Decades ago, unbeknownst to each other, two chemists were independently working on a screening approach to identify new potential drugs. Both published papers about the technique around the same time. So now, when scientists write papers that cite the technique, who should get credit for discovering it?
Decades later, that question still hasn’t been answered — and the researchers continue to argue, this time over one’s decision not to cite the other’s work.
More than 30 years ago, Árpád Furka—now retired from Eötvös Loránd University in Budapest—developed an approach he says has had “outstanding importance” in drug development. The technique, called split-mix synthesis, made it possible to synthesize and screen millions of peptides at once, instead of one by one. Furka patented the method in 1982, presented an abstract in 1988, and published a paper in 1991.
But Kit Lam—chair of the Department of Biochemistry and Molecular Medicine at the University of California Davis Cancer Center in Sacramento—told us that, unaware of Furka’s discovery, he “independently came up with the idea” for split-mix synthesis in 1989 and published a 1991 letter in Nature , shortly before Furka’s paper appeared, describing the technique. From there, Lam developed the “one-bead one-compound” (OBOC) approach, which allowed researchers to create libraries of small molecules, not just peptides.
Now, decades later, the two researchers are still arguing over who should get credit for the technique. Furka claims Lam took credit for his discovery and has repeatedly failed to cite his work and contribution to the field. Lam told Retraction Watch that he does not dispute that Furka was the first to report the split-mix technique, but claims he took the concept an important step beyond what Furka had reported.
Furka, however, contends that split-mix synthesis and OBOC are essentially the same:
It is the intrinsic feature of the split-mix method that produces OBOC compound libraries.
This debate is described in Brent Stockwell’s 2013 book, “The Quest for the Cure,” which explores the history of drug development. In the book, Stockwell—a professor of Biological Sciences and Chemistry at Columbia University in New York City—notes the “bitter feelings between Lam and Furka” and concludes:
Ultimately, it is fair to say that both Lam and Furka were instrumental in bringing this powerful new technology to the world of synthesis and drug discovery.
Last year, Lam published two reviews that describe the split-mix method but do not cite Furka’s work. Furka wrote to both two journals to complain about the omission.
The journals had different approaches to resolving the complaint. Current Opinion in Chemical Biology allowed Lam to rebut Furka’s letter regarding “Combinatorial chemistry in drug discovery.” Advanced Drug Delivery Review published a corrigendum to Lam’s review, “Tumor-targeting peptides from combinatorial libraries,” which now includes a reference to Furka’s 1991 paper on the history of split-mix strategies.
Ben Davis, the editor-in-chief of Current Opinion in Chemical Biology, explained that the decision to publish the letters to the editor “hinged on fact that Current Opinion is an opinion journal:”
I believe science should be as transparent as possible, and by publishing the letters, we hoped to minimize any filtering of the authors’ views and allow readers to make their own judgment.
(We asked Hamid Ghandehari, the editor-in-chief of Advanced Drug Delivery Reviews, why the journal decided to publish a correction in this case, but did not hear back.)
This is not the first time Lam has published an erratum for failing to cite Furka’s work. Lam corrected his 1991 letter in Nature for “inadvertently” omitting a citation to Furka’s 1988 abstract that “independently described a similar synthetic method.”
Given that Lam could likely predict how Furka would react if his work wasn’t cited, we asked Lam why he didn’t consistently cite Furka’s work:
I did cite Furka’s paper in a lot of my early papers. It has been over 25 years, OBOC is now a standard procedure and I have published over 100 papers on the subjects. Our original Nature article has had over 1000 citations. I do not see the need for citing Furka’s paper on every OBOC paper, unless the focus is on synthetic methods and on history of combinatorial chemistry. This is particularly true when there is a limit in number of citations one may use. That was indeed the case for our mini-review article in Current Opinion in Drug Discovery.”
He added:
I have not heard [from Furka] for years until recently, relating to his complaint about my two articles.
We asked Furka why, after 30 years, he continues to pursue this issue:
Imagine that the best article of your life is advertised by another person … I wish [to] restore my reputation as the inventor of the first published combinatorial synthesis.
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“Our paper appeared 16 months after submitting the manuscript. During this period,patent applications were submitted by four different groups all based on our splitmix method: HUEBNER and SANTI (Chiron group) [7] on May 15, 1990, LAM et al.(Salmon-Hruby group) [8] on July 2, 1990, HOUGHTEN et al. (Richard Houghten’s
group) [9] on November 21, 1990 and DIMARCHI et al. (Eli Lilly group) [10] on June 18, 1991. It was particularly painful that Professor Hruby, the Editor-in-Chief of the journal where our manuscript was submitted, participated in patenting and his group also submitted a paper to Nature [11] and presented a lecture to the 12th American Peptide Symposium [12], claiming in both papers that they invented the split-mix method. Shortly after the appearance of our paper, Dr. Richard Houghten and his group (Torrey Pines Institute for Molecular Studies, San Diego) made also
a presentation at the Symposium on the Innovation & Perspectives in Solid Phase Synthesis and Related Technologies [13] and submitted a paper to Nature [14] in which our split-mix synthesis was described. I would also like to call your attention to a remarkable coincidence. The number of the filed patents was exactly the same as the number of those that had had access to our manuscript: the editor of the journal and three reviewers. Do you think that such a radically new idea like that of the split-mix synthesis may suddenly and independently occur in four different
heads not earlier and not later but exactly at the same time when our manuscript is being reviewed for publication, and one of those heads is that of the chief editor of the journal (or of one of his associates) to which our manuscript had been submitted?”
Really difficult to figure out who was first…
https://pp.bme.hu/ch/article/view/247/141
“Really difficult to figure out who was first…”, why?
Not really that difficult, just look at the timelines along with the circumstantial and contextual environment, a classical convergence of opportunity and motivation.
Árpád FURKA, in “THE CONCEALED SIDE OF THE HISTORY OF COMBINATORIAL CHEMISTRY” posted at https://pp.bme.hu/ch/article/view/247/141 spells out in detail, and with documentary evidence, the origins and evolution of his thoughts on the subject. These spanned the time frame from 1980 to 1991. During this time he did not have money and could not find sponsors to patent his process. He did, however, declare it in a notarized letter (June 15th, 1982) and made two International Presentations in 1988: [1] The 14th International Congress of Biochemistry, Prague {Cornucopia of Peptides by Synthesis, Abstr. 14th Int. Congr. Biochem., Prague, Czechoslovakia, 1988, Vol. 5., p. 47.} and [2] The 10th International Symposium of Medicinal Chemistry, Budapest {More Peptides by Less Labour, Abstr. 10th Int. Symp. Med. Chem., Budapest, Hungary, 1988, p. 288}. One would think that the Archival evidence of these still exists.
According to Furka, a full manuscript, entitled ‘General method for rapid synthesis of multi-component peptide mixtures’ was sent to Professor Hruby, University of Arizona, Tucson, and was received on February 12, 1990. Dr. Hruby was then Editor-in-Chief of the International Journal of Peptide and Protein Research. It took 16 months from submitting the manuscript to its publication in “International Journal of Peptide and Protein Research” – Vol. 37: Issue 6; June 1991, Pages 487–493.
During these 16 months Furka’s paper would be in the custody of Prof. Hruby, Kit Lam was at this time a researcher in Prof.Hurby’s lab, proximity and accessibility to the manuscript is mute. It would be released subsequently to three other reviewers in the ‘peer review process’, so now four groups have direct access to the manuscript. In this same time period the exact four (4) groups applied for patents covering the same method.
HUEBNER and SANTI (Chiron group) on May 15, 1990,
HUEBNER, V. D. – SANTI, D. V., Controlled Synthesis of Peptide Mixtures Using Mixed, Resins. US Patent 5,182,366 (Filed May 15, 1990).
LAM et al.(Salmon-Hruby group) on July 2, 1990
LAM, K. S. – SALMON, S. E. – HRUBY, V. J. – HERSCH, E.M. – AL-OBEIDI, F., Random Bio-Oligomer Library, a Method of Synthesis Thereof, and a Method of Use Thereof, PCT patent application, WO 92/00091 (Filed July 2, 1990)
HOUGHTEN et al. (Richard Houghten’s group) on November 21, 1990
HOUGHTEN, R. A. – CUERVO, J. H. – PINILLA, C. – APPEL, JR. J. R. – BLONDELLE, S., Synthesis of Equimolecular Multiple Oligomer Mixtures, Especially of Oligopeptide Mixtures, PCT Patent Application, WO 92/09300 (Filed November 21, 1990).
DIMARCHI et al. (Eli Lilly group) on June 18, 1991
DIMARCHI, R. D. – GESSELSCHEN, P. D. – OWENS, R. A., Rapid Synthesis and Screening of Peptide Mimetics, Patent application, filed June 18, 1991
Lam now claims ownership of the combinatorial process, renaming it The One Bead One Compound [OBOC] method.
His arguments for his claim is that “unaware of Furka’s discovery, he “independently came up with the idea” for the split-mix synthesis in 1989 and published a 1991 letter in Nature , shortly before Furka’s paper appeared, describing the technique.” Not knowing the precise months and in what is at best 1 yr +, 1990 must have been a remarkably hectic year – an epiphany, formulating a hypothesis, designing experiments for testing, executing experiments, identification of resulting peptides, verification, publishing letter to Nature to validate claims, filing patent and creating a corporation to execute and commercialize the idea all effectively in essentially one year.
Yes, creating a corporation, not to be stopped here, the Lam group goes on to capitalize on their new found fortune.
They, including Hruby, formed The Selectide Corporation, a Delaware Registered Corporation based in Arizona, in June 20, 1991. Then in 1995 Jennifer Boice on Jan 04, 1995, writing under ‘Business in The Tucson Citizen’ reported that “Marion Merrell Dow Inc. today announced it has bought Oro Valley-based Selectide Corp. for between $55 million and $60 million.”
From the foregoing, it should be clear who ‘The Father of Combinatorial Chemistry’ really is.
Does the University of California or its School of Medicine at Davis find this acceptable? Appalling to say the least!
Pseudomonas toyotomiensis
Let the documents speak
It seems worthwhile to consider the statements of Furka and Lam in the light of the available original documents. According to the author of the „Chemists duke it out over who was first to discover a 30-year-old technique” Furka states: “the technique, called split-mix synthesis, made it possible to synthesize and screen millions of peptides at once, instead of one by one. Furka patented the method in 1982, presented an abstract in 1988, and published a paper in 1991”.
1. In fact the invention was not patented but described it in a notarized document. The copy of the original Hungarian document and its English version is available at:
https://mersz.hu/mod/object.php?objazonosito=matud202006_f42772_i4
2. In 1988 two posters were published at two international conferences:
http://szerves.chem.elte.hu/furka/CornuEndAbs.html
and
http://szerves.chem.elte.hu/furka/LessLaborAndAbs.html
The content of the above documents entirely support the statement of Furka.
Lam states: “he was unaware of Furka’s discovery, he “independently came up with the idea” for split-mix synthesis in 1989 and published a 1991 letter in Nature”
This statement could be proved by a reliable document dated before 12 February 1990, the date of sending the manuscript of Furka to Professor Hruby, but no such document is known. There are however, documents that contradict Lam’s statement:
1. In a correction (Nature 1992, 358; 434) published to their original Nature paper of Lam et al. (Nature 1991, 354, 82) Lam writes:
„In this paper we inadvertently omitted to cite the work of Fukura and colleagues (A. Fukura, F. Sebestyen, M. Asgedom and G, Dibo 14th Int. Congr. Biochem. FR3,1988)”.
This proves that Lam has already known the 1988 publication of Furka et al. but not cited it. In his correction published in Nature he misspelled the name of Furka. One may ask: is it normal to reinvent a new chemical method 3 years after its original publication and not citing the original publication stating that he was unaware of it?
2. In the Corrigendum to ‘Tumor-targeting peptides from combinatorial libraries’[Adv Drug Deliv Rev.110–111 (2017) 13–37] Lam himself admits: the
„split-mix strategy [Furka et al.] are commonly used for the synthesis of OBOC peptide libraries …. Á. Furka, F. Sebestyén, M. Asgedom, G. Dibó, General method for rapid synthesis of multicomponent peptide mixtures, Int. J. Pept. ProteinRes. 37 (1991) 487–493.
The documents cited above clearly prove that Lam is not the inventor of split-mix synthesis of OBOC libraries.
Lam seems to be only a self-appointed inventor in combinatorial chemistry. It is a question what actions will be taken by the University of California Davis?