Who invented optogenetics?

Wayne State University. Ever heard of it? Probably not. How about Zhuo-Hua Pan? No? No bell ringing? Let’s try a different approach: ever heard of Stanford University? Why, yes, it’s one of the most prestigious and famous universities in the world. And now the last question: do you know who Karl Deisseroth is? If you’re not a neuroscientist, probably not. But if you are, then you would know him as the father of optogenetics.

Optogenetics is the newest tool in the biology kit that allows you to control the way a cell behaves by shining a light on it (that’s the opto part). Prior to that, the cell in question must be made to express a protein that is sensitive to light (i.e. rhodopsin) either by injecting a virus or breeding genetically modified animals that express that protein (that’s the genetics part).

If you’re watching the Nobel Prizes for Medicine, then you would also be familiar with Deisseroth’s name as he may be awarded the Nobel soon for inventing optogenetics. Only that, strictly speaking, he did not. Or, to be fair and precise at the same time, he did, but he was not the first one. Dr. Pan from Wayne State University was. And he got scooped.98.png

The story is at length imparted to us by Anna Vlasits in STAT and republished in Scientific American. In short, Dr. Pan, an obscure name in an obscure university from an ill-famed city (Detroit), does research for years in an unglamorous field of retina and blindness. He figured, quite reasonably, that restoring the proteins which sense light in the human eye (i.e. photoreceptor proteins) could restore vision in the congenitally blind. The problem is that human photoreceptor proteins are very complicated and efforts to introduce them into retinas of blind people have proven unsuccessful. But, in 2003, a paper was published showing how an algae protein that senses light, called channelrhodopsin (ChR), can be expressed into mammalian cells without loss of function.

So, in 2004, Pan got a colleague from Salus University (if Wayne State University is a medium-sized research university, then Salus is a really tiny, tiny little place) to engineer a ChR into a virus which Pan then injected in rodent retinal neurons, in vivo. After 3-4 weeks he obtained the expression of the protein and the expression was stable for at least 1 year, showing that the virus works nicely. Then his group did a bunch of electrophysiological recordings (whole cell patch-clamp and voltage clamp) to see if shining light on those neurons makes them fire. It did. Then, they wanted to see if ChR is for sure responsible for this firing and not some other proteins so they increased the intensity of the blue light that the ChR is known to sense and observed that the cell responded with increased firing. Now that they saw the ChR works in normal rodents, next they expressed the ChR by virally infecting mice who were congenitally blind and repeated their experiments. The electrophysiological experiments showed that it worked. But you see with your brain, not with your retina, so the researchers looked to see if these cells that express ChR project from the retina to the brain and they found their axons in lateral geniculate and superior colliculus, two major brain areas important for vision. Then, they recorded from these areas and the brain responded when blue light, but not yellow or other colors, was shone on the retina. The brain of congenitally blind mice without ChR does not respond regardless of the type of light shone on their retinas. But does that mean the mouse was able to see? That remains to be seen (har har) in future experiments. But the Pan group did demonstrate – without question or doubt – that they can control neurons by light.

All in all, a groundbreaking paper. So the Pan group was not off the mark when they submitted it to Nature on November 25, 2004. As Anna Vlasits reports in the Exclusive, Nature told Pan to submit to a more specialized journal, like Nature Neuroscience, which then rejected it. Pan submitted then to the Journal of Neuroscience, which also rejected it. He submitted it then to Neuron on November 29, 2005, which finally accepted it. Got published on April 6, 2006. Deisseroth’s paper was submitted to Nature Neuroscience on May 12, 2005, accepted on July, and published on August 14, 2005… His group infected rat hippocampal neurons cultured in a Petri dish with a virus carrying the ChR and then they did some electrophysiological recordings on those neurons while shining lights of different wavelengths on them, showing that these cells can be controlled by light.

There’s more on the saga with patent filings and a conference where Pan showed the ChR data in May 2005 and so on, you can read all about it in Scientific American. The magazine is just hinting to what I will say outright, loud and clear: Pan didn’t get published because of his and his institution’s lack of fame. Deisseroth did because of the opposite. That’s all. This is not about squabbles about whose work is more elegant, who presented his work as a scientific discovery or a technical report or whose title is more catchy, whose language is more boisterous or native English-speaker or luck or anything like that. It is about bias and, why not?, let’s call a spade a spade, discrimination. Nature and Journal of Neuroscience are not caught doing this for the first time. Not by a long shot. The problem is that they are still doing it, that is: discriminating against scientific work presented to them based on the name of the authors and their institutions. Personally, so I don’t get comments along the lines of the fox and the grapes, I have worked at both high profile and low profile institutions. And I have seen the difference not in the work, but in the reception.

Personally, so I don’t get comments along the lines of the fox and the grapes, I have worked at both high profile and low profile institutions. And I have seen the difference not in the work, but in the reception.

That’s my piece for today.

Source:  STAT, Scientific American.

References:

1) Bi A, Cui J, Ma YP, Olshevskaya E, Pu M, Dizhoor AM, & Pan ZH (6 April 2006). Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron, 50(1): 23-33. PMID: 16600853. PMCID: PMC1459045. DOI: 10.1016/j.neuron.2006.02.026. ARTICLE | FREE FULLTEXT PDF

2) Boyden ES, Zhang F, Bamberg E, Nagel G, & Deisseroth K. (Sep 2005, Epub 2005 Aug 14). Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience, 8(9):1263-1268. PMID: 16116447. DOI: 10.1038/nn1525. doi:10.1038/nn1525. ARTICLE 

By Neuronicus, 11 September 2016

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The FIRSTS: The rise and fall of Pokemon (2001-2005?)

90pok - Copy

Few people know that Pokemon refers not only to a game, but also to a gene. An oncogene, to be precise, with a rather strange story.

An oncogene is a gene that promotes cancer (from oncology). Conventionally, a gene name is written in lowercase italicized letters (pokemon), whereas the protein the gene makes is not italicized (POKEMON, Pokemon, or pokemon, depending on the species). Maeda et al. (2005) first established in a Petri dish that the Pokemon is required for the growth of malignant tumors. Then, through a series of classic molecular biology experiments, the scientists found out how exactly Pokemon acts to accomplish this (by suppressing the expression of anti-cancer genes). Next, they engineered mice with pokemon overexpressed and saw that the mice with a lot of Pokemon “developed aggressive tumours” (p. 282). Then the authors checked how is this gene behaving in human cancers and found out that “Pokemon is expressed at very high levels in a subset of human lymphomas” (p. 284).

And here is how the gene got its name, according to Pier Paolo Pandolfi, the leader of the research group. Bear with me because it’s complicated. [*Takes deep breath*]: PO in POK stands for POZ domain (poxvirus and zinc finger) and K in POK stands for Krüppel (zinc finger transcription factor) whereas EMON stands for erythroid myeloid ontogenic factor. POK-EMON. Simple, eh? Phew…

Truth be told, Pandolfi first named the gene pokemon at a conference in 2001 (Simonite, 2005). Then the name has been used by researchers at various scientific meetings and poster presentations.

But when the Maeda et al. paper was published in Nature in 2005 which discovered the mechanism through which the gene promotes cancer, a lot of people, scientists and journalists alike, in an attempt at humour, flooded the internet with eye-catching titles along the lines of “Pokemon causes cancer”, “Pokemon kills you” and the like. I mean, even the researchers themselves in the abstract of the paper state: “Pokemon is aberrantly overexpressed in human cancers”. In response, The Pokémon Company threatened to sue for trademark copyright infringement because they didn’t want the game to be associated with cancer, like the gene is, even if the researches said the name is an acronym (maybe they meant backronym?). In the end, the researchers changed the name of the pokemon gene to the far less enticing zbtb7.

As the question mark in the title of the post suggests, the pokeman gene may not be entirely dead yet because there are stubborn scientists that still use the name pokemon and not zbtb7. I hope they have the cash to take on Nintendo if they decide to sue after all.

Too bad the zbtb7 (a.k.a. pokemon) gene was not a beneficial gene… Because another group of researchers named their new-found gene in 2008 pikachurin and so far, Nintendo din not make any waves… That is, probably, because Pikachurin is a protein in the eye retina that is required for proper vision by speeding the electric signals. Zip zip zip Pikachurin goes…

References:

  1. Maeda T, Hobbs RM, Merghoub T, Guernah I, Zelent A, Cordon-Cardo C, Teruya-Feldstein J, & Pandolfi PP (20 Jan 2005). Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature, 433(7023):278-85. PMID: 15662416, DOI: 10.1038/nature03203. ARTICLE | FULLTEXT PDF at Univ. Barcelona
  2. Simonite T (15 Dec 2005). Pokémon blocks gene name. Nature, 438(7070):897. PMID: 16355177, DOI: 10.1038/438897a. ARTICLE 

By Neuronicus, 18 July 2016

Golf & Grapes OR Grandkids (but not both!)

Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license
Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license

Transgenerational epigenetic inheritance (TGI) refers to the inheritance of a trait from one generation to another without altering the DNA code (normally, evolution is driven by changes in the DNA itself). Instead, it happens by modifying the proteins that wrap around the DNA, the histones; these histones, in turn, control what genes will be expressed and when. Until a decade ago, TGI was considered impossible, nay, a scientific heresy since it had too close of a resemblance to Lamarckian evolution. But, true to its guiding principles, the scientific endeavor had to bite the bullet in front of amassing evidence and accept the fact that it may have been a kernel of truth to the so called ‘soft inheritance’.

Anway et al.’s paper was one of the first to promote the concept, ten years ago. They exposed pregnant rats to the pesticides vinclozolin or methoxychlor (only vinclozolin is still used widely in U.S.A. and several EU countries, particularly in agriculture, wine production, and turf maintenance; methoxychlor was banned in the early noughts). The authors found out that more than 90% of the male offspring had “increased incidence of male infertility”. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined” up to great great grandsons, inclusively (Anway et al., 2005). (I don’t want to speculate how they managed to breed the low fertility males…). That doesn’t mean that the F5 generation was OK (the great great great gransons); it means that they stopped investigating after the F4 generation (or they couldn’t breed the F4s). Moreover, the mechanism of inheritance seems to be altered methylation of the DNA histones of the male germline, and not alteration of the DNA itself. Females were affected too, but they didn’t have enough data on that experiment (the Ph.D. student that did the work had to graduate sometime…).

Although the authors used higher amounts of pesticides than they suspected back then, in 2005, to be found in the environment, the study still gives pause for thought. After all, it has been 10 years since this paper plus the previous 20 years of use of the stuff. And no, you cannot get rid of it by washing your grapes and vegetables really thoroughly.

Reference: Anway, M. D., Cupp, A. S., Uzumcu, M., & Skinner, M. K. (3 June 2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science, 308(5727): 1466-1469. DOI:10.1126/science.1108190. Article + Science Cover + FREE PDF

by Neuronicus, 25 September 2015