50th Anniversary of Metabolic Control Analysis

• In December 2021, I, David Fell (dfell at brookes.ac.uk), emailed a limited number of colleagues in the MCA field about whether action should be taken to ensure the 50th anniversary of its founding was marked in the scientific literature. As there was some support for this proposal, the discussion moved on to how this might be implemented and which publications might be approached to host appropriate articles. However, since it was always clear that involvement and authorship should be available to a wider group than initially consulted, there needs to be a means to inform others of the proposal and to distribute comments and contributions received. Email circulation was already proving to be rather unwieldy, a collected set of emails was not a very useful means of introducing the topic to new people, and I didn't want to get into email list management. Hence I have created this page as a sort of bulletin board to record the current state. I will periodically update it with relevant material that people email to me. The most recent contributions will be at the top, with the older material below.

Contents:

1. March 2022
2. January 2022

3. December 2021. Digest of initial discussions.

December 2021

The following emails are in chronological order.

David Fell <dfell at brookes.ac.uk> wrote: It has been in my mind for a while that in 1 year 1 month it will be the 50th anniversary year of the publication of the Control of Flux, and in 2 years 1 month the same for the Heinrich & Rapoport publications. I am writing to you as a set of the people involved in the rise of MCA in the 1980s to enquire whether you agree it would be appropriate to try to mark the occasion by arranging for a number of publications on MCA to appear in 2023. Of course, you might already have thought of this and have your own plans, in which case I wouldn't want to cut across them. However, if my idea interests you, we would need to start some planning and coordination soon in order to ensure publication in 2023. I can think of some possible courses of action:

1. The least likely is that we arrange for a number of original research articles to appear as close together as possible at the appropriate time. However, that would assume sufficient of us had active MCA research at the moment that will reach a publishable state in 2022. Also I assume that those of us who have such projects would probably want the freedom to choose the most appropriate journal. Finally, the reviewing process would probably cause a dispersion of the publication dates.
2. It might be possible to get agreement for publication of a set of linked reviews of the application of MCA in different areas. For example, Biochemical Society Transactions does do this and has a broad scope in the molecular life sciences, though they do prefer currently active fields. Also, although the nature of BST has changed since, it did publish the proceedings of the 21st anniversary meeting. I'm currently on the Editorial Board of BST, and though my term finishes at the end of this year, I could approach them about it. BST does not now publish original research, so it would not be possible to accompany the reviews with articles on new work.
3. The Biochemical Journal and FEBS Journal (as EJB) publish reviews, and did publish quite a fraction of the MCA articles published in the 1980s-90s so might be amenable to approaches to the Reviews editors. This would also allow for the possibility of novel MCA work being submitted as research articles in the same journal.
4. Explore the possibility of an MCA 'Special Issue' in one of the on-line journals that do this (Frontiers / PLOS etc), though the individual journals mostly tend to have narrow subject scopes, which might make this difficult.

Please let me know what you think of this idea, and also whether you have any other suggestions of how we might go about it. To keep things manageable whilst gauging initial interest, I've not attempted to create an all-inclusive mailing list at this stage, though if you think I've made unforgivable omissions, please say so.

Mark Stitt wrote: This is a really nice idea I think you have outlined possible routes – and the issues with each If i might add one thing. At least in my field, I am aware of young scientists – often modelers – who are incorporating the broad concept of sensitivity analysis and control coefficients into their work (e.g. people working with Xinguang Zhu, Steve Long): One way to emphasize the importance of the concepts of Kacser and Burns / Heinrich & Rapoport might be to trace how the basic ideas have entered a lot of mainstream science

Kell, Douglas wrote: Great idea. Def best to support via the likes of Biochem Soc. I did just do a review for them on host engineering, that mentioned MCA https://portlandpress.com/biochemj/article/478/20/3685/229971/Intelligent-host-engineering-for-metabolic-flux. It was evidently news to at least one of the reviewers....

I also recently rehearsed MCA when doing a viva in (virtual) Sweden, where it was also evidently news to some of the rest of the Committee... I'm not do anything experimentally on MCA, however, and as I am mainly working in my start-up I may not have much to say. If that is the same for others maybe a better strategy would be an up-to-date review of MCA with multiple authors, which will make more of the modern folk aware (even if Xinguang Zhu & Steve Long plus those in this mail are, I don't think most folk even know of it...)? (Hans will remember the 'Common Market' review that a few of us did in <ahem> 1985 - I've updated that space too... https://www.sciencedirect.com/science/article/pii/S0065291121000011?dgcid=author with preprint at http://osf.io/2xsz8). I can certainly see areas in which MCA could be seen to have 'entered' mainstream science (if sysbio is even mainstream...), and a snappy intro plus tracing of the development would potentially make a valuable work. I'd be happy to be involved. At least modern e-publishing means that sane journals (incl BJ) don't care about length.

And the of course very first H&R was also 1973 (Heinrich R, Rapoport TA: Linear theory of enzymatic chains: its application for the analysis of the crossover theorem and of the glycolysis of human erythrocytes. Acta Biologica et Medica Germanica 1973; 31:479-494), so I think we could aim for the year rather than the week...

Poss Pedro is someone to include, since Copasi does MCA.

Herbert M Sauro wrote:

I think this is a great idea. I would recommend a special issue otherwise the impact will be diluted if spread out. Possible journals, some already mentioned, include

1. PLOS Comp Bio - I don't think it would be difficult to persuade them to have a special issue
2. Cell Systems - this one would be a great catch and I have some contacts there.
3. MSB - less likely but might be worth a try
4. Current Option series - they do special issues, not sure if novel work can be published however

I also recommend a journal that is widely read in the US, Europe, and the rest of the world, and I think the list just mentioned satisfy that requirement. As much as I love journals like BJ, FEBS, and EJB, my experience is they don't seem to have a high profile in the US. In the last year or two, I've noticed some growing interest in MCA in the US especially among the metabolic modelers.

David Fell:

Thank you for the support for my proposal, and for the various issues that you have raised. I have noted the various suggestions for potential contributors in different fields. I should explain that I did not intend the original email list to cover all potential authors; I was expecting that, if we formulated a specific plan, we would then invite appropriate contributors, at which stage the younger generation of MCA researchers could be invited. However, the first step is the need to find a suitable host publication. Here Herbert and Douglas raised two significant points: whether the European journals I originally mentioned had sufficient impact to raise awareness in the USA, and whether APCs/Open Access charges would be burdensome. I've collected some basic information around these issues for some of the publications mentioned.

1. Molecular Systems Biology. Impact factor 11.4. APC $5000 for articles, reviews free. Reviews 5000 words, <~100 references.

2. Biosystems. Impact factor 1.97. Gold APC: $2210 / Subscription model: free. Review articles on an irregular basis. Reviews editor: Hidde de Jong. Has article collections and special issues from conferences.
3. Biochemical Journal. Impact 3.86. Article Gold OA $3500, waived for 'Read and Publish' institutions. Green OA is free. Reviews 6K-8K words. Complete a pre-submission enquiry form if not invited. There is a reviews editor but couldn't immediately find out who.

4. FEBS Journal. Impact 5.54. OA APC $3800, but subscription access articles free. Has mini-reviews in a series governed by a coordinator; 3K-5K words, <~75 references. State-of-the-art reviews are longer. Review proposals to Editor-in-Chief with 250 word summary and article structure.

5. Plos Computational Biology. Doesn't promote its impact factor on principle, but reported to be about 4.5. Research article APC $2575, reduced for authors from subscribed institutions. Reviews are 3K-6K words, with advance submission of a summary to an editor. Also has historical reviews and teaching tutorials for important concepts. Also has article collections, with a concise collection overview article by the coordinator. Apply to Plos Collections team with a proposal.

We need to ascertain which of these might entertain an MCA issue or collection. Perhaps if Herbert approached Molecular Systems, Jannie Biosystems, and I submitted the form to Biochem J, we might aim to consider the responses in the New Year. If anyone has contacts with someone associated with 4 or 5, perhaps they could make an initial enquiry, otherwise I'll do it in the New Year.

Jean-Pierre Mazat:

Great idea ! May I add some names of people working or using the MCA? Bert Groen (JBC 1982) who gave the second enlightening application of MCA with Hans et others, Raphael Moreno-Sanchez who pursues original drug research based on MCA (Journal of Biomedicine and Biotechnology 2008, Article ID 597913, doi:10.1155/2008/597913 and Current Medicinal Chemistry 2019, 26:6652) and probably many others. These are the first names that come to mind.

Marta Cascante Serratosa:

I think is a wonderful idea what you guys propose and I agree with Herbert that a special issue will be perhaps de perfect format to combine a review and original papers. Also I agree with Herbert that if Cell Systems agree will be fantàstic as will be a great catch contributing to advertise the interest of MCA and the areas of application. Combination of one or two reviews and original work papers will be perfect. If Cell Systems, that I think could be the first option to approach not accept, a second option perhaps could be Plos Comp. Biol. One of the membres of the editorial board was Vassily Hatzimanikatis, (I think he still there). We published this year a paper on combinin MCA with linera programming to key molecular drivers of the metabolic response and Plos Comp. Biol. Assignes to our paper Vasily as editor and we receive very detailed and constructive review that has permit us to improve the manuscript that has been finall published (de Atauri P, Tarrado-Castellarnau M, Tarragó-Celada J, Foguet C, Karakitsou E, Centelles JJ, Cascante M. Integrating systemic and molecular levels to infer key drivers sustaining metabolic adaptations. PLoS Comput Biol. 2021 Jul 23;17(7):e1009234. doi: 10.1371/journal.pcbi.1009234.). I comment to show that also could be a second option to try. Many of you are more expert than me on which journals could be more convenient to approach. Just to say again that I think is a w onderful idea and glad to hepl in what you consider appropriate.

Jan-Hendrik Hofmeyr:

Excellent idea! I would like to add the Elsevier journal BioSystems as a possible candidate. They have done a number of special issues over the last years - I have been involved in the three Special Issues on Code Biology. I am on the editorial advisory board, as is Athel, and could propose a special issue to the editor Andrei Igamberdiev, which I am pretty sure he will be enthusiastic about.

Herbert M Sauro:

I favor cell systems as the first choice followed by PLoS comp bio simply due to their wide readership. The big issue with cell systems (especially) and plos comp bio is the open-access cost which is not trivial. But we should think of this as a one-off special publication where we want to advertise MCA to the wider world and so the cost might be worth it, especially if it's a 50-year anniversary issue. But if the costs are too high for some we'll have to go elsewhere. At my University I generally have to pay the full cost via my grants, others might have better support from their university although my department has told me that they would contribute if funds are short.

Westerhoff, H.V. wrote:

Yes I remember the Common Market review. I definitely think that MCA needs to become known and used more widely and it is this issue rather than the 50 years ago one that I find most important: I am deeply concerned that so little use of it is made. And I am concerned that mentioning the '50 years ago' feature might put many of my junior colleagues off. Would they read '100 years ago Michaelis-Menten'? (too late for that now). So, I would suggest for us to write something in which we consider how MCA (and new versions thereof) should help now in areas where it is not applied yet. Yes, we would mention that Henrik, Jim, Reinhart and Sam and Tom (and perhaps even Joe) started it all 50 years ago, but not emphasize it.

One of the problems with MCA has been the 'M', as it had its major growth in an era where metabolism was considered obsolete. Even though Metabolism has resurfaced, I still think we should emphasize that M=(M)CA is not at all limited to metabolism. Of course it has been applied by David, Boris and myself to single transduction and gene expression, but not yet (much) to single cell transcriptomes, dynamic cell structures, COVID-19, microbiome, spatial distributions, PKPD, Parkinson's, etc.

By the way, Tom Rapoport could still be part of the team, perhaps.

Jean-Pierre Mazat:

I won't be so negative about the MCA and the commemorations of the past. After all, our vision for the future is rooted in the past. I agree that it should be valuable to have new developments and new applications of MCA, but it is not incompatible with the reminder of the work of the pioneers. I agree also that Tom Rapoport should be part of the team. A remark : as you probably know, the Michaelis-Menten equation is due to Victor Henri a Russian psychologist (I simplify a little) as you will read in the paper attached : “Victor Henri: 111 years of his equation”.

Maria Luz Cardenas:

Many thanks David for the message and for the ideas expressed. For the moment I think more or less along the lines of what Hans has expressed. It would be Super if MCA starts to be applied to emergent fields as microbial consortia for example. In that context, metabolism is recovering importance. But to just make a commemoration I don’t think that it would have major repercussion. The Michaelis-Menten centenary was a little different because almost everybody new about the famous equation; that is not the case of MCA. So its going to appear just old.

Athel Cornish-Bowden:

I've discussed this with Marilú, and it turns out that our points of view are more different than I expected. I am enthusiastic about the idea, whereas she is thinking more along the lines of what Hans has said, as she has just written to you. I think some people are interested in the origins of ideas. The paper that Ute Deichmann, Stefan, Jean-Pierre and I published in 2014 [Commemorating the 1913 Michaelis–Menten paper Die Kinetik der Invertinwirkung: three perspectives, FEBS J. 281, 435–463] has now been cited 34 times -- not a huge number, to be sure, but not negligible, either.

The paper on Victor Henri that Jean-Pierre, Serge Nicolas and I had in the same year [Victor Henri: 111 years of his equation, Biochimie 107, 161–166] has the more modest total of 8. My paper on the discovery of feedback inhibition [Zacharias Dische and the discovery of feedback inhibition: A landmark paper published in the forerunner of Biochimie. 2021, Biochimie 182: 120–130. doi:10.1016/j.biochi.2020.11.013] has just one (by us!). Marilú's paper of 2013 [Michaelis and Menten and the long road to the discovery of cooperativity, FEBS Lett 587, 2767–2771] has 20: I think it's an important paper that deserves more than that.

If this goes ahead you should certainly invite Dominique de Vienne to participate, as he is one of the only people actively trying to advance control analysis at this moment. Marilú is an examiner for one of his PhD students the day after tomorrow. I feel it would be overkill to have separate collections for Kacser & Burns and Heinrich & Rapoport. Better cover both together, especially as everyone agrees that they were independent. As for journals, I agree with Jannie that BioSystems would be a good choice. Both of us have good relations with the Editor-in-Chief. I think Stefan is also on the Editorial Board. In the past I would have suggested the Journal of Theoretical Biology, but the world has moved on and I've pretty much broken loose.

Herbert M Sauro:

As for a journal I would still recommend trying to get published in a high profile journal. People tend to have alerts set up for the major journals (instead of going to a physical library as we used to), and if we got published in a major journal it would end up in their mailbox. I can see where Hans is coming from, and he makes some good points. Maybe instead of a 50 year anniversary, it could be positioned as a special issue on the state and latest research on the quantitative control and regulation of metabolism. Makes it sound more alive. Another suggestion is that collectively we could produce an online course to raise awareness.