你们生物PHD猥琐男女平时吃不吃核桃补补脑？# Biology - 生物学
s*y
1 楼
现在红遍天下的光遗传学，大家（包括我）都认为是Stanford的Deisseroth创造的。但
是昨天我不小心看到了一篇新闻文章，才惊讶的发现其实最早做出来的，有可能是
Wayne State University的潘卓华。虽然他的投稿时间和Deisseroth的类似，但是因为
他是一个没有什么名气的学者，而且他的文章包装得不对，所以他的文章被百般耽误，
最后比Deisseroth的晚了一年才发表。
在2004年底潘就做出了和Deisseroth几乎一样的文章，除了用的细胞略微不同：他做的
神经细胞是从视网膜分离的，而Deisseroth 做的神经细胞是从大脑分离的。然后他把
文章陆续投向Nature, Nature Neuroscience,Journal of Neuroscience，却统统遭到
了拒稿。然后大半年之后，也就是2005年8月份，Deisseroth 的文章发表在Nature
Neuroscience上。潘得知之后，心都凉了。
有意思的是潘卓华发现自己的文章被人scoop之后写信问 Nature Neuroscience为什么
两篇几乎一模一样的文章，他们接受了Deisseroth 的文章而不接受他的文章。对方回
应说，虽然两篇文章非常相似，但是Deisseroth 的文章是作为一个技术文章来推销的
，而潘的文章是作为恢复视觉的研究文章来写的。所以对方觉得他的文章"too
narrow", "too focused".
潘的文章最后发表在Neuron 上。他的文章比Deisseroth的更为完整，因为Deisseroth
的只用了细胞，而他是直接用了老鼠来证明。但是这一切都晚了，因为他的文章最后比
Deisseroth的晚了整整一年，大部分人看了都直接以为他的文章是跟风的，没有新意的
一个“你做了细胞，我就做做老鼠看看”那种工作。于是Deisseroth成为了光遗传之父
，而潘卓华什么都不是,他的实验室勉强维持着一个R01的水平
https://www.statnews.com/2016/09/01/optogenetics/
He may have invented one of neuroscience’s biggest advances. But you’ve
never heard of him
Zhuo-Hua Pan in his lab at Wayne State University in Detroit.
The next revolution in medicine just might come from a new lab technique
that makes neurons sensitive to light. The technique, called optogenetics,
is one of the biggest breakthroughs in neuroscience in decades. It has the
potential to cure blindness, treat Parkinson’s disease, and relieve chronic
pain. Moreover, it’s become widely used to probe the workings of animals’
brains in the lab, leading to breakthroughs in scientists’ understanding
of things like sleep, addiction, and sensation.
So it’s not surprising that the two Americans hailed as inventors of
optogenetics are rock stars in the science world. Karl Deisseroth at
Stanford University and Ed Boyden at the Massachusetts Institute of
Technology have collected tens of millions in grants and won millions in
prize money in recent years. They’ve stocked their labs with the best
equipment and the brightest minds. They’ve been lauded in the media and
celebrated at conferences around the world. They’re considered all but
certain to win a Nobel Prize.
There’s only one problem with this story:
It just may be that Zhuo-Hua Pan invented optogenetics first.
Even many neuroscientists have never heard of Pan.
Pan, 60, is a vision scientist at Wayne State University in Detroit who
began his research career in his home country of China. He moved to the
United States in the 1980s to pursue his PhD and never left. He wears wire-
rimmed glasses over a broad nose framed by smile-lines in his cheeks. His
colleagues describe him as a pure scientist: modest, dedicated, careful.
Pan was driven by a desire to cure blindness. In the early 2000s, he
imagined that putting a light-sensitive protein into the eye could restore
vision in the blind — compensating for the death of rods and cones by
making other cells light-sensitive.
That was the germ of the idea of optogenetics — taking a protein that
converts light into electrical activity and putting it into neurons. That
way, scientists could shine light and stimulate the neurons remotely,
allowing them to manipulate brain circuits. Others had experimented with
trying to make neurons light-sensitive before, but those strategies hadn’t
caught on because they lacked the right light-sensitive protein.
That all changed with the first molecular description of channelrhodopsin,
published in 2003.
Channelrhodopsin, a protein made by green algae, responds to light by
pumping ions into cells, which helps the algae search out sunlight.
That “was one of the most exciting things in my life,” Pan said. “I
thought, wow! This is the molecule we are looking for. This is the light
sensor we are looking for.”
By February 2004, he was trying channelrhodopsin out in ganglion cells —
the neurons in our eyes that connect directly to the brain — that he had
cultured 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 him $300,000, with the comment that
his research was “quite an unprecedented, highly innovative proposal,
bordering on the unknown.”
A side view of a blind mouse’s retina containing channelrhodopsin. The
round structures at the bottom are the cell bodies of the neurons.
A close-up of the mouse retina showing neurons with channelrhodopsin and
green fluorescent protein.
Pan didn’t know it at the time but he was racing against research groups
across the United States and around the world to put channelrhodopsin into
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 as well, 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 they were by no means the only scientists experimenting with ways to
control neurons with light. By 2004, Gero Miesenbock and Richard Kramer had
already published articles using other, more complicated molecules for that
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 paper about the
discovery of channelrhodopsin. Deisseroth got in touch with the paper’s
author, Georg Nagel, in March 2004 and asked if Nagel would collaborate,
sharing the channelrhodopsin DNA so Boyden could try it out in neurons. In
August 2004, Boyden shined light on a brain neuron in a dish and recorded
electrical activity from the channelrhodopsin.
Pan had done the same thing with retina neurons six months earlier. But then
he got scooped.
‘We didn’t feel very lucky’
Boyden, who is now a professor at MIT, was surprised when told by STAT that
Pan ran the experiment first.
“Wow. Interesting. I didn’t know that,” Boyden said.
“It’s funny to think about how science regards when something is proven,”
he added, noting that scientists build on each others’ work, sometimes
working together while at other times working in parallel, scrambling onto
one another’s shoulders. “There’s both intentional and unintentional
teamwork,” he said.
The Stanford press office said Deisseroth was unavailable. In response to
questions provided by STAT, spokesman Bruce Goldman wrote that Pan’s study
was “a far cry from the use of optogenetics … to open up a new world of
precision neuroscience. That’s the potential revealed in Dr. Deisseroth’s
widely cited 2005 publication.”
Pan said he might have mentioned the timing of his experiment to Boyden once
several years ago, but, Pan said, “I didn’t want to take too much time to
talk about this because people feel uncomfortable.”
That sentiment is in keeping with Pan’s wider approach — diligent,
reserved, outside the limelight. Wayne State is a small university not known
for its scientific research. Pan had gone to a state school for his PhD,
then done mostly obscure research for decades. These things may have
contributed to what happened next, when he tried to get his invention out
into the world: It wasn’t seen as the big advance it was.
A model of a human eye in Pan’s lab.
Pan spent the summer of 2004 figuring out how to get the channelrhodopsin
protein into a living eye. He settled on the idea of using a virus, which
could infect cells in the eye and sneak the channelrhodopsin DNA inside. His
colleague, Alexander Dizhoor, a professor at Salus University, engineered
the channelrhodopsin DNA to add the gene for a protein that fluoresced green
under blue light, so they could track where the channelrhodopsin ended up.
In July 2004, Pan dosed his first rat with the virus. About five weeks later
, he looked at the retinas to see if it had worked. What he saw was a sea of
green — thousands of ganglion cells had the green protein coupled to
channelrhodopsin in their membranes. And when he stuck an electrode in one
of those cells and turned on a lamp, the cell responded with a flurry of
electrical activity. The channelrhodopsin was working. It was just a first
step, but it was a revolutionary step — indicating that Pan’s method may
just be able to restore sight to the blind.
“Everything turned out beautifully,” Pan said.
So Pan and Dizhoor wrote a paper about their work and submitted it to Nature
on November 25, 2004, according to the submission letter Pan shared with
STAT. The editors at Nature suggested they send it on to a more specialized
journal called Nature Neuroscience, which rejected it. Early the next year,
Pan sent the paper to the Journal of Neuroscience, where it was reviewed but
then again rejected.
Disheartened, Pan set to work revising his paper, and in May 2005 traveled
to Fort Lauderdale, Fla. for the Association for Research in Vision and
Opthamologyconference, where he described his work using channelrhodopsin in
neurons.That single lecture, lasting just 15 minutes, would come to be his
clearest stake along the timeline of invention.
It was what came next that would make that stake matter. A few months later,
in August of 2005, Nature Neuroscience published a paper about using
channelrhodopsin to make neurons sensitive to light. The paper was by Edward
Boyden and Karl Deisseroth.
Pan heard the news from a colleague who emailed him the paper. “I felt
terrible. I felt terrible,” Pan said, pausing. “We didn’t feel very lucky
.”
Met with a shrug
Deisseroth and Boyden’s paper was slightly different than Pan’s. They
simply demonstrated that they could use channelrhodopsin to control neurons
’ activity in a dish; Pan had waited to publish until he could make it work
in a live animal. And Deisseroth and Boyden had shown incredibly precise
time control, by turning the light on for just a millisecond. But their
technical feat was essentially the same: They had used channelrhodopsin to
successfully make neurons in a dish respond to illumination.
The Stanford paper took a little while to take off, but take off it did. The
work jump-started both Deisseroth’s and Boyden’s careers, landing them
big money grants and talented students for their labs — Deisseroth at
Stanford and Boyden at MIT. The New York Times started writing about
Deisseroth’s breakthroughs with optogenetics in 2007, and the citations of
the research paper took off exponentially.
By the time Pan finally managed to publish his paper, in Neuron in April
2006, it was mostly met with a shrug. Richard Kramer, a neuroscientist at UC
Berkeley who was also studying vision, remembers, “It wasn’t that
creative, it was just ‘Oh look, you can put channelrhodopsin in neurons
from the brain, you can also put it in neurons from the retina.’ Was it
impressive? No.”
Those handful of months seem to have made all the difference.
Culture dishes growing bacteria and dissection tools used in Pan’s lab.
Why didn’t Pan’s paper get published first? He may never know the answer.
After Boyden’s paper came out, Pan wrote to the editor at Nature
Neuroscience asking how they could have rejected his paper but published
Boyden’s.
In her response, the editor replied that while the papers were similar,
Boyden et al. presented theirs as a new technology rather than as a
scientific finding. Pan’s paper, it seemed, was too narrow, only focusing
on using channelrhodopsin to restore vision, while Boyden’s paper took the
broad view of thinking of channelrhodopsin as a tool for neuroscience in
general.
The reviews that other researchers submitted to the Journal of Neuroscience
shed some more light on what people thought of Pan’s paper. One reviewer
liked it and had some minor suggestions for improvement. The other, in a
single long paragraph, said the research was “ambitious” and “very
preliminary” and concluded that “there is too little here to entice most
neuroscientists.”
In hindsight, Pan’s coauthor Dizhoor can’t help but laugh while reading
that. Reviewers would ultimately greenlight an expanded version of Pan’s
paper, in 2006, with minimal revisions.
But that hasn’t elevated Pan to the optogenetics pantheon. In terms of
publication, he was quite late to the party, with three different groups
publishing papers about channelrhodopsin before he did. He didn’t share in
two big prizes that recently went to Deisseroth and Boyden, the Brain Prize
in 2013 (1 million euros split between six inventors of optogenetics) and
the Breakthrough Prize in 2015 ($3 million each to Boyden and Deisseroth).
Since 2005, Deisseroth has been awarded over $18 million in NIH grants for
his work on optogenetics, and Boyden has received more than $10 million.
Both have other major projects that bring in additional funding to their
labs each year. Boyden is a prolific speaker who’s given multiple TED talks
; Deisseroth was the subject of an in-depth profile in the New Yorker in
2015.
Pan, on the other hand, has cumulatively received just over $3 million over
the past 10 years and holds one NIH grant — the bare minimum to keep a
research program going. Most of the accolades for his work have come from
Wayne State University. According to his website, he’s been invited to give
a couple of talks — most recently at a technology show in Russia.
Pan in his lab at Wayne State University, where he continues to work on
channelrhodopsin.
Rules of the invention game
The whole saga raises the question of what it means to invent something in
science. It’s a question that has plagued scientists in recent years —
including the ongoing CRISPR patent fight — as research becomes ever more
global and the spoils of biotechnology and medical discoveries become ever
more valuable.
The answer, it turns out, shifts depending on context.
Fellow academics often consider the first scientists to publish a paper on a
technique the discoverers or inventors of that technique.
But that metric can be problematic, as Pan’s experience shows. In a recent
essay in the journal eLife, Ronald Vale and Anthony Hyman, two biologists,
laid out the problem. They point out that “the delay between the submission
of a paper and its publication can range from a few weeks to more than two
years,” adding that journals “slow down and create inequities in how
knowledge is transferred from the scientist to the worldwide scientific
community.”
And reviewers can be biased toward familiar names or prestigious
institutions.Blinded review, in which the author’s name is redacted, has
been suggested as a way to minimize that effect, but many scientists are
skeptical that it would work, since research is often discussed ahead of
time at conferences.
Vale and Hyman advocate, instead, for scientists to post drafts of their
work on “preprint servers” such as bioRxiv before they submit it to
journals. If such a server had been widely used by neuroscientists in 2004,
Pan could have posted his rejected findings there, staking his claim.
But whether that would mean he would be on the short list for the Nobel
Prize is unclear. Kramer thinks that even if Pan had published on bioRxiv,
he’d be shut out because he wasn’t the first to publish a peer-reviewed
paper on the technique. That’s what will matter if and when the inventors
of optogenetics win the Nobel.
The legal system doesn’t play by quite the same rules. According to an
American Bar Association representative specializing in patent law, to prove
precedence for a patent in the early 2000s, most of the time you needed to
show both “when someone had actually conceived of the invention — that’s
sort of in your mind the lightbulb going off, ‘Aha! I have it!’ — and
when the invention was reduced to practice — that means you’ve actually
done it and you’ve proven that your idea can work.”
By those standards, a discovery happens at the time of its demonstration in
the lab, even before it’s been posted on a preprint server.
Then there’s the court of public opinion. Scientists are increasingly
public personalities, running Twitter accounts and appearing on late-night
talk shows.
“The quality rising to the top is a little more influenced by non-
scientific things than it used to be,” said Richard Masland, an emeritus
professor at Harvard Medical School, who also holds patents on gene therapy
for blindness.
Being at Wayne State University might have meant that Pan didn’t have the
resources to get a high-profile paper published. There’s the actual costs
of doing high quality of research, but in addition, senior researchers at
top universities usually mentor junior professors, reading their work and
helping them take it to the next level.
Pan agrees that fact may have put him at a disadvantage compared with
scientists at prestigious institutions like MIT or Stanford. “Of course, I
cannot prove that with evidence,” he said. And Pan’s modesty and non-
native language abilities may have kept him from promoting himself as well
as Boyden and Deisseroth did.
“He’s just not as public a speaker and presenter as other people in the
field. And this is an important part of the whole game of being able to get
out there and sell yourself,” Kramer, the UC Berkeley vision researcher,
said.
That publicity can be self-reinforcing. Landmesser, the Case Western
professor who worked on channelrhodopsin in the beginning, said, “I think
there’s always a tendency [that] whoever gets there first gets more
publicity, let’s put it that way.”
A university PR video can spawn a national news article, which spurs someone
to think of your name in nominations for a nice cash prize, which leads to
some TV appearances. The word “inventor” gets used at some point and
before you know it you’re Google’s automatic answer to the question “Who
invented optogenetics?”
A chalkboard and glassware drying rack in Pan’s lab. He has used
channelrhodopsin to help blind mice see.
Ultimately, both Pan and the team of Boyden and Deisseroth won patents for
their discoveries.
Pan’s May 2005 lecture threatened to derail the Boyden-Deisseroth patent
for a while — the US patent office rejected it multiple times because Pan’
s abstract was published more than a year before they got around to filing.
Eventually, Deisseroth and Boyden signed a document stating that they had
invented this method of using channelrhodopsin privately in the lab before
Pan’s conference abstract was published. The relevant patent was issued in
March 2016, almost 10 years after they filed.
Now, Deisseroth is a cofounder and scientific advisor at Circuit
Therapeutics, a company developing a wide range of therapies based on
optogenetics, presumably using Deisseroth’s patented inventions. (Circuit
Therapeutics declined to comment on specifics of their intellectual property
licenses.)
Pan won a patent as well, to use channelrhodopsin to restore vision in the
eye. His patent was licensed by RetroSense, which won an award from the
Angel Capital Association in 2015. Retrosense — whose CEO in passing told
STAT about Pan’s role in the invention of optogenetics — began clinical
trials this year to put the algae proteins in blind people using gene
therapy. It’s the first application of optogenetics in humans and the first
time a non-human gene is being used in a gene therapy trial.
Right now, there are blind people in Texas walking around with algae DNA and
proteins in their eyes. And that was what Pan was in it for all along. “
One thing I still feel glad about is that even right now our clinical study
is still ahead of anyone,” Pan said.
But given that there are no gene therapies approved for clinical use in the
United States, the road to successfully using optogenetics in humans will
likely be a long one. Yang Dan, a professor of neuroscience at UC Berkeley
who uses optogenetics to study sleep, isn’t betting on optogenetics cures
being in the clinic any time soon. “I believe that these safety checks will
take a long, long time,” she said.
As for the invention itself, some scientists say Pan may not have had the
big, award-worthy vision that Deisseroth and Boyden had. Stefan Herlitze,
one of the others who was scooped for the first publication about
channelrhodopsin in neurons, said, “Of course I have to say, Deisseroth and
Boyden, they really developed the field further.”
Boyden echoed this. “Karl and I were very interested in the general
question of how to control cell types in the brain,” he said. “In recent
years, we worked to push these molecules to their logical limits.”
So maybe it doesn’t matter who invented optogenetics, just who has
stretched science’s boundaries the furthest.
Asked whether he deserves the recognition that Boyden and Deisseroth have
enjoyed, Pan declined to answer. He later told STAT that Deisseroth “also
did a very excellent job, no doubt. But he’s also very lucky because if our
paper was ahead of him, the story would be different. We would have gotten
more credit.”
That is about as much as Pan is willing to say about the way his cards fell.
Today he’s still in Detroit. He’s been working on new versions of
channelrhodopsin that could be used to cure blindness. “My lab is a very
small lab,” Pan said, “We’re mainly interested in trying to restore
vision.”
是昨天我不小心看到了一篇新闻文章，才惊讶的发现其实最早做出来的，有可能是
Wayne State University的潘卓华。虽然他的投稿时间和Deisseroth的类似，但是因为
他是一个没有什么名气的学者，而且他的文章包装得不对，所以他的文章被百般耽误，
最后比Deisseroth的晚了一年才发表。
在2004年底潘就做出了和Deisseroth几乎一样的文章，除了用的细胞略微不同：他做的
神经细胞是从视网膜分离的，而Deisseroth 做的神经细胞是从大脑分离的。然后他把
文章陆续投向Nature, Nature Neuroscience,Journal of Neuroscience，却统统遭到
了拒稿。然后大半年之后，也就是2005年8月份，Deisseroth 的文章发表在Nature
Neuroscience上。潘得知之后，心都凉了。
有意思的是潘卓华发现自己的文章被人scoop之后写信问 Nature Neuroscience为什么
两篇几乎一模一样的文章，他们接受了Deisseroth 的文章而不接受他的文章。对方回
应说，虽然两篇文章非常相似，但是Deisseroth 的文章是作为一个技术文章来推销的
，而潘的文章是作为恢复视觉的研究文章来写的。所以对方觉得他的文章"too
narrow", "too focused".
潘的文章最后发表在Neuron 上。他的文章比Deisseroth的更为完整，因为Deisseroth
的只用了细胞，而他是直接用了老鼠来证明。但是这一切都晚了，因为他的文章最后比
Deisseroth的晚了整整一年，大部分人看了都直接以为他的文章是跟风的，没有新意的
一个“你做了细胞，我就做做老鼠看看”那种工作。于是Deisseroth成为了光遗传之父
，而潘卓华什么都不是,他的实验室勉强维持着一个R01的水平
https://www.statnews.com/2016/09/01/optogenetics/
He may have invented one of neuroscience’s biggest advances. But you’ve
never heard of him
Zhuo-Hua Pan in his lab at Wayne State University in Detroit.
The next revolution in medicine just might come from a new lab technique
that makes neurons sensitive to light. The technique, called optogenetics,
is one of the biggest breakthroughs in neuroscience in decades. It has the
potential to cure blindness, treat Parkinson’s disease, and relieve chronic
pain. Moreover, it’s become widely used to probe the workings of animals’
brains in the lab, leading to breakthroughs in scientists’ understanding
of things like sleep, addiction, and sensation.
So it’s not surprising that the two Americans hailed as inventors of
optogenetics are rock stars in the science world. Karl Deisseroth at
Stanford University and Ed Boyden at the Massachusetts Institute of
Technology have collected tens of millions in grants and won millions in
prize money in recent years. They’ve stocked their labs with the best
equipment and the brightest minds. They’ve been lauded in the media and
celebrated at conferences around the world. They’re considered all but
certain to win a Nobel Prize.
There’s only one problem with this story:
It just may be that Zhuo-Hua Pan invented optogenetics first.
Even many neuroscientists have never heard of Pan.
Pan, 60, is a vision scientist at Wayne State University in Detroit who
began his research career in his home country of China. He moved to the
United States in the 1980s to pursue his PhD and never left. He wears wire-
rimmed glasses over a broad nose framed by smile-lines in his cheeks. His
colleagues describe him as a pure scientist: modest, dedicated, careful.
Pan was driven by a desire to cure blindness. In the early 2000s, he
imagined that putting a light-sensitive protein into the eye could restore
vision in the blind — compensating for the death of rods and cones by
making other cells light-sensitive.
That was the germ of the idea of optogenetics — taking a protein that
converts light into electrical activity and putting it into neurons. That
way, scientists could shine light and stimulate the neurons remotely,
allowing them to manipulate brain circuits. Others had experimented with
trying to make neurons light-sensitive before, but those strategies hadn’t
caught on because they lacked the right light-sensitive protein.
That all changed with the first molecular description of channelrhodopsin,
published in 2003.
Channelrhodopsin, a protein made by green algae, responds to light by
pumping ions into cells, which helps the algae search out sunlight.
That “was one of the most exciting things in my life,” Pan said. “I
thought, wow! This is the molecule we are looking for. This is the light
sensor we are looking for.”
By February 2004, he was trying channelrhodopsin out in ganglion cells —
the neurons in our eyes that connect directly to the brain — that he had
cultured 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 him $300,000, with the comment that
his research was “quite an unprecedented, highly innovative proposal,
bordering on the unknown.”
A side view of a blind mouse’s retina containing channelrhodopsin. The
round structures at the bottom are the cell bodies of the neurons.
A close-up of the mouse retina showing neurons with channelrhodopsin and
green fluorescent protein.
Pan didn’t know it at the time but he was racing against research groups
across the United States and around the world to put channelrhodopsin into
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 as well, 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 they were by no means the only scientists experimenting with ways to
control neurons with light. By 2004, Gero Miesenbock and Richard Kramer had
already published articles using other, more complicated molecules for that
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 paper about the
discovery of channelrhodopsin. Deisseroth got in touch with the paper’s
author, Georg Nagel, in March 2004 and asked if Nagel would collaborate,
sharing the channelrhodopsin DNA so Boyden could try it out in neurons. In
August 2004, Boyden shined light on a brain neuron in a dish and recorded
electrical activity from the channelrhodopsin.
Pan had done the same thing with retina neurons six months earlier. But then
he got scooped.
‘We didn’t feel very lucky’
Boyden, who is now a professor at MIT, was surprised when told by STAT that
Pan ran the experiment first.
“Wow. Interesting. I didn’t know that,” Boyden said.
“It’s funny to think about how science regards when something is proven,”
he added, noting that scientists build on each others’ work, sometimes
working together while at other times working in parallel, scrambling onto
one another’s shoulders. “There’s both intentional and unintentional
teamwork,” he said.
The Stanford press office said Deisseroth was unavailable. In response to
questions provided by STAT, spokesman Bruce Goldman wrote that Pan’s study
was “a far cry from the use of optogenetics … to open up a new world of
precision neuroscience. That’s the potential revealed in Dr. Deisseroth’s
widely cited 2005 publication.”
Pan said he might have mentioned the timing of his experiment to Boyden once
several years ago, but, Pan said, “I didn’t want to take too much time to
talk about this because people feel uncomfortable.”
That sentiment is in keeping with Pan’s wider approach — diligent,
reserved, outside the limelight. Wayne State is a small university not known
for its scientific research. Pan had gone to a state school for his PhD,
then done mostly obscure research for decades. These things may have
contributed to what happened next, when he tried to get his invention out
into the world: It wasn’t seen as the big advance it was.
A model of a human eye in Pan’s lab.
Pan spent the summer of 2004 figuring out how to get the channelrhodopsin
protein into a living eye. He settled on the idea of using a virus, which
could infect cells in the eye and sneak the channelrhodopsin DNA inside. His
colleague, Alexander Dizhoor, a professor at Salus University, engineered
the channelrhodopsin DNA to add the gene for a protein that fluoresced green
under blue light, so they could track where the channelrhodopsin ended up.
In July 2004, Pan dosed his first rat with the virus. About five weeks later
, he looked at the retinas to see if it had worked. What he saw was a sea of
green — thousands of ganglion cells had the green protein coupled to
channelrhodopsin in their membranes. And when he stuck an electrode in one
of those cells and turned on a lamp, the cell responded with a flurry of
electrical activity. The channelrhodopsin was working. It was just a first
step, but it was a revolutionary step — indicating that Pan’s method may
just be able to restore sight to the blind.
“Everything turned out beautifully,” Pan said.
So Pan and Dizhoor wrote a paper about their work and submitted it to Nature
on November 25, 2004, according to the submission letter Pan shared with
STAT. The editors at Nature suggested they send it on to a more specialized
journal called Nature Neuroscience, which rejected it. Early the next year,
Pan sent the paper to the Journal of Neuroscience, where it was reviewed but
then again rejected.
Disheartened, Pan set to work revising his paper, and in May 2005 traveled
to Fort Lauderdale, Fla. for the Association for Research in Vision and
Opthamologyconference, where he described his work using channelrhodopsin in
neurons.That single lecture, lasting just 15 minutes, would come to be his
clearest stake along the timeline of invention.
It was what came next that would make that stake matter. A few months later,
in August of 2005, Nature Neuroscience published a paper about using
channelrhodopsin to make neurons sensitive to light. The paper was by Edward
Boyden and Karl Deisseroth.
Pan heard the news from a colleague who emailed him the paper. “I felt
terrible. I felt terrible,” Pan said, pausing. “We didn’t feel very lucky
.”
Met with a shrug
Deisseroth and Boyden’s paper was slightly different than Pan’s. They
simply demonstrated that they could use channelrhodopsin to control neurons
’ activity in a dish; Pan had waited to publish until he could make it work
in a live animal. And Deisseroth and Boyden had shown incredibly precise
time control, by turning the light on for just a millisecond. But their
technical feat was essentially the same: They had used channelrhodopsin to
successfully make neurons in a dish respond to illumination.
The Stanford paper took a little while to take off, but take off it did. The
work jump-started both Deisseroth’s and Boyden’s careers, landing them
big money grants and talented students for their labs — Deisseroth at
Stanford and Boyden at MIT. The New York Times started writing about
Deisseroth’s breakthroughs with optogenetics in 2007, and the citations of
the research paper took off exponentially.
By the time Pan finally managed to publish his paper, in Neuron in April
2006, it was mostly met with a shrug. Richard Kramer, a neuroscientist at UC
Berkeley who was also studying vision, remembers, “It wasn’t that
creative, it was just ‘Oh look, you can put channelrhodopsin in neurons
from the brain, you can also put it in neurons from the retina.’ Was it
impressive? No.”
Those handful of months seem to have made all the difference.
Culture dishes growing bacteria and dissection tools used in Pan’s lab.
Why didn’t Pan’s paper get published first? He may never know the answer.
After Boyden’s paper came out, Pan wrote to the editor at Nature
Neuroscience asking how they could have rejected his paper but published
Boyden’s.
In her response, the editor replied that while the papers were similar,
Boyden et al. presented theirs as a new technology rather than as a
scientific finding. Pan’s paper, it seemed, was too narrow, only focusing
on using channelrhodopsin to restore vision, while Boyden’s paper took the
broad view of thinking of channelrhodopsin as a tool for neuroscience in
general.
The reviews that other researchers submitted to the Journal of Neuroscience
shed some more light on what people thought of Pan’s paper. One reviewer
liked it and had some minor suggestions for improvement. The other, in a
single long paragraph, said the research was “ambitious” and “very
preliminary” and concluded that “there is too little here to entice most
neuroscientists.”
In hindsight, Pan’s coauthor Dizhoor can’t help but laugh while reading
that. Reviewers would ultimately greenlight an expanded version of Pan’s
paper, in 2006, with minimal revisions.
But that hasn’t elevated Pan to the optogenetics pantheon. In terms of
publication, he was quite late to the party, with three different groups
publishing papers about channelrhodopsin before he did. He didn’t share in
two big prizes that recently went to Deisseroth and Boyden, the Brain Prize
in 2013 (1 million euros split between six inventors of optogenetics) and
the Breakthrough Prize in 2015 ($3 million each to Boyden and Deisseroth).
Since 2005, Deisseroth has been awarded over $18 million in NIH grants for
his work on optogenetics, and Boyden has received more than $10 million.
Both have other major projects that bring in additional funding to their
labs each year. Boyden is a prolific speaker who’s given multiple TED talks
; Deisseroth was the subject of an in-depth profile in the New Yorker in
2015.
Pan, on the other hand, has cumulatively received just over $3 million over
the past 10 years and holds one NIH grant — the bare minimum to keep a
research program going. Most of the accolades for his work have come from
Wayne State University. According to his website, he’s been invited to give
a couple of talks — most recently at a technology show in Russia.
Pan in his lab at Wayne State University, where he continues to work on
channelrhodopsin.
Rules of the invention game
The whole saga raises the question of what it means to invent something in
science. It’s a question that has plagued scientists in recent years —
including the ongoing CRISPR patent fight — as research becomes ever more
global and the spoils of biotechnology and medical discoveries become ever
more valuable.
The answer, it turns out, shifts depending on context.
Fellow academics often consider the first scientists to publish a paper on a
technique the discoverers or inventors of that technique.
But that metric can be problematic, as Pan’s experience shows. In a recent
essay in the journal eLife, Ronald Vale and Anthony Hyman, two biologists,
laid out the problem. They point out that “the delay between the submission
of a paper and its publication can range from a few weeks to more than two
years,” adding that journals “slow down and create inequities in how
knowledge is transferred from the scientist to the worldwide scientific
community.”
And reviewers can be biased toward familiar names or prestigious
institutions.Blinded review, in which the author’s name is redacted, has
been suggested as a way to minimize that effect, but many scientists are
skeptical that it would work, since research is often discussed ahead of
time at conferences.
Vale and Hyman advocate, instead, for scientists to post drafts of their
work on “preprint servers” such as bioRxiv before they submit it to
journals. If such a server had been widely used by neuroscientists in 2004,
Pan could have posted his rejected findings there, staking his claim.
But whether that would mean he would be on the short list for the Nobel
Prize is unclear. Kramer thinks that even if Pan had published on bioRxiv,
he’d be shut out because he wasn’t the first to publish a peer-reviewed
paper on the technique. That’s what will matter if and when the inventors
of optogenetics win the Nobel.
The legal system doesn’t play by quite the same rules. According to an
American Bar Association representative specializing in patent law, to prove
precedence for a patent in the early 2000s, most of the time you needed to
show both “when someone had actually conceived of the invention — that’s
sort of in your mind the lightbulb going off, ‘Aha! I have it!’ — and
when the invention was reduced to practice — that means you’ve actually
done it and you’ve proven that your idea can work.”
By those standards, a discovery happens at the time of its demonstration in
the lab, even before it’s been posted on a preprint server.
Then there’s the court of public opinion. Scientists are increasingly
public personalities, running Twitter accounts and appearing on late-night
talk shows.
“The quality rising to the top is a little more influenced by non-
scientific things than it used to be,” said Richard Masland, an emeritus
professor at Harvard Medical School, who also holds patents on gene therapy
for blindness.
Being at Wayne State University might have meant that Pan didn’t have the
resources to get a high-profile paper published. There’s the actual costs
of doing high quality of research, but in addition, senior researchers at
top universities usually mentor junior professors, reading their work and
helping them take it to the next level.
Pan agrees that fact may have put him at a disadvantage compared with
scientists at prestigious institutions like MIT or Stanford. “Of course, I
cannot prove that with evidence,” he said. And Pan’s modesty and non-
native language abilities may have kept him from promoting himself as well
as Boyden and Deisseroth did.
“He’s just not as public a speaker and presenter as other people in the
field. And this is an important part of the whole game of being able to get
out there and sell yourself,” Kramer, the UC Berkeley vision researcher,
said.
That publicity can be self-reinforcing. Landmesser, the Case Western
professor who worked on channelrhodopsin in the beginning, said, “I think
there’s always a tendency [that] whoever gets there first gets more
publicity, let’s put it that way.”
A university PR video can spawn a national news article, which spurs someone
to think of your name in nominations for a nice cash prize, which leads to
some TV appearances. The word “inventor” gets used at some point and
before you know it you’re Google’s automatic answer to the question “Who
invented optogenetics?”
A chalkboard and glassware drying rack in Pan’s lab. He has used
channelrhodopsin to help blind mice see.
Ultimately, both Pan and the team of Boyden and Deisseroth won patents for
their discoveries.
Pan’s May 2005 lecture threatened to derail the Boyden-Deisseroth patent
for a while — the US patent office rejected it multiple times because Pan’
s abstract was published more than a year before they got around to filing.
Eventually, Deisseroth and Boyden signed a document stating that they had
invented this method of using channelrhodopsin privately in the lab before
Pan’s conference abstract was published. The relevant patent was issued in
March 2016, almost 10 years after they filed.
Now, Deisseroth is a cofounder and scientific advisor at Circuit
Therapeutics, a company developing a wide range of therapies based on
optogenetics, presumably using Deisseroth’s patented inventions. (Circuit
Therapeutics declined to comment on specifics of their intellectual property
licenses.)
Pan won a patent as well, to use channelrhodopsin to restore vision in the
eye. His patent was licensed by RetroSense, which won an award from the
Angel Capital Association in 2015. Retrosense — whose CEO in passing told
STAT about Pan’s role in the invention of optogenetics — began clinical
trials this year to put the algae proteins in blind people using gene
therapy. It’s the first application of optogenetics in humans and the first
time a non-human gene is being used in a gene therapy trial.
Right now, there are blind people in Texas walking around with algae DNA and
proteins in their eyes. And that was what Pan was in it for all along. “
One thing I still feel glad about is that even right now our clinical study
is still ahead of anyone,” Pan said.
But given that there are no gene therapies approved for clinical use in the
United States, the road to successfully using optogenetics in humans will
likely be a long one. Yang Dan, a professor of neuroscience at UC Berkeley
who uses optogenetics to study sleep, isn’t betting on optogenetics cures
being in the clinic any time soon. “I believe that these safety checks will
take a long, long time,” she said.
As for the invention itself, some scientists say Pan may not have had the
big, award-worthy vision that Deisseroth and Boyden had. Stefan Herlitze,
one of the others who was scooped for the first publication about
channelrhodopsin in neurons, said, “Of course I have to say, Deisseroth and
Boyden, they really developed the field further.”
Boyden echoed this. “Karl and I were very interested in the general
question of how to control cell types in the brain,” he said. “In recent
years, we worked to push these molecules to their logical limits.”
So maybe it doesn’t matter who invented optogenetics, just who has
stretched science’s boundaries the furthest.
Asked whether he deserves the recognition that Boyden and Deisseroth have
enjoyed, Pan declined to answer. He later told STAT that Deisseroth “also
did a very excellent job, no doubt. But he’s also very lucky because if our
paper was ahead of him, the story would be different. We would have gotten
more credit.”
That is about as much as Pan is willing to say about the way his cards fell.
Today he’s still in Detroit. He’s been working on new versions of
channelrhodopsin that could be used to cure blindness. “My lab is a very
small lab,” Pan said, “We’re mainly interested in trying to restore
vision.”
