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热度 4已有 2345 次阅读2015-12-8 11:36 |个人分类:辩论争鸣|系统分类:学术打假| 张生家, 鲁白

从“光遗传”到“磁遗传”:张生家的丰富经历和鲁白的一片空白 ... ...

在“张生家案”的调查中,《科学伦理》遇见了清华大学的一个黑箱子:鲁白对张生家的不公开指控和清华的不公开调查。虽然这个20158月就有了的指控,但到今日还未有调查结果公布。不过,鲁白在“论文抢发”风波发生后告诉了《自然》并由《自然》公布于世界:张生家偷了他的想法。

张生家偷了鲁白的什么想法?《科学伦理》直接问了鲁白、也催问了清华,但始终没有回答。

不过,从鲁白想当张生家论文的通讯作者不成而告张生家“学术不端”看,这被“偷”的想法一定与张生家的论文的主题有关了。

张生家论文的主题是“磁遗传”,这是一个较为新颖的名词。这个新东西怎么被张生家注意而且还真干上了?那就要看张生家过去是干什么的了。

张生家过去干过“光遗传”,而且还干的不错。

因为至少有(美国)《科学》论文作证:

Science. 2013 Apr 5;340(6128):1232627. doi: 10.1126/science.1232627.

Optogenetic dissection of entorhinal-hippocampal functional connectivity.

Zhang SJ1, Ye J, Miao C, Tsao A, Cerniauskas I, Ledergerber D, Moser MB, Moser EI.

Erratum in

·         Science. 2013 Apr 19;340(6130):273.

Abstract

We used a combined optogenetic-electrophysiological strategy to determine the functional identity of entorhinal cells with output to the place-cell population in the hippocampus. Channelrhodopsin-2 (ChR2) was expressed selectively in the hippocampus-targeting subset of entorhinal projection neurons by infusing retrogradely transportable ChR2-coding recombinant adeno-associated virus in the hippocampus. Virally transduced ChR2-expressing cells were identified in medial entorhinal cortex as cells that fired at fixed minimal latencies in response to local flashes of light. A large number of responsive cells were grid cells, but short-latency firing was also induced in border cells and head-direction cells, as well as cells with irregular or nonspatial firing correlates, which suggests that place fields may be generated by convergence of signals from a broad spectrum of entorhinal functional cell types.

Comment in

·         Neuroscience. A trace of your place. [Science. 2013]

 

而当年干出这个名堂后,张生家和他老婆还在挪威的大学里风光了一阵:

http://www.ntnu.edu/news/2013-news/light-switches

A “light switch” in the brain illuminates neural networks

(04.04.2013) Researchers from NTNU's Kavli Institute of Systems Neuroscience are able to see which cells communicate with each other in the brain by flipping a neural light switch. The results of their efforts are presented in an article in the 5 April issue of Science magazine.

There are cells in your brain that recognize very specific places, and have that and nothing else as their job. These cells, called place cells, are found in an area behind your temple called the hippocampus. While these cells must be sent information from nearby cells to do their job, so far no one has been able to determine exactly what kind of cells work with place cells to craft the code they create for each location. Neurons come in many different types with specialized functions. Some respond to edges and borders, others to specific locations, others act like a compass and react to which way you turn your head.



Now, researchers at the Kavli Institute for Systems Neuroscience have developed a range of advanced techniques that enable them to identify which neurons communicate with each other at different times in the rat brain, and in doing so, create the animal's sense of direction.

"A rat's brain is the size of a grape. Inside there are about fifty million neurons that are connected together at a staggering 450 billion places (roughly)," explains Professor Edvard Moser, director of the Kavli Institute. "Inside this grape-sized brain are areas on each side that are smaller than a grape seed, where we know that memory and the sense of location reside. This is also where we find the neurons that respond to specific places, the place cells. But from which cells do these place cells get information?"

From spaghetti to light switches
The problem is, of course, that researchers cannot simply cut open the rat brain to see which cells have had contact. That would be the equivalent of taking a giant pile of cooked spaghetti, chopping it into little pieces, and then trying to figure out how the various spaghetti strands were tangled together before the pile was cut up.
A job like this requires the use of a completely different set of neural tools, which is where the "light switches" come into play.

Neurons share many similarities with electric cables when they send signals to each other. They send an electric current in one direction – from the "body" of the neuron and down a long arm, called the axon, which goes to another nerve cell next in line. Place cells thus get their small electric signals from a whole series of such arms.

So how do light switches play into all of this?

Viruses do the work 
"What we did first was to give these nerve arms a harmless viral infection," Moser says. "We designed a unique virus that does not cause disease, but that acts as a pathway for delivering genes to specific cells. The virus creeps into the neurons, crawls up against the electric current, and uses the nerve cell's own factory to make the genetic recipe that we gave to the virus to carry."

The genetic recipe enabled the cell to make the equivalent of a light switch. Our eyes actually contain the same kind of biological light switch, which allows us to see. The virus infection converts neurons that have previously existed only in darkness, deep inside the brain, to now be sensitive to light.

Then the researchers inserted optical fibres in the rat's brain to transmit light to the place cells that had light switches in them. They also implanted thin microelectrodes down between the cells so they could detect the signals sent through the axons every time the light from the optical fibre was turned on.

"Now we had everything set up, with light switches installed in cells around the place cells, a lamp, and a way to record the activity," Moser said.

10,000 times
The researchers then turned the lights on and off more than ten thousand times in their rat lab partners, while they monitored and recorded the activity of hundreds of individual cells in the rats' grape-sized brains. The researchers did this research while the rats ran around in a metre-square box, gathering treats. As the rats explored their box and found the treats, the researchers were able to use the light-sensitive cells to reveal how the rat's brain created the map of where the rat had been.

When the researchers put together all the information afterwards they concluded that there is a whole range of different specialized cells that together provide place cells their information. The brain's GPS – its sense of place – is created by signals from head direction cells, border cells, cells that have no known function in creating location points and grid cells. Place cells receive both information about the rat's surroundings and landmarks, but also continuously update their own movement, which is actually independent on sensory input.

"The biggest mystery is the role that the cells that are not part of the sense of direction play. They send signals to place cells, but what do they actually do?" wonders Moser.
 
"We also wonder how the cells in the hippocampus are able to sort out the various signals they receive. Do they ‘listen' to all of the cells equally effectively all the time, or are there some cells that get more time than others to ‘talk' to place cells?"

The findings are published in Science on Friday 5 April.

 

于是乎,爱国的张生家就想起要用这有用的知识和技术报效祖国。他要当海龟了!

这不,在网上一搜,还搜出一张当年张生家学术讲座的海报:

http://imibr.bnu.edu.cn/nview_39.html

Lecture: Optogenetic Decoding of the Neural Circuit of the Brain’s GPS

 Speaker:     

Sheng-Jia Zhang, Ph.D.

Group Leader

Kavli Institute for Systems Neuroscience and Centre for Neural Computation

Norwegian University of Science and Technology (NTNU), Norway

 

Title: Optogenetic Decoding of the Neural Circuit of the Brain’s GPS

 

Time: 10:00 am, September 26, 2013

LocationConference Room 308, Brain Imaging Center

 

Abstract:

Both the hippocampus and the medial entorhinal cortex are key components of the brain’s map of the spatial environment. The spatial map or the brain’s GPS contains a number of functionally specialized cell types, including, in the hippocampus, place cells, and, in the medial entorhinal cortex, grid cells, head-direction cells, and border cells. However, the functional interaction between a single hippocampal place map and the multiple medial entorhinal spatial maps is poorly understood. Hippocampal place signals may be generated by transformation of spatial input from the medial entorhinal cortex but which cell types contribute to this process remains elusive, given that only a subset of the entorhinal projection neurons target the hippocampus. In this lecture, I will introduce how a combined optogenetic-electrophysiological strategy is initiated to estimate the identity and quantity of medial entorhinal functional cell types with monosynaptic projections to the hippocampus; I will talk about the power and promise of my self-developed retrograde virus for genetically tagging project-targeted and circuit-specific intervention of the hippocampal-entorhinal space memory circuit; I will show you both gain-of-function and loss-of-function optogenetic control over the space memory circuit; I will suggest that place cells are generated by convergence of signals from multiple functional cell types, with grid cells as the main contributor; Finally, I will describe the therapeutic application of  translational optogenetics to neurologic diseases as well as the decisive role of optogenetics in brain activity mapping project.

 

Brief introduction to the speaker:

Dr. Shengjia Zhang graduated from Wuhan University (China)with Bachelor’s and Master’s Degrees in Virology and Molecular Biology in 1987 and 1990. He obtained his Ph.D. from University of Heidelberg (Germany) in Neurobiologyin 2006. Dr. Zhang’s research interest is to understand the neural circuitry and mechanisms underlying cognition and behavior, with a focus on space memory, by using ontogenetic, neuroanatomical, and electrophysiological tools. His work has been published in several high-profile journals including Science, Nature Neuroscience and Journal of Neuroscience.

 

张生家得到了国内几个大学的OFFER,但他最终选择了清华,成了清华的一个PI

 

http://www.cls.edu.cn/english/PrincipalInvestigator/pi/index2777.shtml

Sheng-Jia Zhang

http://www.cls.edu.cn/uploads/Boosen1429156560.jpg

Sheng-Jia Zhang

E-mail: [email protected]

Telephone (Lab): +86 10 627 97935

 

Research Area

The Nobel Prize in Physiology or Medicine 2014, awarded to John O’Keefe, May-Britt Moser and Edvard I. Moser, not only recognizes their groundbreaking contributions “for their discoveries of cells that constitute a positioning system in the brain” but also provides the whole field of systems neuroscience with a unique computational readout and downstream output for dissecting the high-order cortical computation. Taking advantage of our special expertise on both advanced molecular biology and in vivo electrophysiology, our lab focuses on decoding, at single-neuron and single-spike levels, the molecular and cellular substrates of the brains inner GPS composed of all different functionally specialized cell types including place cell, head-direction cell, border and grid cells. To reach this aim, we are employing interdisciplinary approaches including CRISPR/Cas9-based gene editing of rodents and marmosets, projection-targeted viral tracing, cell-type-specific optogenetics and pharmacogenetics, activity-dependent labeling of only activated ensembles, tempospatial two-photon imaging in vivoextracellular and intracellular recording and computational modeling in freely moving and genetically tractable animals. Our long-term goal is to bridge from genes to circuits to minds to behaviors to find out how space memory codes are computed, formed and transformed at multiple levels. In addition, we are also interested in translational optogenetics and neuroscience at circuit-level correction for relevant neurological diseases.

 

Selected Publications:

1.  Ito, HT, Zhang SJ, Witter MP, Moser EI, Moser MB. (2015). A prefrontal-thalamo-hippocampal circuit for goal-directed spatial coding. Nature in press.

2.  Zhang SJ*, Ye J*, Couey JJ, Witter MP, Moser EI, Moser MB. (2014). Functional connectivity of the entorhinal-hippocampal space circuit. Philos. Trans. R. Soc. Lond. B Bio. Sci. 369, 20120516.

3Zhang SJ*#, Ye J*, Miao C, Tsao A, Cerniauskas I, Ledergerber D, Moser MB, Moser EI#. (2013). Optogenetic dissection of entorhinal-hippocampal functional connectivity. Science 340 (6128), 1232627 (Selected as an Enhanced 14-Page Research Article).

4.  Couey JJ*, Witoelar A*, Zhang SJ*, Zheng K, Ye, J, Dunn B, Czajkowski R, Moser, MB, Moser EI, Roudi Y, Witter MP. (2013). Recurrent inhibitory circuitry as a mechanism for grid formation. Nature Neuroscience 16, 318-324.

5.  Czajkowski R, Sugar J, Zhang SJ, Couey JJ, Ye J, Witter MP. (2013). Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input. Journal of Neuroscience 33, 15779-15792.

6.   Zhang SJ, Buchthal B, Lau D, Hayer SN, Dick O, Schwaninger M, Veltkamp R, Zou M, Weiss U, Bading H. (2011). A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. Journal of Neuroscience 31, 4978-4990.

7.  Zhang SJ, Zou M, Lu L, Lau D, Ditzel DAW, Delucinge-Vivier C, Aso Y, Descombes P, Bading H. (2009). Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genetics 5(8), e1000604.

8.  Zhang SJ, Steijaert MN, Lau D, Schütz G, Delucinge-Vivier C, Descombes P, Bading H. (2007). Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53, 549-562. 

 (*co-first/# co-corresponding):

 

到了清华,他听说北大谢灿那里有“磁蛋白”,这一下子就把埋在他心中的“磁遗传”给“吸”了出来,因为他知道:“磁遗传”比“光遗传”有更多的优越性。

 

所以他与谢灿见了面,两人竟一拍即合地开始了合作,而且是真诚的合作。

 

不过天有不测之云。忽然半路杀出个鲁白,要当张生家论文的通讯作者,结果当然被按国际惯例办事的张生家给顶了回去。于是就发生了只有特色国才可能发生的特色事:张生家不仅被鲁白告成偷他的思想,还被谢灿指责为虚构合作。

 

那么鲁白真的有“磁遗传”的想法吗?我们查遍文献,未见踪影。不说“磁遗传”,就连“光遗传”研究领域,也未见鲁白的身影。

 

所以,如果清华大学不公布鲁白指控张生家偷他想法的证据,我们就只有相信那个黑箱子里没有靠得住的证据证明鲁白早于张生家之前有什么“磁遗传”的想法。


路过

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发表评论 评论 (5 个评论)

回复 icalys 2015-12-8 22:33
到底是什么证据把nature news的记者也忽悠了,拿出来看看。
回复 姚小鸥 2015-12-8 23:06
nature news的记者有义务把事儿搞清楚,再加报道。
回复 Jingangyuxiang 2015-12-9 04:18
磁遗传要比光遗传有优越感,但是文章里提到的人都不知道光和磁的本质是什么。
回复 scidancer 2015-12-9 07:50
did the person who showed the claimed accusations to Nature reporter commit a crime of leaking goverment secrets? If the person name is known, someone might report ths person for leaking goverment secretes. Nature reporter claimed he has seen the official document of the accusation. The person who gave this document actually commited a crime since the document is in the process of investigation, and is not a final conclusion to be released to the public.
回复 求真留实 2015-12-9 07:58
哈哈!被指控的人到现在想看都不给看那指控的内容,倒叫《自然》的通讯员看了并在《自然》透露张生家偷idea。这是什么行为?

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