The Re­mark­able Ju­lian Davies

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by Roberto

If I were asked to name sci­en­tists who have deeply in­flu­enced the evo­lu­tion of my own think­ing along the decades, there's lit­tle doubt that Ju­lian Davies would be at the top of the list. Ju­lian died this past Feb­ru­ary 2nd, shortly af­ter turn­ing 93. My in­ten­tion here is not to write an obit­u­ary; his col­leagues from Uni­ver­sity of British Co­lum­bia memo­ri­al­ized him nicely in the ASM's web­site. Rather, I'll share a few per­sonal mem­o­ries of my in­ter­ac­tions over many decades with this re­mark­able man.

Ju­lian Davies. Source

Our first en­counter, if mem­ory serves me right, was at the 1978 Cold Spring Har­bor Sym­posium. It was an im­por­tant gath­er­ing to cel­e­brate the 25th an­niver­sary of the dis­cov­ery of the dou­ble he­lix. It was also one of my first sci­en­tific meet­ings. Feel­ing very awk­ward amongst all the mol­e­c­u­lar bi­ol­ogy celebri­ties present, it was a won­der­ful re­lief to have the fa­mous Ju­lian Davies come by and show in­ter­est in my work. That be­gan a friend­ship that lasted for decades. Dur­ing the 1980s and 1990s our paths crossed many times, of­ten at sci­en­tific meet­ings. Then, start­ing in 1998 and for more than two decades, we met (al­most) yearly at the Spet­ses and Dubrovnik Sum­mer Schools. We be­came good friends. With­out fail, in his pre­sen­ta­tions and our dis­cus­sions it was very clear that he was an "out of the box" thinker. This was also clear in many of his pub­li­ca­tions. I'll fol­low with a few ex­am­ples. (And by the way, I'm con­fi­dent you will en­joy read­ing Julian's STC posts on small mol­e­cules and at­tend­ing con­fer­ences.)

I for­get what Gor­don Con­fer­ence it was, but dur­ing his pre­sen­ta­tion on the pos­si­ble ori­gins of an­tibi­otic re­sis­tance genes he noted that some an­tibi­otic prepa­ra­tions con­tained trace amounts of the DNA of the pro­duc­ing or­gan­ism. Of course, those mi­crobes would have genes that ren­dered them im­mune to the ac­tion of the an­tibi­otic. What bet­ter set­ting to trans­fer those genes to other bac­te­ria than within a pa­tient un­der­go­ing treat­ment with that drug? I don't know whether such a tran­fer has ever been demon­strated but I do know that hear­ing of the idea forced me to think deeply about the ori­gins of an­tibi­otic re­sis­tance.

In 1990 Ju­lian wrote a provoca­tive es­say en­ti­tled: "What are an­tibi­otics? Ar­chaic func­tions for mod­ern ac­tiv­i­ties." In it he put forth the idea that "from the be­gin­nings of bio­chem­i­cal evo­lu­tion struc­tures of the an­tibi­otic type were formed by chem­i­cal con­den­sa­tions in the ab­sence of en­zymes. These mol­e­cules played roles in prim­i­tive re­ac­tions as... ac­tual cat­a­lysts (non-pep­tide fore­run­ners of en­zymes) in a va­ri­ety of con­den­sa­tion re­ac­tions such as trans­la­tion, tran­scrip­tion, etc."  Once again, his ideas forced me to think deeply. Is it pos­si­ble that at one time an­tibi­otics were the func­tional pre­cur­sors of, for ex­am­ple, ri­bo­so­mal pro­teins? The fact that sev­eral mod­ern-day an­tibi­otics bind to con­served re­gions of ri­bo­so­mal RNA sup­ports this idea.

I found most thought-pro­vok­ing Julian's stud­ies on the ef­fects of an­tibi­otics at subin­hibitory con­cen­tra­tions. In his 2006 re­view on the sub­ject, he states: "all an­tibi­otics, re­gard­less of their re­cep­tors and mode of ac­tion, ex­hibit the phe­nom­e­non of horme­sis and pro­voke con­sid­er­able tran­scrip­tion ac­ti­va­tion at low con­cen­tra­tions."  This, cou­pled with the fact that in many nat­ural set­tings an­tibi­otics are made in very small amounts, leads to the in­escapable con­clu­sion that these mol­e­cules are not used ex­clu­sively as killing agents in mi­cro­bi­o­log­i­cal war­fare. Rather, they might of­ten serve as cues (and even as sig­nals) that trig­ger global phys­i­o­log­i­cal changes, but do not cause death, in the re­cip­i­ent cells. Such a view still goes con­trary to the think­ing of many chem­i­cal and evo­lu­tion­ary bi­ol­o­gists. But it is a view that I have ex­plored and dis­cussed re­peat­edly in my own writ­ings.

In re­cent years Ju­lian turned his at­ten­tion to the search for al­ter­na­tive strate­gies that might help al­le­vi­ate the an­tibi­otic re­sis­tance cri­sis. Specif­i­cally, he in­ves­ti­gated the an­cient med­i­c­i­nal ap­pli­ca­tions of nat­ural clay min­er­als. In a se­ries of fas­ci­nat­ing stud­ies, which I fol­lowed with alacrity, he re­ported on the po­tent an­tibac­te­r­ial ac­tiv­ity and mi­cro­bial di­ver­sity of Kisameet Clay, a med­i­c­i­nal clay used by in­dige­nous peo­ple of British Co­lum­bia for many gen­er­a­tions. The con­cept emerges that the si­mul­ta­ne­ous ap­pli­ca­tion of many dif­fer­ent an­timi­cro­bials each one at very low con­cen­tra­tions might, in the long run, be more ef­fec­tive and less prone to the prob­lems of re­sis­tance. I strongly be­lieve in this con­cept. But when I've dis­cussed this idea with col­leagues steeped in the process of drug de­vel­op­ment, they see no clear path for such ap­proaches to pass the cur­rent reg­u­la­tory hur­dles. So, while in na­ture this may be the way that an­timi­cro­bials func­tion best, the con­cept – like a lot of Julian's think­ing – may be way ahead of its time.

With­out a doubt, the piece of Julian's writ­ing that most deeply af­fected me was his "Every­thing De­pends on Every­thing Else" es­say from 2009, in­spired by the credo of the Haida peo­ple. As I have elab­o­rated on else­where, this es­say is Julian's philo­soph­i­cal treat­ment of the in­ter­con­nect­ed­ness of every­thing which, in his opin­ion, in the mi­cro­bial world is largely me­di­ated through small mol­e­cules. Read­ing this es­say helped me so­lid­ify my own thoughts on uni­ver­sal in­ter­con­nect­ed­ness evolv­ing from the age-old tenet of Bud­dhist phi­los­o­phy: This is be­cause that is...

As I close my eyes be­fore writ­ing these last few lines what I see is not only Ju­lian the in­spir­ing sci­en­tist. I see him en­thu­si­as­ti­cally rid­ing a bi­cy­cle up and down steep hills as we cir­cle the is­land of Spet­ses. He is smil­ing, he em­anates good cheer, and he is still there.

 

Com­ments Ar­riv­ing

From Fer­nando Ba­quero: In the field of mi­cro­bi­o­log­i­cal sci­ences, my dear friend Ju­lian Davies was a cat­a­lyst for re­search that opened new av­enues of knowl­edge. For some mys­te­ri­ous rea­son, cer­tain mi­cro­bi­ol­o­gists be­come fas­ci­nated by in­tra­cel­lu­lar pathogens, and I'm sure Ju­lian was one of them, at least dur­ing a sig­nif­i­cant pe­riod of his fruit­ful life. His fo­cal point was My­cobac­terium, which was closely re­lated to his old fam­ily, Strep­to­myces. Dur­ing his sec­ond stay at the Pas­teur In­sti­tute in 1985, while work­ing in the biotech­nol­ogy de­part­ment, he in­flu­enced the My­cobac­terium re­search con­ducted by Brigitte Gic­quel and the Span­ish mi­cro­bi­ol­o­gist Rafael Gómez-Lus. By the way, the dis­ci­ple and fol­lower of Gómez-Lus at the Uni­ver­sity of Zaragoza, Car­los Mar­tin, is now in the fi­nal phase of hu­man test­ing for the promis­ing new vac­cine MTBVAC. At the Pas­teur In­sti­tute, he also deeply in­flu­enced Pas­cale Cos­sart, who was seek­ing a field of re­search in non-tu­ber­cu­lous in­tra­cel­lu­lar pathogens. Ul­ti­mately, she chose Lis­te­ria mono­cy­to­genes as a model or­gan­ism and de­vel­oped a splen­did sci­en­tific ca­reer, con­tribut­ing sig­nif­i­cantly to our un­der­stand­ing of in­tra­cel­lu­lar pathogen bi­ol­ogy. In sum­mary, every­thing that a unique sci­en­tist like Ju­lian is able to pro­duce has cas­cad­ing con­se­quences in the global net­work of sci­ence. As he stated in the ti­tle of a Re­view pub­lished in 2009, "every­thing de­pends on every­thing else."

 

From Amy Cheng Vollmer: I so en­joyed your STC re­mem­brance of Ju­lian and the im­pact that he had on you. I only met him once for about 20 min­utes, but his joy for sci­ence and dis­cov­ery was com­pletely con­ta­gious — and in­fected me for life!

 

From Paul Rainey (via Bluesky): Poignant mem­ory: Bel­la­gio, Rock­e­feller cen­tre. Sit­ting be­side fire. Rest earned. Ju­lian de­cides we need drama. A real life who­dun­nit un­folds. Ex­cep­tion­ally re­luc­tant ac­tor was ap­pointed pro­tag­o­nist. Turns out I could act. Suc­cess­fully in­crim­i­nated Jeff H Miller for sloppy re­pair.