Professor G rubb has a long-lasting career in chemistry, starting from 1970, 47 years ago, at the D epartm ent o f C linical Chemistry, Faculty o f M edicine, at Lund U niversity in Sweden. H is interest during the firs t years was devoted to studies on im m unoglobulins and the title o f his PhD thesis is Im m uno
globulins and crossed Immunoelectrophoresis. D u rin g the late 1970s, he turned his interest to w hat has been his m ain scientific focus then and w hich has led him to the very fru itfu l collaboration w ith the U n ive rsity o f Gdańsk. This interest started w ith a report published in Scandinavian Journal o f Laboratory Investigation in 1979, in w hich he quantifie d “ gamma-trace” in biologica l observation lead to the discovery that “ gamma-trace” is an in h ib ito r o f papain, i.e., its im p o rta n t function is to serve as a protease in h ib ito r. “ Gamma-trace”
was subsequently given the name cystatin C. I t has been found that cystatin C is one o f the m ost im portant extracellular cysteine protease inhibitors.
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Having realized that “ gamma-trace” , o r cystatin C, is an im portant cysteine protease in h ib ito r, Professor G rubb continued w ith studies tryin g to elucidate the structure o f the protein and how the structure is related to the protease in h ib ito ry activity. The aim was to use the knowledge on the structure o f the in h ib ito ry site to synthesize low -m olecular-w eight substances w hich could m im ic the protease in h ib ito ry activity o f cystatin C. By chance it was discovered that cystatin C fractions lacking the m ost am ino-term inal part lost a lo t o f its in h ib ito ry activity, indicating the im portant role o f this part o f the molecule.
This hypothesis has later been confirm ed when recombinant cystatin C could be produced and when site-directed mutagenesis showed that the am ino-term inal end, together w ith the second hairpin loop, are crucial fo r its protease inhibitory activity. Once it was realized that the am ino-term inal segment was im portant, Professor G rubb trie d to fin d chemists able to synthesize peptidyl derivati
ves w hich could m im ic the amino acid sequence o f this segment. Facilitated by a Polish chemist in Sweden, Jerzy Trojnar, in 1986 he contacted Professor Zbigniew Grzonka at the U niversity o f Gdańsk, w hich was the starting po in t o f the very fru itfu l collaboration between Professor G rubb and the Faculty o f Chem istry at the U niversity o f Gdańsk.
Professor G rzonka and his co lla b o ra to rs, am ong them Franciszek K asprzykow ski and Leszek Ł a n kie w icz, synthesized several p e p tid y l derivatives w h ich , like cystatin C, co u ld fu n c tio n as cysteine protease in h ib ito rs. Interestingly, some o f the in h ib ito rs also showed a n ti-vira l and anti-bacterial activity. I t was the publication in N ature in 1989 describing that one such peptidyl derivative could in h ib it the grow th o f group A streptococci in vitro and in vivo by in h ib itin g bacterial proteases w h ich alerted m yself to the role o f cystatin C as an extracellular protease in h ib ito r. In collaboration w ith Professor G rubb and scientists at the Faculty o f C hem istry in Gdańsk m y group has subsequently published a series o f papers dem onstrating that peptidyl derivatives, based upon the active site o f cystatin C, can in h ib it the breakdown o f bone and, more surprisingly, in h ib it the differentiation o f bone resorbing osteoclasts.
The com plete characterization o f the fu n c tio n o f cystatin C has been revealed by studies on the three-dim ensional structure o f cystatin C, an area in w hich Professor G rubb has successfully collaborated w ith Polish scientists at the Faculty o f C hem istry in Gdańsk and w ith crystallographers at the Adam M ickiew icz U niversity o f Poznań, in clu d in g M ariusz Jaskólski, R obert Janowski, and M aciej Kozak. A fte r the in itia l three-dim ensional structure o f crystalline dim eric cystatin C , form ed by dom ain-sw apping, had been dem onstrated in a paper in N ature S tru ctu ra l Biology in 2001, the three-dim ensional structure o f m onom eric cystatin C was also revealed.
These findings have been crucial fo r firm conclusions regarding the structure,
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function, and sta b ility o f cystatin C. Interestingly, other very w ell recognized international groups had, p rio r to the successful collaboration w ith the Polish groups, failed to obtain reliable three-dimensional structure o f the recombinant cystatin C protein provided by Professor G rubb.
Professor G rubb has n o t o n ly investigated the structure and fu n ctio n o f cystatin C b u t also dem onstrated its role in several patho-physiological conditions. H e has studied how cystatin C is catabolized and excreted by the kidneys and found that circulating levels o f cystatin C is the best marker fo r kidney function. Nowadays, analysis o f cystatin C is used clinically to m onitor kidney functio n . The interest and acceptance o f Professor G rubb’s studies in this fie ld is indicated by the fact that more than 3,500 studies have been published emphasizing the role o f cystatin C in m o n ito rin g kidney function.
H is vast knowledge in the biology o f cystatin C has recently resulted in his w hich is a pathogenetic mechanism in the Icelandic disease, nowadays called
“ cerebral am yloid angiopathy” , associated w ith brain haemorrhage, stroke, and dementia. By using peptidyl derivatives they have also shown how the o lig o m e riza tio n can be in h ib ite d . These observations may n o t o n ly be o f im portance fo r the form ation o f am yloid aggregations in cerebral am yloid angiopathy b u t also in diseases such as A lzheim er’s and Parkinson’s.
Summary
Professor G rubb has an outstanding scientific track record and is certainly a scientist in the international fro n t. H e has been able to com bine clinical m edicine w ith excellent knowledge in chem istry and biochem istry w hich has led to his im portant contributions n o t only to basic scientific knowledge in the b io lo g y o f cystatin C m olecule b u t also to discovering its im p o r
tance in kidney function and role in am yloid form ation in diseases such as cerebral am yloid angiopathy. In these achievements, Polish scientists at the Faculty o f C hem istry in Gdańsk have played a m ost crucial role. The co l
laborations between Professor Anders G rubb and his co-workers in Lund and Polish scientists in Gdańsk and Poznań have resulted in a large am ount o f beautiful scientific findings and observations w hich have been published
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in a long lis t o f 35 papers appearing in many prestigious journals from the year 1990. This collaboration has been m ost instrum ental fo r the fact that Professor G rubb is a w o rld leading scientist in the structure and function o f cystatin C, spanning from basic chem istry to biochem istry and function and to the role o f cystatin C in pathological conditions.
G othenburg, 13 February 2018 U lf H . Lerner, D D S , PhD Senior Professor
Centre o f Bone and A rth ritis Research Sahlgrenska Academy
U niversity o f G othenburg
O pinia
prof. U lfa Lemem
tłumaczenie z angielskiego oryginału -p ro f. Franciszek Kasprzykowski