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. September 2022 Latest Announcement

2. August 2022

3. April 2022.

4. March 2022. Expression of interest from Interfaces Focus.

5. January 2022. Contributions from Tom Rapoport and Dominique de Vienne.

6. December 2021. Digest of initial discussions

September 2022

• If you would like to publicise the BioSystems special issue to your colleagues or to relevent meetings you are attending, please use the attached flyer or slide.

August 2022

BioSystems has released the first announcement about the Special Issue 'MCA at 50: an update' on its website at https://www.sciencedirect.com/journal/biosystems/about/forthcoming-special-issues.

Submissions will open through Editorial Manager (BioSystems) in November with a deadline for first drafts in January 2023. It is important that submissions should choose article type VSI: MCA at 50: an update.

The Guest Editors for the Special Issue are David Fell, Johann Rohwer and Emma Saavedra. Could intending authors please notify us with an outline of their intended contribution before submission so that we can attempt to ensure we have got representative coverage of the field.

We will attempt to publicise the call for papers at relevant forthcoming conferences (e.g. ISGSB).

June 2022

• BioSystems has agreed to host the Special Issue on MCA next year. The provisional timetable is for a call for papers in September, and submission of final versions by mid January 2023.

• David Fell has submitted the proposal form to BioSystems for a Special Issue on MCA in 2023.

April 2022

Newest communications first.

• Athel Cornish-Bowden reported an initially favourable response from the Editor of BioSystems, with an invitation to submit a formal proposal.

• Edda Klipp: That is a very nice idea! Thanks for involving me. I am so happy to join that endeavor.

• Marta Cascante: I am glad to hear on the Update of the MCA 50th Anniversary and with the diferent idees! From my side just let you know that we still working in MCA and that we just published recently a paper in Plos Computational Biology fully based in MCA:<<BR>>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. PMID: 34297714; PMCID: PMC8336858
  We are working in related tòpics and glad to contribute with a new research paper based in MCA if w ego for a special issue. The suggestion of Herbert on Cell Systems is an excellent idea as first option. If they are not interested of course other options also interesting.
  

• David Fell: The Interfaces Focus format, even if we get approval, might not cover all the aspects that people wish to cover. I do not think it would need to be the sole route we pursue, as long as we ensure that there is distinct content in different publications. In that context, does anyone want to explore other possibilities? E.g. Jannie proposed BioSystems.

March 2022

Newest communications first.

• David Fell asks for your responses to the desirability of preparing a proposal to Interfaces Focus. Extracts of emails will be posted here.

• Senior Publishing Editor Tim Holt replied:
  
  Thank you for your email. As J R Soc Interface does not publish collections of papers Professor Cogdell agreed for me to run your proposal past Professor Russell Foster, editor of Interface Focus. I am happy to say that Professor Russell likes the idea of a themed issued on the topic of MCA. He would be particularly keen to see the proposed structure of the issue with paper titles (with brief summary if possible) and especially how the stage would be set in an introduction and a vision for the future in a concluding paper.
  
  I hope this idea appeals and would be grateful if you could let me know whether you wish to take it forward.

• Whilst waiting for Cell Systems, he enquired with Royal Society Interfaces and received an encoraging response.
• Herbert has not received any reply from Cell Systems.
• As Herbert Sauro had volunteered to contact Cell Systems, I invited him to go ahead. We prepared a brief summary of the case for having a set of publications to mark the anniversary.

  "We are approaching the 50th anniversary of the development of the field of Metabolic Control Analysis (MCA) and it would be an appropriate time to reflect on its continuing impact on the biological sciences. In 1973, two independent groups produced the papers that led to its rise: from Edinburgh, Kacser and Burns published “The Control of Flux” (Symp. Soc. Exp. Biol. 27, 65-104), whilst from Berlin, Heinrich and Rapoport published “Linear Theory of Enzymatic Chains” (Acta Biol. Med. Ger. 31, 479-94). The Heinrich and Rapoport work is, however, better known from the two papers in the European Journal of Biochemistry the following year (42, 89-95 and 97-105). Both groups quickly recognised the commonality of their approaches and eventually adopted a unified terminology under the title MCA. In essence they were applying sensitivity analysis to the factors, such as enzyme activity, that potentially influence metabolic variables such as fluxes and concentrations. They showed by mathematical arguments and experimental data that the then current biochemical dogma of control of a metabolic pathway by a rate-limiting step was too simplistic and that the criteria used to identify such steps were unreliable. Initially the uptake of MCA was slow, but increased markedly during the 1980s as early adopters developed new experimental techniques to quantify the sensitivities, including the use of emerging molecular biology techniques to manipulate enzyme activities. By the beginning of this year, Kacser & Burns (1973) had 1790 citations, and over the last 5 years has been accumulating over 20 citations per year. Heinrich and Rapoport (1974) have 1,170 citations to one or both papers and are still receiving citations at the rate of about 15 per year. The influence of these papers has extended far beyond metabolic biochemistry. Both initial groups used metabolic model building and dynamic simulation to complement and illustrate their mathematical and experimental arguments, and these tools also became more widely adopted with the growth of MCA. It is often argued that MCA was one of the fore-runners of Systems Biology, along with other developments from around that time such as Savageau’s Biochemical Systems Theory and Garfinkel’s development of metabolic simulation software. These approaches then spread into other areas such as signal transduction and the cell cycle. There was from the start, though, a strong coupling between MCA and genetics. Kacser was based in a genetics department, and his approach to MCA was built on theories of genotype-phenotype relationships. In fact, the link between MCA and genetics was explicitly made in the Kacser & Burns 1981 paper “The Molecular Basis of Dominance” (Genetics, 97, 639-66), itself a paper with 793 citations, still growing. It is for this reason that MCA has had applications in quantitative genetics and evolution as well as becoming part of the interpretative framework for complex genetic diseases such as the mitochondrial cytopathies. Other application areas include evaluating the efficacy of potential drug targets and targets for genetic modification in biotechnology. Hence the 50th anniversary of the start of MCA would be an appropriate occasion to promote the achievements of this approach and would be relevant to a range of fields within the molecular biosciences."

January 2022

Following up on suggestions received, I sent Tom Rapoport and Dominique de Vienne a resume of the proposal.

Tom Rapoport replied:

Second, thanks a lot for sending me the email exchange. Of course, I am happy to see that there is so much interest in celebrating the 50^th anniversary of MCA. Who would have thought that it will be remembered after so many years (although, as some people pointed out, it is unknown to many others).

As you know, my research is now in a very different field, so I cannot contribute anything on new aspects of MCA. However, if you think it would be of interest, I could write a personal reminiscence of our work on MCA. Some aspects are actually funny. Such as that the papers got rejected by Joe Higgins and were only accepted because the editor-in-chief, Claude Liebecq, noticed that Higgins (who was on the editorial board) had not accepted a single paper yet. Or, that the printers of Eur. J. Biochem. were in despair because of the many equations that were almost invisible by the time the paper was accepted, as we used an East German copying machine, where the letters faded away after a short time (but the reviewing process took 3 months). I would also add a homage to Reinhard and my dad, who were instrumental in developing MCA, and the shock, when we discovered that Kacser and Burns had developed more or less the same theory. Of course, it would be a short piece, and as Hans pointed out, young people don’t care about the history of science and might find it boring.

But, even without a contribution from my side, I hope you can arrange for a series of papers on MCA. Perhaps, it might be wise to broaden the scope and commission more generally papers on mathematical modeling of metabolism or even mathematical modeling of other systems? As several people pointed out, metabolism has experienced a renaissance, and systems biology was at least popular for several years (not sure whether it still is).

Dominique de Vienne replied:

Your proposal is excellent, and I'm all for it. As you point out, Kacser and Burn's work has had a strong impact in genetics (to give metabolic bases to dominance, epistasis, heterosis, pleiotropy, QTL distribution, etc.), but also in evolution (study of the distribution of allele effects under selection for optimal flux, dynamics of maintenance/loss metabolic genes after genome duplication, etc.). In my lab, we recently modelised the evolution of enzyme concentrations relying on MCA (preprint here : https://www.sciencedirect.com/science/article/pii/S0022519322000133?casa_token=w6Odte4LCMMAAAAA:oX3JY9aGKb_tKnR_bktH0lBsdw2j8GmuolWMp1bZw2llAZ5l8uGTE_mKPISNsTd7gyGTEXpXJLcq

To my knowledge, there is no synthesis in the literature of all that this theory has contributed to genetics, quantitative genetics and evolution. Your proposal would provide an excellent opportunity to fill this gap. In a word, I'm in !

Herbert Sauro commented:

I think Dominique makes a very good point as to what the successes really have been as a result of MCA. Such a paper would be useful for people to see. It's a harder one to write about as it would require some research but one could consider success both in the theory, the contribution to conceptual advances, and contributions to practical advances both for understanding real systems and engineering them. People like Frank Bruggeman and Bas would be good choices for showing how MCA helps explain the 'design' of glycolysis. I suppose one could also extend it to modeling in general, and in fact, Bas just published a review of the progression in modeling glycolysis but we'd have to make sure the modeling papers fit into the general theme.

For new results, I could talk to Peters St John who wrote that PLoS Comp Bio on using Bayesian analysis if he would be interested in writing something (we should have a couple of US authors if possible).

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:

Don't forget Cell Systems (I think you accidently mistook MSB for CS), but MSB is also a potential option. Impact fact 10.3, APC $8900 which is an insane amount. However:

Cell Systems is hybrid OA. This means that as an author, you can choose to be OA if you wish. If you don't choose to be OA, your paper will be available by subscription for one year, but after that year, it will be freely available to everyone.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.