine light and stimulate neurons remotely, allowing them to manipulate brain circuits. Others had experimented with trying to make light-sensitive neurons before, but these strategies have not caught on because they lacked the right light-sensitive protein.

All that changed with the first molecular description of Channelrhodopsin , published in 2003.

Channelrhodopsin, a protein produced by green algae, responds to light by pumping ion into cells, which helps search sunlight algae.

That “was one of the most exciting things in my life,” Pan said. “I thought, wow! This is the molecule that we are looking for. This is the light sensor we are looking for”.

In February 2004, he was trying Channelrhodopsin out in the ganglion cells – neurons in the eyes that are connected directly to the brain – which had grown in a dish. They became electrically active in response to light. Over the moon with excitement, Pan applied for a grant from the National Institutes of Health. The NIH awarded $ 300,000, with the comment that his research was “a whole unprecedented proposal, highly innovative, close to the unknown.”

Optigenetics
Zhuo-Hua Pan A side view of the retina of the blind mouse containing Channelrhodopsin view. Circular structures at the bottom are the cell bodies of neurons.
Optigenetics
Zhuo-Hua Pan A close-up of the mouse retina showing neurons with channelrhodopsin and green fluorescent protein.

Pan did not know it at the time, but was running against research groups in the United States and around the world to put channelrhodopsin in neurons.

Deisseroth and Boyden were working at Stanford, where Deisseroth was finishing a postdoc and Boyden was finishing graduate school. At least two other groups were in the game and led by Stefan Herlitze and Lynn Landmesser, who were at Case Western Reserve University at the time, and Hiromu Yawo at Tohoku University in Japan.

And it was by no means the only scientists experimenting with ways to control neurons with light. For 2004, Gero Miesenböck and Richard Kramer had already published articles using more complicated molecules for this purpose. But Channelrhodopsin was the tool that was about to revolutionize the field.

The Stanford group had been toying with the idea of ​​controlling neurons with light for quite some time. They had also noticed the article on the discovery of Channelrhodopsin. Deisseroth contacted with the paper’s lead author, Georg Nagel, in March 2004 and asked if Nagel collaborate, sharing DNA Boyden Channelrhodopsin and could prove in neurons. In August 2004, Boyden shone light on brain neuron on a plate and electrical activity recorded from the Channelrhodopsin.

Pan had done the same with retinal neurons previous six months. But then it got picked.

“We do not feel very lucky ‘

Boyden, now a professor at MIT, was surprised when told by STAT Pan made the experiment first.

“Wow. Interesting. I did not know that, “Boyden said.

” It’s funny to think about how science relates to when testing something, “he added, noting that scientists are based on the work of others, sometimes working together, while at other times working in parallel, clambering over one another’s shoulders. “There is so much work in intentional and unintentional team,” he said.

the press office of Stanford said Deisseroth was not available. in response to questions provided by STAT, spokesman Bruce Goldman wrote that the study of Pan was “far from the use of optogenetics … to open a new world of neuroscience precision. That is the development potential in the widely quoted 2005 publication of Dr. Deisseroth. “

Pan said he could have mentioned the time of experiment to Boyden once several years ago, but Pan said,” I i do not want to take a long time to talk about this because people feel uncomfortable “

that sentiment is according to the broader Pan approach -.. diligent, quiet, out of the limelight Wayne State is a small college It not is known for their scientific research. Pan had gone to a state school for his doctoral thesis, then conducted research on all dark for decades. These things may have contributed to what happened later, when he tried to get his invention in the world :. it was not seen as the breakthrough was

Dr. Zhuo Hua Pan lab
Sean Proctor for STAT a model of a human eye in the laboratory of Pan.

Pan spent the summer of 2004 to find ways to get the channelrhodopsin protein in a living eye. He settled on the idea of ​​using a virus, which could infect cells in the eye and sneak into the DNA Channelrhodopsin. His colleague, Alexander Dizhoor, professor at the University of Salus, designed the DNA Channelrhodopsin add the gene for a protein that fluoresces green under blue light, so you could go where the Channelrhodopsin ended.

In July 2004, Pan dosed its first rat with the virus. About five weeks later, he looked in the retinas to see if it had worked. What he saw was a sea of ​​green – thousands of ganglion cells had the green protein associated with Channelrhodopsin in their membranes. And when he stuck an electrode in one of those cells and lit a lamp, the cell responded with a burst of electrical activity. The Channelrhodopsin was working. It was only a first step, but it was a revolutionary step -. It is indicating that the method of Pan may only be able to restore sight to the blind

“Everything went very well,” Pan said

Thus Pan y. Dizhoor wrote an article about his work and submitted it to Nature on November 25, 2004, according to the letter Pan shared with STAT. The editors of the nature suggested they send a call over journal Nature Neuroscience, which rejected it. Early the following year, Pan sent the document to the Journal of Neuroscience, where he was examined, but then rejected again.

disheartened, Pan went to work reviewing their role, and in May 2005 traveled to Fort Lauderdale, Florida. For Association for Research in Vision and Ophthalmology conference, in which he describes his work using channelrhodopsin in neurons. That one conference , lasting only 15 minutes, would be its clearest along the timeline of the invention bet.

It was what came next that would make the game field. A few months later, in August 2005, the journal Nature Neuroscience published an article on the use of Channelrhodopsin for neurons sensitive to light. Document was by Edward Boyden and Karl Deisseroth.

Pan heard the news from a colleague who sent you email the document. “I feel terrible. I felt very bad,” Pan said, pausing. “We do not feel very lucky.”

met with a shrug

role

Deisseroth and Boyden was slightly different from Pan They just showed they could use Channelrhodopsin to control the activity of neurons in a dish.; Pan had hoped to publish until he could make it work in a living animal. And Deisseroth and Boyden had proved incredibly accurate time control, turning the light on for just a split second. But his technical prowess was essentially the same: They had used Channelrhodopsin to successfully neurons respond on a plate for lighting

Ed Boyden
Keith Bedford / The Boston Globe . Ed Boyden at MIT Media Lab in February.

The role of Stanford took some time to take off, but it did take off. Work started both playoff races Deisseroth and Boyden, landing authorization grants large amounts of money and talented students for their labs – Stanford Deisseroth and Boyden at MIT. The New York Times began write about Deisseroth progress with optogenetics in 2007, and research appointments took off exponentially.

At the time Pan finally managed to publish role in Neuron in April 2006, he was mostly met with a shrug. Richard Kramer, a neuroscientist at the University of Berkeley, who was also studying vision, recalls, “It was not so creative, it was just ‘Oh look, you can put channelrhodopsin in neurons of the brain, you can also put in neurons the retina. “It was awesome? No “.

The handful of months seem to have made all the difference.

Dr. Zhuo Hua Pan lab
Sean Proctor for STAT Plates culture of bacteria and dissecting tools used in the laboratory of Pan growth.

Dr. Zhuo Hua Pan lab

Why not paper Bread get first published? We may never know the answer. After role of Boyden came out, Pan wrote to the editor in the journal Nature Neuroscience wondering how you could have rejected his role, but published Boyden.

in its response, the editor responded that although the papers were similar, Boyden et al. presented his as a new technology rather than as a scientific finding. the article Pan, apparently, was too narrow, only it focuses on the use of channelrhodopsin to restore vision, while the role of Boyden took the broad view of thinking channelrhodopsin as a tool for neuroscience in general.

comments other researchers presented to the Journal of Neuroscience shed some more light on what people thought Pan paper. A reviewer liked and had some small suggestions for improvement. The other, in one long paragraph, said the research was “ambitious” and “very preliminary” and concluded that “there is not enough here to attract most neurologists.”

In retrospect, co-author of Pan Dizhoor can not help laughing when reading that. Contributors ultimately green light to an expanded version of document Pan in 2006 with minor revisions.

But that has not raised the optogenetics Pan pantheon. As for the publication, which was quite late to the party, three groups with different publishing articles on Channelrhodopsin before him. He did not share in two major awards recently went to Deisseroth and Boyden brain Prize in 2013 (1 million euros divided six inventors of optogenetics) and progress Award in 2015 ($ 3 million each one for Boyden and Deisseroth).

Karl Deisseroth
Steve Jennings / Getty Images for Newcomer Award Karl Deisseroth accepts the 2016 Advancement Award in Life Sciences in Mountain View, California.

Since 2005, Deisseroth has awarded more than $ 18 million in NIH grants for his work on optogenetics, and Boyden has received more than $ 10 million. Both have other important projects that provide additional funding for their laboratories each year. Boyden is a prolific speaker who has multiple TED Talks ; Deisseroth was the subject of a profile depth in the New Yorker in 2015.

Pan, by contrast, has cumulatively received just over $ 3 million in the last 10 years and it has an NIH grant – the minimum necessary to maintain an ongoing research program. Most praise for his work have come from the Wayne State University. According to its website, which has been invited to give a couple of conversations -. More recently at a technology fair in Russia

Dr. Zhuo Hua Pan
Sean Proctor for STAT Pan in his lab at Wayne State University, which continues to work in channelrhodopsin.

played the game invention

The complete saga raises the question of what it means to invent something in science. It is a question that has plagued scientists in recent years – including the CRISPR patent fight in progress -. As research becomes increasingly global and spoils of biotechnology and medicine discoveries become increasingly valuable

The answer, it turns out, changes depending on the context.

The academic peers often consider the first scientists to publish a paper on a technique of the discoverers or inventors of the technique.

But this metric can be problematic, since experience shows Pan. In a recent essay in the journal eLife, Ronald Vale and Anthony Hyman, two biologists, exposed the problem. They note that “the delay between the filing of a document and publication can vary from a few weeks to more than two years,” adding that magazines “slow and create inequalities in how knowledge is transferred from the scientific to the scientific throughout the world community. ”

And employees can be biased toward familiar names or prestigious institutions. opinion Blinded , in which the author’s name was written, has been suggested as a way to minimize this effect, but many scientists are skeptical that it would work, because research is often discussed before time at conferences.

Vale and promote Hyman, however, for scientists to publish drafts of his work on “preprint servers” such as bioRxiv before they undergo magazines. If a server of this kind had been widely used by neurologists in 2004, Pan could have published their findings rejected there, staking his claim.

But that would mean he would be on the short list for the Nobel Prize is unclear. Kramer believes that even if Pan had published the bioRxiv, would be excluded because it was not the first to publish a peer-reviewed technical article. That’s what matters, as long as the inventors of optogenetics win the Nobel.

The legal system does not play by exactly the same rules. According to a representative of the American Bar Association specializing in patent law, to prove precedence for a patent in the early 2000s, most of the time it takes to display both “when someone had actually conceived of the invention – which is almost mind the light bulb going off, ‘Aha I have it “-! and when the invention is reduced to practice -. that means you’ve really done and have shown that their idea can work”

by these standards, a discovery occurs at the time of its manifestation in the laboratory, even before it has been published in the preprint server.

Then there is the court of public opinion. Scientists are increasingly public figures, running and Twitter accounts displayed in night talk shows.

“The quality rising to the top is a little more influenced by things that are not scientific than it used to be,” said Richard Masland, emeritus professor of the Faculty of Medicine of Harvard, who also owns the patents gene therapy for blindness.

Being Wayne State University could have meant that Pan does not have the resources for a high-profile role published. There are real costs to make high-quality research, but also the senior researchers at top universities usually mentor of young teachers, reading their work and help them take it to a higher level.

Pan agree that in fact may have put him at a disadvantage compared with scientists at prestigious institutions like MIT or Stanford. “Of course, I can not prove it with evidence,” he said. And modesty skills and foreign language pan may have kept him from promoting himself, as did Boyden and Deisseroth.

“He is not just as a public speaker and host of others in the field. And this is an important part of the whole game to get out and sell himself,” Kramer, the researcher vision UC Berkeley, said.

that advertising can be self-reinforcing. Landmesser, Professor at Case Western who worked on Channelrhodopsin in the beginning, said, “I think there is always a tendency [that] Whoever gets there first gets more publicity, we will speak.”

A PR University video can generate an article of national news, that drives someone to think of his name in nomination for a good cash prize, leading to some aspects TV. The word “inventor” is used at some point and before you know it you are Google automatic response to the question “Who invented optogenetics?”

Dr. Zhuo Hua Pan
Sean Proctor for STAT A slate and glass drying rack in the laboratory of the pan. It has been used to help blind see Channelrhodopsin mice.

Dr. Zhuo Huan Pan

Ultimately, both the pan and the team Boyden and Deisseroth won patents for their discoveries.

conference can Pan 2005 threatened to derail Patent Boyden-Deisseroth for a while -. The patent office of the United States rejected several times because abstract of Pan was published more than a year before they got around the presentation

Eventually, Deisseroth and Boyden signed an indicating document that had invented this method channelrhodopsin private use in the laboratory before the publication of the Pan conference abstract. the corresponding patent was published in March 2016, almost 10 years after it was filed.

Now, Deisseroth is a co-founder and scientific advisor in the circuit Therapeutics, a company developing a wide range of applications based on optogenetics, presumably by Deisseroth patented inventions therapies. (Therapeutic Circuit declined to comment on specific aspects of their intellectual property licenses.)

Pan won patent and use Channelrhodopsin to restore vision in the eye. His patent was licensed by RetroSense, who won a prize Del Angel Capital Association in 2015. Retrosense – whose CEO last said STAT on the role of the pan in the invention of optogenetics – began clinical trials this year to put the proteins of algae in blind people using gene therapy. It is the first application of optogenetics in humans and the first time a non-human gene is being used in a gene therapy trial.

At this time, there are blind people in Texas walking with DNA and proteins seaweed in his eyes. And that was what was in it for bread all the time. “One thing I still feel happy about is that even now our clinical study is still ahead of anyone,” Pan said.

However, since there is no gene therapies approved for clinical use in the United States, the road to optogenetics used successfully in humans is likely to be very long. Yang Dan, a professor of neuroscience at the University of California, Berkeley, which uses optogenetics to study the dream, is not betting on optogenetics be in clinical cure in the short term. “I think these security checks take a long, long time,” he said.

Regarding the invention itself, some scientists say that bread may not have had the great vision worthy prize, which Deisseroth and Boyden had. Stefan Herlitze, one of the other which was collected by first publication on channelrhodopsin in neurons, said: “Of course I have to say, Deisseroth and Boyden, who actually developed further the field.”

Boyden echo of this was done. “Karl and I were very interested in the general question of how to control the types of cells in the brain,” he said. “In recent years, we have worked to encourage these molecules to their logical limits.”

So maybe it does not matter who invented optogenetics, the limits of science simply has stretched further.

asked him if he deserves the recognition that Deisseroth and Boyden have enjoyed, Pan refused to answer. Later he said Deisseroth STAT “also did a very good job, no doubt. But it is also very lucky, because if our work was ahead of him, the story would be different. We have gotten more credit.”

That’s about the same as the pan is willing to say about how your cards fell. Today it is still in Detroit. He has been working on new versions of Channelrhodopsin that could be used to cure blindness. “My lab is a very small laboratory,” Pan said, “We are especially interested in trying to restore vision.”

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