Gene Wiki Overview

Published by gtaylor on 12 September 2006 - 11:44am
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genewiki intro.doc504.5 KB

Community 

general open research

See the attached document for an overall concept of our Gene Wiki idea.

Please login and add comments on your thoughts on this project. Type of feedback we're looking for:

  1. Would this feature be useful to you for in-silico drug design? E.g. If you're a malaria scientist, is this useful for malaria drug target identification or should we focus our efforts on another genome?
  2. Are you interested in reaching out to world-wide resources such as India to help with this work?
  3. Would you use this feature openly if it were deployed on The Synaptic Leap? Please explain if you think it should be deployed somewhere else.
  4. What is your specialty and how would you use this feature? E.g. what contributions would you make to a community driven drug development?
  5. Which feature do you think is most useful?
  6. Are there important other features that you want added in the first or second version of the tool?

The more comments the better - even if they're negative. I want some online brainstorming.

Cheers!

Comments

Saj's picture

Reply to Marc Marti-Renom and Ginger Taylor from Saj

 
Re: would the McKerrow lab at QB3/UCSF find the Gene Wiki useful 

Hiya Guys

 

Here are some thoughts/comments/suggestions specifically relating to the McKerrow lab; this is from the standpoint of lab that has had a long interest in a specific part of biology – and I’ve tried to address the Gene Wiki issue from a focus of ongoing research, and how/when the Gene Wiki would be of use to the developing research.  Note that the McKerrow lab has already selected a drug target area to study, hence any collated information on a Gene Wiki would have little sway on the current research choice and/or direction; of course additional ‘fruitful’ research directions are always sought after.  I’m assuming that the Gene Wiki concept would have come about recently, after a substantial foundation had already been established by the McKerrow group. (for Gene Wiki overview – see Marc’s informative presentation at Google - http://video.google.com/videoplay?docid=-62034306No5396416135 and also the attached file attached 'genewiki intro.doc' file).

 

The McKerrow lab has a long documented schistosome research interest, therefore the available B. glabrata Gene Wiki would be of direct interest, as is.  The lab is also vested in several other parasites of humans, that would all collectively be under the umbrella of ‘neglected tropical diseases’.  The latter along with schistosome research is the ‘bread and butter’ of the Sandler Center for Basic Research in Parasitic Diseases, of which Jim McKerrow is the Director (www.ucsf.edu/McKerrow ).  Additional parasites of interest include, Trypanosoma brucei, T. cruzi, Entamoeba, Leishmania, Giardia, Cryptosporidium and of course, the intrepid malaria parasite, Plasmodium,

 

By in large, the main thrust of the McKerrow lab’s focus is on a set of enzymes termed, proteases; which spans back decades and well of 100 publications.  Therefore, in this case the drug target class of interest has already been selected (due to the expertise in a particular area), sometimes without any priori as to function and/or homology to host enzyme(s), and therefore a Gene Wiki in this specific case would be of little use at this stage of the ‘target validation conveyor belt’.  The McKerrow lab thrives on validating a given parasite protease using recombinant, biochemical and cell based technologies; now this is where a Gene Wiki would be of most use.  Lets say that there is functional information available from other annotated genomes, that could be linked to a potential parasite orthologous protease that we are interested in, this would certainly assist in target validation.  Cross talk between many genomes would be what is needed here. If a homologue of protease X also occurs in yeast, model nematode(s), fruit flies, or zebra fish (organisms that a amenable to genetic manipulation on a dynamic global scale, and so substantial gene-function information has been collected) this information could be extrapolated, to at the very least shed light on possible function and go towards assessing protease X’s validity as a potential biocide target. Comparing to the numerous genomes from parasitic organisms would also be beneficial, not by merely listing orthologous genes and/or proteins, but by allowing a functional information filter (for parasite genome sequences see, www.ebi.ac.uk/parasites/paratable.html). 

 

The Gene Wiki concept is indispensable for gene(s) that have ‘no known function’, here any input would benefit enormously.  However, as in our case, with protease in parasitic organisms, we can list exactly how many potential proteases there are in any given annotated genome, by BLASTing template proteases. Of these, we can narrow down would-be targets by considering which part of the lifecycle the protein is around, and further decrease this number by localization and/or effect of broad spectrum chemical inhibitors.  Additional validation could indeed come from the Gene Wiki: has this type of enzyme been successfully targeted already in other system; are there chemical libraries available elsewhere.  To summarise here, the Gene Wiki would not have been used in the initial stages in the McKerrow lab, but would certainly be valuable at the latter stages of target validation; and once validated, this knowledge can be added to the specific Gene Wiki of interest (as is essentially Marc’s ‘gene basket’ brainchild).  In addition, due to the longevity of the McKerrow group in the field of parasite proteases, I don’t imagine that we would turn to the Gene Wiki to direct wet lab work.  This is due to a well established ‘validation pathway’ with regards to experiments needed and due to the substantial resources available in house.  We would be (and in fact are) a resource for protease research globally, a resource that can be added to all parasite protease Gene Wiki’s.

 

Whilst a genome specific Gene Wiki site will, over time and input, be beneficial to a given scientific community, it does stand alone.  The Plasmodium falciparum Gene Wiki site, would be bolstered if it were linked to the genomes of Plasmodium berghei (the rodent model malaria, which is routinely manipulated at the genetic level; http://www.sanger.ac.uk/Projects/P_berghei/ ) and Toxoplasma gondii (a closely related human parasite which is also amenable to genetic exploitation; http://www.toxodb.org/toxo/home.jsp ); both of the latter having a significant functional information available.   For completeness, there should be a lot of cross talk between the aforementioned genomes and model organisms, as mentioned above.   Effectively a Gene Wiki wish list would contain the Gene Wiki on many transparent, but linked, levels (some of these are already covered by the current Gene Wiki template). 1. organism based  - looking at respective open reading frames within one genome and  – 2. gene based – looking at gene X from many genomes with bias to a known function; as this is essentially the most informative in the validation process, cataloguing lists of orthologues is merely ‘stamp collecting’ when it come to target validation. 3.  linked resources to a gene and/or gene-product such as: chemical and immuno reagents, experts in the field within a particular organism, available genetic null and/or gene silenced clones and recombinant orthologues generated, and literature available from other systems.  This approach will allow scientists from, sometimes disparate backgrounds, to add useful information about an orthologous gene-product to the same Gene Wiki, but from different organisms - this collated knowledge will be invaluable in primary target validation as well as downstream confirmatory work.  The data is out there   -it simply needs meshing together (by the right folk!). How possible is this? 

 

Finally, a different thrust of the broader Sandler Center for Basic Research in Parasitic Diseases, is a sort of reverse approach, where a drug’s chemcial activity is used to target, rather than target the site of drug action.  Here, FDA approved drugs are screen against live parasites, any hits obtained are therefore with drugs that have been approved for use in humans.  Work is in the early stages, however even now the initial results looks very promising (www.ucsf.edu/McKerrow/fruit.html ).  Here the specific target of the FDA approved drug may not be known, and some may say that it does not matter as long as the drug targets the parasite over the host.  Here, the Gene Wiki approach would have no rational forward directional drug discovery approach, as even pshychoactive or hypertensive drugs may be antiparasitic .  Although at this stage it would exponentially advantageous if the in silico screen that is added to a Gene Wiki utilizes FDA approved compounds as well as those chemical that are drugable and also lead compound. An option to in silico screen only the FDA compounds or a given in house library may be a useful additional tool, at least for the McKerrow lab.

 

Overall – the Gene Wiki is a very powerful forward thinking concept.  Its strength is the direct relevant information that can be gathered for any given gene or gene product.  The downside is that targets that are ‘tip of the iceberg’ have already been selected, and so unless one works in an area, with say gene/protein X, what is the incentive add info to a Gene Y Wiki?  The Gene Wiki will be of most use when an established lab (such as the McKerrow) is branching out in a new research direction and so the collated data on the Gene Wiki can be perused effectively.  Also, if the Gene Wiki is up to date, this information will let the scientific community as whole know who is doing what  - so as not to overlap research.  Finally, what the McKerrow, and other, labs need at the Gene Wiki level is functional information as gleaned from trawls from other organisms. If a single click of the mouse can filter in known (not hypothetical) biological function for a given gene-product from various organisms, this would indeed go a long way facilitating which protein(s) are short listed for target validation. 

 

Answers to specific Qs put forward in 'genewiki intro.doc'

1. Is the Gene Wiki  idea useful in drug design?

The Gene Wiki concept will be a useful aid to the validation process, especially to initial in vitro/in vivo characterization.  The McKerrow lab already has many validated targets from various parasitic organisms in place, and so the lab would probably not turn to a Wiki for a given protein that has a lot of research hours behind it.

 

2. Are you interested in reaching out to global resources?

 Reaching out to worldwide resources can be beneficial, however, the Sandler Center is set up to have all drug targeting resources/facilities/expertise in house.  There are always instances when global resources are useful, for example, to scale up a drug lead for animal or phase I preclinical trials.  Here I would add that the McKerrow lab is exceptional, and so many ‘traditional’ labs would certainly see this ‘out reaching’ as beneficial.

 

3. Where would you deploy the Gene Wiki?

 Whereas, each Gene Wiki may be genome linked, and therefore based at that site, it would be useful if the Gene Wiki be also linked to respective genomes; this layering cumulative information on what would be a transparent Gene Wiki (see points above)

 

4. what is your speciality, and what contribution can you make in drug develpoment?

The McKerrow lab specialty is proteases as drug targets.  The lab could add ‘useful data’ of a Gene Wiki from a given parasite genome, that could be cross referenced by scientists interested in the same biological pathway from diverse organisms.

 

5. mostuseful feature?

 Vote scoring.

 

6. are there important feature you would add?

In addition to lists of orthologous genes, include an option where only known 'protein function' from other systems can be seen together.  Also, an in silico screen capability using sub libraries - ie. chemicals libraries that individual labs have in house.

additional points/Qs

 

Many established labs have already opted for a given scientific interest.  What would be the motivation for these (often well funded  - large labs) to look at the Gene Wiki site for their protein X?  how would one get these labs to add data to a Wiki site, which in effect would be giving ‘free IP’ to unscrupulous users such competitors or pharma? Does this even matter? Or is this a KARMA issue?????

 

On a much larger issue, how do we change the way scientist view open source (including the Gene Wiki) as a valuable and dynamically useable resource? What would the carrot be?

 

Can one refer to the (non-peer reviewed; at least in the conventional sense) Gene Wiki information in a communication, presentations, posters, talks?

 

In addition to the voting system and Wiki format - what information does the Gene Wiki provide, that is not accessible at annotated genome sites, at NCBI or the results of a BLAST analysis?

MUCH FOOD FOR THOUGHT

Saj

 
 
 
 

cdsouthan's picture

Could this important subject be updated  and cover the current state of  the Plasmodium proteome annotation ?