CDI-Type I: Chemistry Crowdsourcing using Open Notebook
Science
PI: Jean-Claude Bradley, Drexel University
Abstract
The current system of dissemination of scientific data and knowledge is far less efficient than it needs to
be to facilitate improved collaborative science, especially considering current publication vehicles and
infrastructure. There is a growing movement promoting more Open Science with the belief that a more
transparent scientific process can perform far more effectively. The logical extension of this concept is full
transparency - exposing a researcher's complete record of progress to the public in near real time. Not
only will such a process enable ongoing data sharing it also provides an opportunity to develop
collaborative communities of scientists and, at the conclusion of data acquisition, can enable communal
extraction of conclusions when necessary. We have named this approach Open Notebook Science and
have demonstrated its implementation and feasibility with the UsefulChem project, started in the summer
of 2005, with the aim of synthesizing novel anti-malarial compounds. Our system currently uses free
hosted services using general blog and wiki functions to facilitate replication across any scientific
domains. These services are not chemically intelligent and are limited to text and graphic based data
sharing only. For Open Notebook Chemistry the ability to intelligently manipulate, manage and search
chemical structures and associated data is necessary and we have demonstrated proof of concept
capabilities by integrating with the ChemSpider service, a free access online database managing
chemical structures and focused on developing a structure centric community for chemists. This work will
require the development of a chemically intelligent software platform to extend the capabilities of both the
blog and the wiki environment for managing Open Notebook Science. The exposure of raw experimental
procedures and data in a semantically rich format will enable the participation of both human and
autonomous agents in the process of scientific discovery. This phenomenon of spontaneous group
intelligence, referred to as "Crowdsourcing", has proven valuable in several contexts. Already, productive
collaborations have been forged within the UsefulChem project with groups from Indiana University,
Nanyang Technological University, the National Cancer Institute and UC San Francisco.
Intellectual Merit
The trends of Open Science, crowdsourcing, automation and cheminformatics are creating new
opportunities for increasing the efficiency of discovery. The integration of these phenomena promises to
enable new forms of scientific collaboration. This project brings together people who are uniquely
qualified to create an infrastructure to realize that potential.
Broader Impact
By its very nature, crowdsourcing is designed to connect people together in constructive and unexpected
ways. A key component of this project is to leverage the knowledge gained from an experiment in
crowdsourcing in a particular field and make it easier for it to be applied in other scientific collaborations.
The open nature of the project ensures that this knowledge will be disseminated nearly in real-time and
others interested in replicating such systems will have immediate access to advice and resources from
the participants. Already this replication effect has taken place, with other laboratories exposing their
work to Open Notebook Science conditions, stimulated by reports of the UsefulChem project.
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
List of Participants
Jean-Claude Bradley, Drexel University, PI:
Jean-Claude Bradley is an Associate Professor of Chemistry and E-Learning Coordinator for the College
of Arts and Sciences at Drexel University. He leads the UsefulChem project, an initiative started in the
summer of 2005 to make the scientific process as transparent as possible by publishing all research work
in real time to a collection of public blogs, wikis and other web pages. Jean-Claude coined the term Open
Notebook Science to distinguish this approach from other more restricted forms of Open Science. The
main chemistry objective of the UsefulChem project is currently the synthesis and testing of novel anti-
malarial agents. The cheminformatics component aims to interface as much of the research work as
possible with autonomous agents to automate the scientific process in novel ways. Jean-Claude teaches
undergraduate organic chemistry courses with most content freely available on public blogs, wikis, games
and audio and video podcasts. Openness in research meshes well with openness in teaching. Real data
from the laboratory can be used in assignments to practice concepts learned in class. Jean-Claude has a
Ph.D. in organic chemistry and has published articles and obtained patents in the areas of synthetic and
mechanistic chemistry, gene therapy, nanotechnology and scientific knowledge management.
Kevin Owens, Drexel University, co-PI
Kevin Owens is an Associate Professor of Chemistry at Drexel University. His research group focuses on
the use of mass spectrometry for both biological and synthetic polymer analysis, specifically mechanistic
studies of the Matrix-Assisted Laser Desorption/Ionization (MALDI) process, application of MALDI to
synthetic polymer analysis, development of sample preparation methodologies for quantitative analysis by
MALDI Time-of-Flight Mass Spectrometry (TOFMS), TOFMS instrument development, and the application
of chemometric techniques (particularly correlation analysis) to aid in the automated interpretation of
mass spectral data. His latest work in the area of mass spectral interpretation involves the combination of
genetic algorithm techniques with correlation analysis to create mass spectral filters for the automated
identification of chemical substructures. His group maintains a number of wikis describing several of their
current research efforts. Kevin has a Ph.D. in analytical chemistry, and teaches the two-quarter
undergraduate instrumental analysis sequence, the graduate/undergraduate chemical information
retrieval course, as well as the graduate level mass spectrometry and statistics & experimental design
courses.
Antony Williams, ChemSpider, Senior Personnel
Antony Williams is a Senior Fellow at the National Institute of Statistical Sciences, is the President of
ChemZoo Inc., and is the host of ChemSpider, a Structure Centric Community for Chemists. Antony has
worked in academia, in industry (Eastman-Kodak) and in the commercial cheminformatics sector in the
role of Chief Science Officer. He has authored and co-authored over 100 scientific publications and
multiple invited book chapters. He has two issued patents and has one pending. His formal training is as
an NMR Spectroscopist with a focus on small molecule structure elucidation and analytical data
processing algorithms. the last decade of his career has been focused on the development of integrated
sample, structure and analytical data management systems at the desktop and at the enterprise level
utilizing web-based technologies. In the past year he has established a free access website, ChemSpider,
to provide access to chemistry-related information for almost 20 million chemical entities and their
associated data. He is interested in all aspects of cheminformatics, with special interest in chemical
structure handling, nomenclature and computer-assisted structure elucidation. He conducts research in
the area of data processing techniques for spectroscopy and development of the semantic web.
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
Justification of Intellectual Partnership
This project aims to synergize the following tools and processes:
1) Crowdsourcing
2) Open Notebook Science
3) Automation and reaction optimization
4) Cheminformatics
Crowdsourcing is a term introduced by Jeff Howe to describe the solution of problems through a
distributed network of people.(1) Although there are several examples of crowdsourcing in science, most
are not open. The best known example is Innocentive, where scientific problems are made public with
prizes for the solvers.(2) However, the proposed solutions are not made public and accepted solutions
are intended to be proprietary to the company funding the solution. Innocentive is also collaborating with
the Rockefeller Institute for help to combat third world and orphan diseases.(3) Other non-commercial
examples in science include Stadust@home (4) and GalaxyZoo (5), initiatives designed to identify
astronomical objects. Some recent examples of crowdsourcing in chemistry are Chemmunity (6), the
Synaptic Leap (7), OrgList (8), Chemists Without Borders (9) and ChemUnPub (10).
The term "Open Notebook Science" was coined to represent a form of Open Science where the
laboratory notebook is made public in as close to real time as possible.(11) The Bradley lab has
demonstrated the feasibility of carrying out Open Notebook Science since the summer of 2005 with the
UsefulChem project. Experiments are stored on wiki pages, much like in a paper notebook, but with
hyperlinks to all the raw data collected.(12) There is also a blog to report on the overall progress of the
scientific work. (13) The blog and wiki receive about 200 hits per day. Over time, a collaboration with
other scientists has evolved. Rajarshi Guha at Indiana University and Tsu-Soo Tan from Nanyang
Polytechnic in Singapore have invested significant amounts of time in running docking calculations for
UsefulChem virtual libraries and reporting their results openly, in near real-time. Dan Zaharevitz, from the
National Cancer Institute has contributed by testing compounds for potential anti-tumor activity. Phil
Rosenthal, from UCSF, is in the process of testing some compounds for anti-malarial activity.(14) Other
individuals from around the world have contributed by engaging in open discussions in the blogosphere.
The UsefulChem project has also been cited in the peer-reviewed literature. (15, 16)
These examples of spontaneous collaboration clearly indicate that there is a huge potential for doing
science under open conditions. However, in order to take full advantage of this potential, additional
elements must come into play. Currently, experimental results on the wiki pages are written in a format
amenable to human interpretation. The system could be made much more powerful by representing the
information in a format understandable by machines as well, so as to contribute to the growing semantic
web.
As a step in this direction, each experiment page has a "tag" section at the end where more machine-
friendly representations of molecules used in the experiment are listed. As an example, InChI codes are
alphanumeric representations of molecules using standards supported by IUPAC. Since these InChIs are
indexed by search engines, such as Google, it permits an unambiguous means of retrieving relevant
information about each chemical. Other means of representing chemicals (SMILES, chemical names)
suffer from having non-unique representations.
This tagging system works for simple retrieval of an exact chemical structure but fails to allow more
sophisticated queries, such as, identifying chemical substructures, similarity of structure, whether a
chemical is a reagent or a product, the reaction conditions, and details regarding characterization of the
materials, etc. ChemSpider (17) is a free access online database working to build a structure community
for chemists and offers some of the necessary capabilities to facilitate this crowdsourcing project. The
system has been built specifically with the intention of hosting chemical structures and related information
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
such as analytical data. The system presently hosts almost 20 million chemical structures and is the first
online system to facilitate public depositions of single structures or collections, property data, unstructured
annotations and analytical data. ChemSpider (CS) has been designed with the needs of the chemist in
mind and over 3000 chemists per day use the system for the purpose of searching for data and
information associated with chemical entities. The system has already started to deliver on its promise to
facilitate connectivities via the semantic web by providing open web services to allow other platforms to
integrate and derive value from the information available online. CS has already committed to two
directions of related interest to this project : Development of a platform for collaboration between chemists
(
18
) and the development of a structure-based encyclopedia for chemists, WiChempedia (
19
). These
developments will provide core functionality to support our Open Notebook Science efforts. Additional
capabilities will be introduced on an as-needed basis to facilitate our efforts in terms of the support of
experimental data capture, control and reporting as outlined below.
The final component of this partnership is the automation of the execution of some of the experiments.
This will allow us to take scientific crowdsourcing to the next level, where the online community can not
only provide feedback but also directly carry out simple experiments. We propose to incorporate a
ChemSpeed Technologies AG Accelerator SLT100 Synthesizer system into the proposed workflow. (20)
The Accelerator is a fully-automated robotic synthesis platform capable of both solution and solid phase
synthesis. The unit holds a maximum of 12 reactor arrays, where each of the arrays contains a number of
identical reactors with available volumes between 2-100 mL. For example, there are 16 reactors/array
using 2 mL or 13 mL reactors. The reactors can be heated and cooled over the range of -70 to +180C
and they can be vortexed up to 1400 rpm. An inert or reactive gas blanket or vacuum (down to 10 mbar)
can be applied to the array for evaporation. The robotic system is equipped with a pipetting head
composed of 4 independent needles attached to 2-way 6-port ceramic valves enabling the direct use of
16 solvents. The unit has solid dispensing capability with 1mg-10g capacity (with a resolution of 0.1mg).
Each reactor array may be equipped with automated filter capability with either the filtrate or precipitate
available for subsequent reaction steps. An HPLC injection valve or other analytical capabilities are
available as options. The ChemSpeed Autosuite instrument operation software includes a simple drag
and drop programming interface built on an SQL database. We expect this will allow easy integration with
the open source concept which serves as the basis of this proposal.
Research program
The following scientific objectives will be initiated as projects:
1) Determining optimal conditions for the precipitation of Ugi products.
The Ugi reaction provides a rapid access to large combinatorial spaces by bringing together an amine, an
aldehyde, a carboxylic acid and an isonitrile.(21) In addition, reaction conditions are generally very
convenient: methanol at room temperature is a common protocol. The Bradley group has used the Ugi
reaction to synthesize potential anti-malarial compounds. They observed that sometimes the products
simply crystallized from the reaction mixture.(22) Although NMR monitoring indicated that the reaction
proceeded smoothly in most cases, the products did not always precipitate. The ability to purify products
by a simple filtering step translates into a significant advantage compared against the alternatives, which
would usually consist of chromatography, a costly and inefficient process that severely limits scaling up.
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
Since the Ugi reaction is of value to the generation of product libraries in multiple applications, the ability
to predict the crystallization event should be of significant value to the chemistry community. By
generating models to accurately predict precipitation, virtual libraries being screened for a desired activity
can be further screened for ease of preparation. A better understanding of the solubility of Ugi products
in different solvents using more sophisticated models may also recommend different reaction conditions
for those products that do not crystallize from the standard protocol using methanol.
The simplicity of this initial project is well suited for crowdsourcing. The results (precipitate/no precipitate)
are simple and easy to tabulate. Anyone familiar with QSAR analysis can propose a model and suggest
combinations of starting materials to most efficiently test it. The experiments are simple to execute either
manually or with the assistance of automation. In the case of precipitates, all products will be
characterized by standard techniques (H NMR, C NMR, IR, MS, HRMS).
In addition to the general crowdsourcing effort, co-PI Kevin Owens will leverage his knowledge of
experimental (i.e., factorial) design and optimization methodology (e.g., simplex optimization) to help
guide synthetic reaction optimization. With respect to the prediction of precipitation, the genetic algorithm
approach can quickly build a diverse set of Ugi products created using the parallel synthesis capability of
the automated chemical reactor system requested as part of this proposal. The wide compound diversity
will allow the QSAR methods to more quickly explore the experiment space and develop a robust
predictive capability.
2) Mechanistic investigations
This project will also explore the effectiveness of crowdsourcing to solve mechanistic problems. An initial
problem will focus on the acid-catalyzed cleavage of furfuryl groups.(23) It has been observed that
compounds such as A cleave to yield de-furfurylated product B and some intractable material, perhaps
resulting from the polymerization of side product C. A mechanism proposed to account for this behavior
is shown below. Derivatives of A will be synthesized and the rate of this transformation measured via
NMR spectroscopy. Electron donating groups on the furfuryl ring are predicted to accelerate the
cleavage while electron-withdrawing should slow it. Quantitative models for this reaction, specific test
reactions, and alternative mechanisms will be sought from the online chemical community.
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
3) Other projects will be selected from crowdsourcing efforts
Over time, suggestions will be taken from the online community for additional problems of importance that
can be solved with our growing infrastructure of students, collaborators and informatics and automation
tools.
Educational program
This project offers educational opportunities for both graduate and undergraduate students at several
levels. The following skills will be acquired:
1) Organic and analytical chemistry skills
Students working in the Bradley laboratory will learn standard organic chemistry techniques, including
executing experiments then isolating and fully characterizing products with conventional spectroscopic
analysis (NMR, IR, MS, HRMS). Students working in the Owens lab will learn analytical skills, including
qualitative and quantitative mass spectrometry techniques. Students in both groups will learn and apply
the principles of experimental design and optimization for improved synthesis and analysis..
2) Networking
Students will be required to record their experiments using an Open Notebook on a wiki and will receive
and respond to comments from the online world. Maintaining a public laboratory notebook can be a very
efficient way to learn about the proper way to document an experiment because the adviser and other
interested parties can provide immediate and ongoing feedback, which is impossible with a conventional
closed paper notebook. They will also be encouraged to engage in conversation about their project on
various social networks, including mailing lists (e.g. OrgList, UsefulChem), our collaborators' blogs and
wikis, Facebook, Nature Networks, SciVee, Flickr, etc. Not only will interacting with peers and mentors be
valuable as a learning experience, the contacts formed may be helpful for the progress of the student's
career after graduation.
3) Automatic reactor programming
Students will be charged with setting up, running and maintaining the automated chemical synthesis
system. Coupled with their work doing conventional manual organic synthesis, these students will be
competitively trained to enter the 21
st
century chemistry workforce.
4) An understanding of cheminformatics
In order for the experiments to be properly indexed by ChemSpider and other automatic aggregators,
students will have to learn how to generate and use representations of molecules using modern
cheminformatics techniques (e.g. use structure drawing tools for the generation of SMILES, InChI, and
InChIKey molecular representations). They will also need to become familiar with tools for the
manipulation of analytical data, image management tools, etc. and will learn to order their data
management processes and behaviors in a logical manner in order to capture, document and mine data
in an electronic environment. It is becoming increasingly important for chemists to be fluent with these
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
representations to optimally use software and online databases.
Timeline
Year 1:
During the first year, the main focus will be on finding collaborators from the online community.
Experiments will be performed manually until the automatic reactor has been installed and students
trained to operate it. Informatics tools to represent experimental workflows and reactions through their
various entity-state-increment-transition relationships will be developed. In a reaction workflow at any
point in time chemical entities are involved and are at a particular state (mixed, unmixed, heated, stirred)
for a particular time increment and then pass through a transition to another state (analytical data
acquired, new material added etc.). These relationships can be described in a logical sequence and
described in a manner allowing the data to be mined throughout a workflow sequence. Informatics tools
to describe, capture, manage and datamine will be developed.
Year 2:
The automated reactor will be implemented and made available for direct operation by the crowdsourcing
community under the oversight of the PI and co-PI. Enhanced workflow management tools to generate
workflow documents capable of driving the automation systems will be developed. Data will be generated
in a standard manner to allow data capture and management on the ChemSpider platform.
Year 3:
Projects suggested by the crowdsourcing community will be evaluated and resources will be allocated to
execute the experiments, under supervision of the PI and co-PI. As sub-projects get completed, work will
be submitted for traditional peer reviewed publication. Arguments in the papers will be supported by links
to the original experiments in the online open notebook wiki, giving unprecedented systematic access to
experimental raw data to be re-analyzed or re-purposed by anyone. Co-authorships will be based on
documented contributions from members in the community who sufficiently participated.
Desired Project Outcomes
1) From the larger perspective a key outcome is the establishment of a precedent and model to
demonstrate how crowdsourcing can be used to solve scientific problems. As the project evolves
progress will be reported on social software networks. This type of dissemination has proved effective to
identify collaborators in the online world for the UsefulChem project, primarily through the use of blogs.
Another key advantage is that reports of what appears to work or not work are generally followed quickly
with helpful discussions in the blogosphere, in addition to being helpful to others with related projects. The
demonstration that an automatic reactor can be effectively added to the scientific crowdsourcing toolkit is
also a key outcome.
2) At a more basic level, meeting the scientific objectives outlined in this proposal will benefit the scientific
community in a more direct way. The Ugi reaction is already used by many groups and further
understanding of how to prepare these products using a much simpler purification protocol can be quite
valuable in many areas. For example, several of the Ugi products from UsefulChem project have been
predicted to possibly act as anti-malarial and anti-tumor agents and testing is underway.
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008
References
1) Howe, J. The Rise of Crowdsourcing, Wired, June 2006.
(
http://www.wired.com/wired/archive/14.06/crowds.html
)
2)
http://www.innocentive.com
3)
http://www.innocentive.com/servlets/project/Pavilion.po?p=Rockefeller%20Foundation
4)
http://stardustathome.ssl.berkeley.edu
5)
http://www.galaxyzoo.org
6)
http://www.chemmunity.com
7)
http://www.thesynapticleap.org
8)
http://www.orglist.net
9)
http://www.chemistswithoutborders.org
10)
http://www.chemunpub.it
11)
http://drexel-coas-elearning.blogspot.com/2006/09/open-notebook-science.html
12)
http://usefulchem.wikispaces.com/All+Reactions
13)
http://usefulchem.blogspot.com
14)
http://usefulchem.blogspot.com/2007/12/first-falcipain-2-targets-shipped.html
15) Todd, M. Open Access and Open Source in Chemistry, Chemistry Central Journal 2007, 1:3.
(doi:10.1186/1752-153X-1-3)
16) Lancashire, R. The JSpecView Project: an Open Source Java viewer and converter for JCAMP-DX,
and XML spectral data files, Chemistry Central Journal 2007, 1:31. (doi:10.1186/1752-153X-1-31)
17)
http://www.chemspider.com
18)
http://www.chemspider.com/blog/the-chemspider-team-chooses-our-future-platform-for-collaboration-
microsoft-sharepoint.html
19)
http://www.chemspider.com/blog/wichempedia-is-now-on-its-way.html
20) Chemspeed, Augst, Switzerland
http://www.chemspeed.com/index.php
21)
Ugi, I.; Werner, B.; Dömling, A. (2003). "
The Chemistry of Isocyanides, their
MultiComponent Reactions and their Libraries
".
Molecules
8: 53-66.
22)
http://usefulchem.blogspot.com/2007/11/combiugi-update-master-table.html
23)
http://usefulchem.blogspot.com/2007/05/missing-methyl-mystery-mechanism.html
Nature Precedings : doi:10.1038/npre.2008.1505.1 : Posted 9 Jan 2008