CFM: a database of experimentally validated protocols for chemical compound-based direct reprogramming and transdifferentiation

Implementation

We collected protocols from PubMed and Google Scholar using the keywords ‘direct reprogramming’ AND ‘chemicals OR small molecules’, ‘transdifferentiation’ AND ‘chemicals OR small molecules’, ’direct cell conversion’ AND ‘chemicals OR small molecules’. In this way, more than 1000 papers were obtained. Experts prefiltered papers based on the content of key sections (abstract, introduction, method) discarding irrelevant papers. We manually extracted information from each relevant article and added data about small molecules implicated in protocol from PubChem as a part of postprocessing. The overview of the whole workflow can be seen in Figure 2.

The database can be queried at cfm.mipt.ru/query page (Figure 3). By default, all protocols are listed. If no protocols match a query, the whole database is displayed (default view). Search is case-independent. The first column contains a link to protocol description in the cfm.mipt.ru/viewProtocol/<protocolId> format, where protocol ID is an inner identifier. The protocol description page contains article information (DOI, article title, and authors), source and target cell lines , initial cell culture description, the species from which the source cell line was obtained, the total protocol duration, the media in which the protocol was implemented, protocol yield (with comments on how it was calculated), chemicals (with their methods of effect is known), transcription factors, stress factors and growth factors used during the procedure and some comments on the protocol in general. Also, we provide a simple interface for rating protocols for registered participants. After curation, the rating will be available on the protocol page. All rated protocols are shown in a personal user account (cfm.mipt.ru/login). A researcher can add a protocol (and a published related paper) to the CFM database by submitting it through cfm.mipt.ru/add after the email is verified by a CFM administrator. Detailed information about verification can be found on the Add Protocol page.

Figure 2. Data processing workflow diagram.

Figure 3. Database interface screenshot.

We strongly believe that the development and maintenance of such a database will encourage researchers to keep improving protocols for cell conversion. Among all cell conversions, reprogramming protocol still dominates over trans-differentiation Figure 1. As it is clear from the Figure 1B and C, fibroblasts are widely used as an initial cell type in various protocols, while other cell types are underrepresented. Although fibroblasts might be an easy cell type to obtain in the clinic, other initial cell types such as blood cells could be also of use. As can be seen in Figure 1D, there is a small group of chemicals effective in several protocols, suggesting that they target a general mechanism. Possibly other chemicals from the same functional class, such as epigenetic drugs, should also be tested for their cell conversion potential. Further research on the regarding relations between cell conversions and chemicals, media, transcription factors, etc. should lead to the development of a computational framework that will facilitate acceleration of the search for conditions conducive to new cell conversions which are highly applicable in medicine (for example,^6-8).

Operation

We perform all computations on the server side, so the user only needs to have a web browser to use our service. However, we recommend not to access the service from smartphones because our interface is not optimized for them.

Querying the database

In Figure 4, as well as on Figure 3, you can see examples of querying the database. New fields of search can be added using the green ADD button; unnecessary fields can be removed using the red DELETE button.

Figure 4. Query to the database.

Molecular similarity calculation

We calculate the similarity of molecules based on their SMILES. Retrieving Morgan fingerprints from them, we calculate the Tanimoto similarity and provide the result to the user. The interface can be seen in Figure 5.

Figure 5. SMILES similarity interface.