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A Tribute to Professor Per Artursson - Scientist, Explorer, Mentor, Innovator, and Giant in Pharmaceutical Research

Published:October 20, 2020DOI:https://doi.org/10.1016/j.xphs.2020.10.031

      Abstract

      This issue of the Journal of Pharmaceutical Sciences is dedicated to Professor Per Artursson and the groundbreaking contributions he has made and continues to make in the Pharmaceutical Sciences. Per is one of the most cited researchers in his field, with more than 30,000 citations and an h-index of 95 as of September 2020. Importantly, these citations are distributed over the numerous fields he has explored, clearly showing the high impact the research has had on the discipline. We provide a short portrait of Per, with emphasis on his personality, driving forces and the inspirational sources that shaped his career as a world-leading scientist in the field. He is a curious scientist who deftly moves between disciplines and has continued to innovate, expand boundaries, and profoundly impact the pharmaceutical sciences throughout his career. He has developed new tools and provided insights that have significantly contributed to today’s molecular and mechanistic approaches to research in the fields of intestinal absorption, cellular disposition, and exposure-efficacy relationships of pharmaceutical drugs. We want to celebrate these important contributions in this special issue of the Journal of Pharmaceutical Sciences in Per’s honor.

      Keywords

      Introduction

      This issue of the Journal of Pharmaceutical Sciences is dedicated to Professor Per Artursson and the groundbreaking contributions he has made and continues to make in Pharmaceutical Sciences. This article is a short portrait of Per, with emphasis on his personality, driving forces and the inspirational sources that shaped his career as a world-leading scientist in the field. Per is genuinely curious and bold, is most comfortable when performing research across disciplines, and happiest when moving on to embark on the next adventure (Fig. 1). He is generous with his ideas and thoughts, often concluding ‘Why not share? Most important is that it [the research] will be done, and I will not have time to pursue all my ideas!’ Many of us have reflected over the efforts he has put into becoming a leader in many different fields, some of them discussed here. The truth is that these changes have been essential for Per, to gain new energy and not become bored. While he clearly knows that he could have been satisfied with his ground-breaking work on Caco-2 cells, leaning back already in his 40s, he summarizes his decisions with ‘How fun would that be? I want to try new waters and develop my ideas!’ Indeed, he has been very successful in developing those ideas. He is one of the most cited researchers in his field, with more than 30,000 citations and an h-index of 95 as of September 2020. Importantly, these citations are distributed over the numerous fields he has explored, clearly showing the impact the research has had also outside the seminal work on Caco-2 cells.
      Figure thumbnail gr1
      Figure 1Per at his work desk at Uppsala University, happily enjoying a confocal image of nanoparticle transport across the intestinal lumen.
      Figure thumbnail gr2
      Figure 2Per after trekking in the north of Sweden, early 80’s.
      Figure thumbnail gr3
      Figure 3Per with family during the sabbatical in Texas 1996.
      Figure thumbnail gr4
      Figure 4Per celebrating the 50 years jubilee of his supervisor Ingvar Sjöholm's dissertation. This comes with traditional celebration in the Uppsala University building and the jubilee doctor is honored with among others cannon salute and bell ringing (upper left). Per together with wife Karin during their midsummer celebration 2020. Midsummer is more important than Christmas to Swedes, and was this year celebrated under corona-safe conditions in the beautiful Swedish nature (upper right). The drug delivery group at Uppsala University pictured summer 2018. The group has ~45 members and now encompasses two research streams (drug delivery and disposition, and molecular pharmaceutics) and hosts UDOPP, the national platform for ADME profiling (lower panel).

      Early Years

      Per grew up in Karlskoga, a blue-collar town dominated by a big steel industry, Bofors. Bofors was famous for their arms, ammunition and explosives production and built its reputation from the time when it was owned by Alfred Nobel, the man behind the Nobel Prize. Per's father was an economist who was expected to take over his grandfather's scrap metal business. The business did not do well and after the takeover, Per's father had to work hard to get it on its feet. Per learnt to read already at the age of four, and as a child he used to get up at 5 am to be with his father during breakfast where he sat and read a children's book while his father was reading the newspaper. This was the time for private, informal conversations on many different subjects, and Per's memories from these moments are fond ones. Per's mother was raised on a farm and entered high school against her father's will, completed her studies with (at that time, very rare) top grades and then took a job as a doctor’s secretary, during which time she met her husband. When Per was born, she soon stopped working and became a housewife. She was a very caring mother and her home was open for Per's friends who loved to come there and play. Per has a 3 years younger brother, Lars, who works in Stockholm as a chief economist. Growing up, the two brothers shared much fun during the pre-school years, but the age gap made them end up in different circles of friends after they started school. Today they again have good fun together and spend time together at holidays, one-on-one or joined by their families.
      While Per did not grow up in an academic home, his parents were extensive readers and politically aware. They strongly emphasized the importance of school and there were daily discussions about news and politics at meals. With limited opportunities to choose their own education and path in life, they did not want their children to take over the family business but to study and find their own paths in life. To their disappointment, Per, who was a straight-A student for many years, lost interest in school and took his hobby, photography, more and more seriously. He worked at a local newspaper at nights and on weekends, which gave him free access to professional equipment, and he also competed and made the final selection in national and a few international competitions, winning some. When the offer came to work as a substitute photographer for a year at the region’s largest newspaper, he accepted and dropped out after the second year of high school. The director of studies at the high school called him to his office and told him that he was wasting his talent, and that if he left school he would never come back. Per himself considers the break from school the best thing he could have done to get motivated for studies again. After a while working full time as a photographer the initial excitement of meeting and photographing athletes, famous artists and other interesting people wore off, and he started finding it repetitive and realized that this was not what he wanted to do for the rest of his life. However, his background in the visual arts has clearly affected his approach to communicate science, where he has emphasized visual means of conveying information, in oral presentations as well as in research papers. It has also left any group member of the drug delivery group with memories of many long photo shoots when the group is to be captured, not seldom in a snowy landscape outside the biomedical center in Uppsala. The ‘exotic’ background would, according to Per, be a good bait (together with the excellent science) to attract talented students and researchers to the group. After a gap year, he went back to high school and ended up in what he describes as a very interesting small group of 16 students, four of whom (including Per) were to end up as professors at Uppsala University. Motivation returned, as did the grades, and after the mandatory time in the Swedish armed forces, where he was trained to lead an artillery platoon, he joined the School of Pharmacy in Uppsala in 1977.
      As a university student he was very organized and focused, often done in good time with his studies to allow a visit to the cinema the night before an exam. Movies have always been an interest of Per’s, with Star Wars (all editions) being on the top of his list. Visual impressions, may it be photography or movies, have been a means of relaxation and an energizer for Per since his youth. Per had a great time in Uppsala and while he decided to take the studies seriously, he also took part in the student life. There was a surplus of female students at the parties for pharmacy students, so Per was often asked by his male student friends outside the school of pharmacy to bring them as guests. Per on the other hand enjoyed the parties at the veterinary school the most, and it is perhaps no wonder that his wife is a licensed veterinarian, nor that she also embarked on a scientific career after a few years on the field working as a district veterinarian for domestic animals. Per met Karin at one of the famous summer discos in downtown Uppsala during his PhD studies. Today, Karin is a research coordinator at the Swedish Veterinary Institute and adjunct professor in bacteriology at the Swedish Agricultural University, which is also located in Uppsala.
      When Per completed his studies and became a licensed pharmacist, he realized once again that his current path was not one he wanted to stay on for the rest of his life. He had performed his research semester in biochemistry, working with the oxygen radical-quenching enzyme superoxide dismutase, which at the time was considered a potential biological drug for treatment of oxidative stress, and he wanted to learn more. He asked if he could join one of the research groups at the Department of Biochemistry, but there was no money. In the end, a stipend was installed and in the fall of 1981 he was able to join the department.

      Formative Years - PhD and Postdoctoral Training

      During his thesis he worked with microparticulate formulations intended for parenteral, in particular intravenous, delivery of protein drugs targeting liver cells. This was at a time when very few scientists were working with nano- and microparticulate delivery systems and even fewer were using them as vehicles for proteins. During these formative years, there were two individuals that strongly influenced Per’s scientific approach—his main supervisor Ingvar Sjöholm, and his co-supervisor Peter Edman. Ingvar was an excellent biochemist and outside-the-box thinker, and Peter an extraordinary problem solver that found shortcuts that made the research efficient. Scientific discussions often occurred outside office hours, not seldom after a jog where the small research group ended up with a sandwich and a cup of tea at Ingvar’s house. Peter remembers Per as goal oriented and results driven, spiced with lots of ideas, creativeness and entrepreneurship. Together they discussed many ideas around commercialization and development of products. This was a hobby for Per and Peter, and culminated with the development of ‘Pharmacist Artursson’s mosquito-frightening-ointment’. Per had read that thiamine should work as a mosquito repellant and based on this knowledge he developed an ointment. Peter then took over for the ‘clinical study’ and asked some moose hunters in the northern part of Sweden, famous for its vast amounts of mosquitos, to make use of this ointment during the seasonal hunt. The ointment turned out to be more of a ‘hunter-scaring-ointment’ than a mosquito repellant. Firstly, the mosquito-season was over at the time of the moose hunt and had been replaced by black flies, against which thiamine was useless. Second, the thiamine was not stable in the ointment and smelled like burnt flesh at the time of use, which instead attracted the black flies. Lesson learnt during these early days: there are no shortcuts to successful drug development! The friendship between Per and Peter built during the thesis work turned out to be life-long. Still to date the two join up for a yearly hike in the Swedish mountains. Over the years the hikes have become increasingly comfortable, and are now at the stage of long daily hikes topped with a nice three-course dinner and sleep in a proper bed (Fig. 2).
      As a PhD student, Per was surrounded by biochemists that were experts in protein structure and function. In his first study Per set out to reduce the potential immunological response to microparticle-incorporated proteins by means of pegylation. This resulted in a coincidental finding: when injected intravenously, the pegylated proteins that protruded out from the microparticle surface stabilized the microparticles and prolonged their intravenous half-lives.
      • Artursson P.
      • Laakso T.
      • Edman P.
      Acrylic microspheres in vivo IX: Blood elimination kinetics and organ distribution of microparticles with different surface characteristics.
      Such PEG-induced steric stabilization was at the time of little interest to Per, but in parallel, scientists like Patrick DeLuca, Bob Davis and Lisbeth Illum, and later also liposome scientists both in the US and Europe explored the concept of steric stabilization. These activities led to registered liposome drug products of drugs such as amphotericin B and doxorubicin that reduced the organ toxicity by retaining the drugs longer in the circulation. In subsequent papers in his thesis, he developed biodegradable starch microspheres as protein delivery systems
      • Artursson P.
      • Edman P.
      • Laakso T.
      • Sjöholm I.
      Characterization of polyacryl starch microparticles as carriers for proteins and drugs.
      and performed proof-of-concept studies where he delivered a particle-entrapped enzyme to treat an artificial lysosomal storage disease.
      • Artursson P.
      • Edman P.
      • Sjöholm I.
      Biodegradable microspheres. I. Duration of action of dextranase entrapped in polyacrylstarch microparticles in vivo.
      He also explored the starch microspheres as potential vaccine adjuvants.
      • Artursson P.
      • Edman P.
      • Sjöholm I.
      Biodegradable microspheres II: Immune response to a heterologous and an autologous protein entrapped in polyacryl starch microparticles.
      Sjöholm was a strong promoter of collaborations across scientific disciplines. When Per wanted to study microsphere interactions at the cellular level, he was introduced to Jan Ericsson, a pathologist who also had access to electron microscopy. At the department of pathology, Per learnt to cultivate macrophages and investigate their interactions with different polysaccharide microspheres, of which some were immunostimulatory.
      • Artursson P.
      • Edman P.
      • Ericsson J.L.
      Macrophage stimulation with some structurally related polysaccharides.
      It was at this point that he became fascinated by cell culture, an interest that still remains.
      His thesis consisted of 10 original research papers, and his faculty opponent—Bob Davis from Nottingham University—published Per’s summary as two chapters in a book about particulate drug delivery systems. Davis also introduced him to Eric Tomlinson who had just been recruited by Ciba-Geigy (today’s Sanofi) to set up a new, more or less academic, research unit that he named Advanced Drug Delivery Research (ADDR), and which was located at the Ciba site in Horsham, West Sussex, England. It was Tomlinson who founded the journal Advanced Drug Delivery Reviews, giving it a similar name as the research unit. Per was offered a visiting scientist position and got the deal that while he should share and contribute with his competence in nano- and microparticle formulation, he should also learn something new. After a 4-month trekking tour in South-East Asia with his wife-to-be Karin, he joined the ADDR group on the new year of 1987. With more than 30 PhDs from different disciplines out of a staff of 50, ADDR offered a very stimulating and also challenging scientific environment. Expectations were high and critical thinking was abundant. World leading scientists passed by to give advice as consultants, and projects were killed if they did not deliver. In this environment Per thrived, developed his critical thinking and importantly, learnt to distinguish between criticism of the science and criticism of the individual. Over the years, Per has tried to pass along the lessons he learnt during his post doc fellowship to his students, in order to develop them into critical thinkers.
      Colleagues that influenced his critical thinking during the time at Ciba included his research area head Karel Petrak, an excellent polymer chemist to whom he reported; Andy Muddle, a physical chemist and close workmate who later became entrepreneur and funded a series of companies, including MedPharm; research area head Glynn Wilson, a biochemist who later took up leading positions in big pharma as well as startups; and natural born leader Martin Mackay, a molecular geneticist who later held research director positions at Pfizer and AstraZeneca. To Per’s surprise, the Ciba site in Horsham included a Sports and Social club with tennis courts, a soccer field, a gym and a bar where regular quizzes were held at nights, something quite different from the more Lutheran work environments he had experienced in Sweden. The sports Per practiced at the time were squash and badminton; at one infamous occasion however interrupted by a cricket match where he, completely lacking experience in the game, was called in as a last-minute substitute. He stepped in as the last batter but was immediately dismissed by the first ball he faced (a so-called golden duck), upon which the team lost the match.

      Establishing and Expansive Years

      After spending most of his time working on nanoparticulate delivery systems in projects that for proprietary reasons weren’t published—except for a new approach of producing monodisperse sterically stabilized nanoparticles
      • Artursson P.
      • Brown L.
      • Dix J.
      • Goddard P.
      • Petrak K.
      Preparation of sterically stabilized nanoparticles by desolvation from graft-copolymers.
      —he was during his last months at ADDR introduced to Caco-2 cells, an intestinal cell line that would shape his carrier more than anything else. At ADDR, Caco-2 cells cultivated on filters were used as a model to study advanced cell physiological processes for the purpose of learning new routes of efficient oral delivery. Very little was published from the work on Caco-2 cells at ADDR, but there were exceptions, such as a study of cobalamin transport
      • Dix C.J.
      • Hassan I.F.
      • Obray H.Y.
      • Shah R.
      • Wilson G.
      The transport of vitamin B12 through polarized monolayers of Caco-2 cells.
      and a review with some original data on drug transport via different routes.
      • Wilson G.
      • Hassan I.F.
      • Dix C.J.
      • et al.
      Transport and permeability properties of human Caco-2 cells: an in vitro model of the intestinal epithelial cell barrier.
      Per became fascinated by the advanced cell culture work, and before his term was completed, he had obtained permission to use the Caco-2 technology when he left ADDR. He applied for and obtained a lecturer position at the Department of Pharmacy, Uppsala University in 1988. Since the department dealt with formulations of orally absorbed drugs, Per decided to investigate and try to predict the intestinal permeability and absorption of such drugs. The aim was to bridge to colleagues working with oral dosage forms, although this turned out to be difficult.
      At that time, the departments were much smaller than today and the Department of Pharmacy had around 10-15 members, PhD students included. Research at the department was focused on solid oral dosage forms for small molecules and their disintegration and dissolution. It was not given that such a traditional research environment would accept a relatively inexperienced lecturer with a background in biochemistry and futuristic formulations of the, at that time, rare protein drugs. However, the young department head Christer Nyström, with support of John Sjögren, the legendary Head of Pharmaceutics at Astra and Nyström’s mentor, saw some potential in Per and he got the position. Moreover, Nyström transferred one of his half-way through PhD students, Eva-Karin Anderberg, to Per and Sjögren donated a series of radiolabeled beta-blockers to be used in the first Caco-2 study.
      • Artursson P.
      Epithelial transport of drugs in cell culture. I: a model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells.
      This paper is one of the 10 most cited research papers in the Journal of Pharmaceutical Sciences. Sjögren also introduced him to a team of recently recruited Astra staff members focusing on drug absorption of orally administered drugs, including Anna-Lena Ungell and Jan Löfroth, which resulted in very fruitful interactions and collaboration for a number of years. This interaction also resulted in the recruitment of Per’s first “own” PhD student, Johan Karlsson (nowadays with family name Palm), with whom he published his most cited paper demonstrating the relationship between Caco-2 cell permeability and human drug absorption.
      • Artursson P.
      • Karlsson J.
      Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.
      Looking back, it is interesting to note that when these results were submitted as a part of a grant application for the Swedish Research Council, the application was rejected on the grounds that the data were too good to be trustworthy! (This changed already the following year and Per has since then received continuous funding from the medical branch of the research council.) A series of Caco-2 papers followed, exploring different drug transport routes,
      • Artursson P.
      • Ungell A.L.
      • Löfroth J.E.
      Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments.
      ,
      • Karlsson J.
      • Kuo S.M.
      • Ziemniak J.
      • Artursson P.
      Transport of celiprolol across human intestinal epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein.
      ways to improve these routes through pharmaceutical excipients and permeation enhancers,
      • Anderberg E.K.
      • Nyström C.
      • Artursson P.
      Epithelial transport of drugs in cell culture. VII: Effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells.
      ,
      • Anderberg E.K.
      • Lindmark T.
      • Artursson P.
      Sodium caprate elicits dilatations in human intestinal tight junctions and enhances drug absorption by the paracellular route.
      and barriers to drug absorption such as the aqueous boundary layer,
      • Karlsson J.
      • Artursson P.
      A method for the determination of cellular permeability coefficients and aqueous boundary-layer thickness in monolayers of intestinal epithelial (Caco-2) cells grown in permeable filter chambers.
      pH dependency
      • Palm K.
      • Luthman K.
      • Ros J.
      • Grasjo J.
      • Artursson P.
      Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs.
      and the mucus layer.
      • Wikman A.
      • Karlsson J.
      • Carlstedt I.
      • Artursson P.
      A drug absorption model based on the mucus layer producing human intestinal goblet cell line HT29-H.
      The latter required a switch to a goblet cell line cloned from another human intestinal cell line HT29. In less known work, the Caco-2 model was also used to study the transport of large molecules using formulations and conjugates such as lipidic amino acid–hormone conjugates,
      • Toth I.
      • Flinn N.
      • Hillery A.
      • Gibbons W.A.
      • Artursson P.
      Lipidic conjugates of luteinizing-hormone-releasing hormone (LHRH)+ and thyrotropin-releasing hormone (TRH)+ that release and protect the native hormones in homogenates of human intestinal epithelial (Caco-2) cells.
      low molecular-weight heparin mixed-micelle formulations,
      • Lohikangas L.
      • Wilen M.
      • Einarsson M.
      • Artursson P.
      Effects of a new lipid-based drug delivery system on the absorption of low molecular weight heparin (Fragmin) in monolayers of human intestinal epithelial Caco-2 cells and after rectal administration to rabbits.
      and an influenza virus formulation.
      • Lazorová L.
      • Artursson P.
      • Engström A.
      • Sjölander A.
      Transport of an influenza virus vaccine formulation (iscom) in Caco-2 cells.
      It should be noted that cell culturing was, and still is, serious business in Per's laboratory. Robust and strict routines are in place in the lab and only students and researchers that have undergone thorough training are allowed to enter the cell culture room and handle the precious cells. Over the years there have been very few incidents of contamination in spite of not making use of antibiotics in the flask-cultured cells. Per and his team has since the mid 90's organized a number of popular cell culture courses, in the current form as a PhD student course taught together with experts from the Karolinska Institute.
      While the Caco-2 years were very rewarding and gave Per worldwide reputation as a scientist with several opportunities to explore his findings commercially, he was and remains a curiosity-driven researcher that felt it was time to advance into at least partly new areas of research. At this time, computer-assisted drug design was gaining ground so he approached colleagues at the Department of Medicinal Chemistry to explore opportunities for computational prediction of drug permeability and absorption. Initially, interest was slim, but during a discussion of essential molecular descriptors with collaborator-to-be Kristina Luthman, she mentioned that she had recently applied molecular shape factors such as surface polarity to describe retention time on chromatographic columns in collaboration with analytical chemist colleague Curt Pettersson.
      • Karlsson A.
      • Luthman K.
      • Pettersson C.
      • Hacksell U.
      Enantioselective ion-pair chromatography of phenolic 2-dipropylaminotetralin derivatives on achiral stationary phases - an experimental and theoretical study of chiral discrimination.
      Per and Kristina eventually decided to use molecular mechanics to determine the dynamic polar surface area of an analogous series of drugs—again the beta-blockers were used—and PhD student Katrin Palm could establish correlations both with permeability
      • Palm K.
      • Luthman K.
      • Ungell A.L.
      • Strandlund G.
      • Artursson P.
      Correlation of drug absorption with molecular surface properties.
      and later, using structurally different drugs, with fraction absorbed.
      • Palm K.
      • Stenberg P.
      • Luthman K.
      • Artursson P.
      Polar molecular surface properties predict the intestinal absorption of drugs in humans.
      In the mid-90’s, the first wave of gene therapy was booming. The therapeutic genes were delivered as colloidal systems, either in viral vectors or as plasmids in non-viral delivery systems such as liposomes or complexed with cationic polymers, but in these early days, the delivery efficiency was very low. Per reasoned that he could perhaps use his experiences from micro- and nanoparticulate delivery systems together with those from advanced cell culture to explore this field. The problem was that his knowledge in molecular biology was limited. Through luck of fortune, he ran into a former colleague from ADDR, Alain Rolland, at a conference. Alain, who arrived at ADDR at the end of Per’s time there, had just taken up a position as head of formulation at a newly founded company named GeneMedicine that worked on gene delivery systems. Money was flowing into the field and Alain convinced Per to join as a visiting scientist, which was facilitated by the fact that the CEO was Eric Tomlinson, the former head of ADDR. Since there was time left on the parental leave, Per and Karin decided to bring the children, then 4 and 6 years old, to the Woodlands, Texas, where they spent most of 1996 (Fig. 3). Per got a very generous offer and moved into a house in a very nice neighborhood, and the Arturssons were immediately invited to participate in the neighbors’ social activities. Once in place, Per focused on non-viral gene delivery systems for local gene delivery and learnt the basic molecular biology required for setting up this research field once back in Sweden. GeneMedicine invested heavily in production of plasmids at the highest quality, since quality was highly correlated to efficiency. Per was struck by what he felt were unlimited resources that had allowed the recruitment of around 90 staff members in a very short time, but also by the pressure created by the financiers’ demands for success. During the time in the Woodlands he was still long-distance supervising, and recalls the problems with sending manuscripts over the slow internet connections of that time, and the need to resort to the more robust fax communication.
      Back in Sweden, he decided to work with reporter genes to study structure-efficiency relationships for gene delivery systems. Importantly, he could obtain large amounts of completely supercoiled plasmids as generous gifts from GeneMedicine. He decided to work with cationic polymers since one such polymer, (poly)ethyleneimine (PEI), had been shown to be a highly efficient non-viral gene delivery system. However, PEI is not degradable and was found to have broad pharmacological effect in itself,
      • Regnström K.
      • Ragnarsson E.G.
      • Köping-Höggård M.
      • Torstensson E.
      • Nyblom H.
      • Artursson P.
      Pei - a potent, but not harmless, mucosal immuno-stimulator of mixed T-helper cell response and FasL-mediated cell death in mice.
      so he decided to investigate the more biocompatible cationic polymer, chitosan, whose mechanism as permeation enhancer he had investigated many years earlier.
      • Flinn N.
      • Hussain I.
      • Shaw A.
      • Artursson P.
      • Gibbons W.A.
      • Toth I.
      Oral absorption studies of lipid-polylysine conjugates of thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH).
      Aware of that the chitosan structure strongly influenced its effect
      • Schipper N.G.
      • Vårum K.M.
      • Artursson P.
      Chitosans as absorption enhancers for poorly absorbable drugs. 1: influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (Caco-2) cells.
      he teamed up with Kjell-Mårten Vårum, a world leading expert on chitosan. Vårum could produce chitosans of defined molecular weight, which allowed Per and his team to deliver another well-cited series of papers on the SAR of chitosan nanoformulation complexes with plasmid DNA, for example.
      • Köping-Höggård M.
      • Tubulekas I.
      • Guan H.
      • et al.
      Chitosan as a nonviral gene delivery system. Structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo.
      ,
      • Köping-Höggård M.
      • Vårum K.M.
      • Issa M.
      • et al.
      Improved chitosan-mediated gene delivery based on easily dissociated chitosan polyplexes of highly defined chitosan oligomers.
      At about that time, it was shown in a high profile paper in Science that Caco-2 cells could be transformed to M-cell like cells that transcytosed bacteria upon heterologous co-culture with primary B lymphocytes from mice.
      • Kerneis S.
      • Bogdanova A.
      • Kraehenbuhl J.P.
      • Pringault E.
      Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria.
      This caught Per’s attention and he introduced a homologous modification of the co-culture by replacing the mouse B-cells with a human B-cell line (Raji). Since similar work was performed by David Brayden’s group, they teamed up and co-published the first paper on this model in 2000.
      • Gullberg E.
      • Leonard M.
      • Karlsson J.
      • et al.
      Expression of specific markers and particle transport in a new human intestinal M-cell model.
      In contrast to normal Caco-2 cells, the M-cell like cells had the capacity to transport nanoparticles and in later studies nanoparticles targeting surface integrins on the M cells were developed to enhance the delivery across these cells and human Peyer’s patches with oral vaccination in mind.
      • Gullberg E.
      • Keita A.V.
      • Salim S.Y.
      • et al.
      Identification of cell adhesion molecules in the human follicle-associated epithelium that improve nanoparticle uptake into the Peyer's patches.
      The co-culture model was difficult to work with and was later improved,
      • Beloqui A.
      • Brayden D.J.
      • Artursson P.
      • Préat V.
      • des Rieux A.
      A human intestinal M-cell-like model for investigating particle, antigen and microorganism translocation.
      but by then Per had again moved on to explore new fields.
      In parallel with the gene delivery research, the concept of making use of molecular descriptors was extended to explore more advanced multivariate analyses for predictions of permeability. In the mid-90's such chemometric approaches were mainly used in the chemistry and processing fields, but Per wanted to continue exploring successful strategies from other fields for their potential use in his own. To build a strong group, Per recruited Ulf Norinder as Adjunct Professor to his group. Ulf was senior scientist at Astra in Södertälje, and got the opportunity to share his time between Astra and Uppsala, being physically present in Per's group once a week. Per, Kristina and Ulf was a senior super-team who together with PhD students Katrin Palm and Patrik Stenberg shaped the development of the field. At approximately the same time as the polar surface area concept was launched, the seminal paper on the Rule-of-5 was published by Christopher Lipinski and colleagues.
      • Lipinski C.A.
      • Lombardo F.
      • Dominy B.W.
      • Feeney P.J.
      Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.
      At one of the late 90's AAPS meetings Per presented the polar surface area work in the same session as Chris gave a talk and invited him over to visit the lab in Uppsala. Chris came to visit soon thereafter (and returned back to visit again in 2008); what an amazing experience for the PhD students, some of them authors on this paper, to present their research and discuss problems with the rock star of medicinal chemistry! While the research community until then had paid most attention to poorly permeable molecules, arguing that solubility could be handled by formulation approaches, the insight (partly resulting from the Lipinski paper) that there was an abundance of poorly soluble molecules across most drug discovery programs inspired Per to explore his research approaches also for solubility. In 1998, Per embarked on studies of solubility by recruiting Christel Bergström as PhD student, later followed by Carola Wassvik. While Per likely thought it would be easier to model solubility (a property determined in water only) as compared to permeability (a property dependent on the biological context in the cell), it turned out to be the other way around. The hypothesis that the polar surface area would predict also solubility proved wrong very early in the project, and neither was the opposite property (the non-polar surface area) very useful in these predictions. Christel remembers how she suddenly found herself taking courses to learn chemometrics, studying books describing all sorts of molecular descriptors, being sent off to a shorter research visit to GSK in Stevenage to learn neural network modeling, and being appointed to the department IT group. At this time she could not have been farther outside of her comfort zone - which more naturally would have been in the wet lab generating high quality experimental datasets (supposedly easily predicted from the polar surface area, according to promises at the start of the studies). Another learning from these efforts is related to difficulties in getting papers published when moving between research topics. It took almost two full years to get the first paper on solubility published,
      • Bergström C.A.
      • Norinder U.
      • Luthman K.
      • Artursson P.
      Experimental and computational screening models for prediction of aqueous drug solubility.
      but when the ice broke many publications followed. With Christel, Per explored solubility mainly from the solvation point of view,
      • Bergström C.A.
      • Norinder U.
      • Luthman K.
      • Artursson P.
      Experimental and computational screening models for prediction of aqueous drug solubility.
      ,
      • Bergström C.A.
      • Wassvik C.M.
      • Norinder U.
      • Luthman K.
      • Artursson P.
      Global and local computational models for aqueous solubility prediction of drug-like molecules.
      whereas Carola focused on the contribution of the solid state to the resulting solubility.
      • Wassvik C.M.
      • Holmén A.G.
      • Bergström C.A.
      • Zamora I.
      • Artursson P.
      Contribution of solid-state properties to the aqueous solubility of drugs.
      Carola was one of Per's many PhD students with joint supervision from industrial researchers. Solubility has since this time been an essential part of the drug delivery group research at Uppsala University, of equal importance as permeability for the development of the research program. The work initiated in 1998 has played a fundamental role in developing and establishing the molecular pharmaceutics theme within drug delivery.
      Around the turn of the century, Per revisited an early interest in the role of membrane transporters on drug permeability. He had touched on this topic already in the first Caco-2 papers
      • Karlsson J.
      • Kuo S.M.
      • Ziemniak J.
      • Artursson P.
      Transport of celiprolol across human intestinal epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein.
      and now set out to further explore it, building on the knowledge emerging from the Human Genome Project and advances in molecular biology. This resulted in papers exploring the regional mRNA transcript levels of key ATP-binding cassette (ABC) transporters and solute carriers (SLCs) in human jejunum and intestinal cell lines, including Caco-2,
      • Englund G.
      • Rorsman F.
      • Rönnblom A.
      • et al.
      Regional levels of drug transporters along the human intestinal tract: co-expression of ABC and SLC transporters and comparison with Caco-2 cells.
      • Engman H.A.
      • Lennernäs H.
      • Taipalensuu J.
      • Otter C.
      • Leidvik B.
      • Artursson P.
      CYP3A4, CYP3A5, and MDR1 in human small and large intestinal cell lines suitable for drug transport studies.
      • Taipalensuu J.
      • Törnblom H.
      • Lindberg G.
      • et al.
      Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers.
      genetic variation in transporters in Swedish populations, clinical impact of transporter inhibition
      • Englund G.
      • Hallberg P.
      • Artursson P.
      • Michaëlsson K.
      • Melhus H.
      Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring.
      and disease-induced alterations in transporter expression.
      • Englund G.
      • Jacobson A.
      • Rorsman F.
      • Artursson P.
      • Kindmark A.
      • Rönnblom A.
      Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1).
      In 2003, Per obtained a major grant from Knut and Alice Wallenberg foundation to establish a center for pharmaceutical screening and informatics. The generous grant opened opportunities to develop robotic miniaturized assays for transporter interactions combined with highly sensitive analytical equipment (LC-MS/MS), allowing large datasets to be established and used to explore the molecular features involved in the interactions. Per recruited PhD students to embark on these experiments, with Pär Matsson being the first to apply this approach to studies of ABC transporters.
      • Matsson P.
      • Englund G.
      • Ahlin G.
      • Bergström C.A.
      • Norinder U.
      • Artursson P.
      A global drug inhibition pattern for the human ATP-binding cassette transporter breast cancer resistance protein (ABCG2).
      ,
      • Matsson P.
      • Pedersen J.M.
      • Norinder U.
      • Bergström C.A.
      • Artursson P.
      Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs.
      Pär identified common and distinctive features in ligand recognition within this important protein family using a combination of experiments and computational modeling techniques. The approach was later extended to additional transporters, in particular focusing on hepatic SLCs.
      • Ahlin G.
      • Karlsson J.
      • Pedersen J.M.
      • et al.
      Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
      ,
      • Karlgren M.
      • Ahlin G.
      • Bergström C.A.
      • Svensson R.
      • Palm J.
      • Artursson P.
      In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions.
      Pär remembers an exciting, but somewhat daunting task as a freshly enrolled PhD student to decide on purchases of robot liquid handling stations and flow cytometers, traversing the intricate bureaucracies of European Union tender procedures, and the great fun that followed when setting up protocols for permeability and transporter screening. A (partly) intentional pedagogic approach from Per’s side—setting the general outline for a project, then giving largely free reins in solving the research problem. Judging from the many successful careers of his students, in researcher and executive positions in pharma industry, in regulatory agencies and in academia, this appears to have been a fruitful approach—in combination with Per taking his own advice for mentees in academia: “when you recruit, go for excellence first (but don’t forget to make sure everyone gets along)”. His sprinkling with a dash of fingertip feeling for what is on (or beyond) the research frontier might also have played a part in the successful outcome, which is evidenced, for example, by eight of his PhD students receiving graduate student awards from the American Association of Pharmaceutical Scientists.
      Similarly to the Caco-2 cell model, other laboratory models developed by Per’s group have also rapidly found their way into industrial settings. One of these is the methodology to measure intracellular unbound drug concentrations in cells.
      • Mateus A.
      • Matsson P.
      • Artursson P.
      Rapid measurement of intracellular unbound drug concentrations.
      Around 2010, Per had the idea to adapt methodology developed in the laboratory of Margareta Hammarlund-Udenaes for the study of unbound drug exposure in brain tissue,
      • Gupta A.
      • Chatelain P.
      • Massingham R.
      • Jonsson E.N.
      • Hammarlund-Udenaes M.
      Brain distribution of cetirizine enantiomers: comparison of three different tissue-to-plasma partition coefficients: K(p), K(p,u) , and K(p,uu).
      ,
      • Fridén M.
      • Gupta A.
      • Antonsson M.
      • Bredberg U.
      • Hammarlund-Udenaes M.
      In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids.
      to a format that could be used to quantitate unbound, pharmacologically active drug concentrations in cell cultures. Together with Pär Matsson, who at that time had recently returned to an assistant professorship at Uppsala University after a postdoctoral fellowship at UCSF, and PhD student André Mateus, he set out to develop a small-scale and easy-to-use method suitable for the industrial setting. In nine research papers and counting, Per and colleagues explored the impact of different cellular distribution mechanisms on unbound intracellular drug exposure as quantified using the concept of intracellular bioavailability (Fic),
      • Mateus A.
      • Matsson P.
      • Artursson P.
      Rapid measurement of intracellular unbound drug concentrations.
      ,
      • Mateus A.
      • Treyer A.
      • Wegler C.
      • Karlgren M.
      • Matsson P.
      • Artursson P.
      Intracellular drug bioavailability: a new predictor of system dependent drug disposition.
      ,
      • Treyer A.
      • Mateus A.
      • Wiśniewski J.R.
      • Boriss H.
      • Matsson P.
      • Artursson P.
      Intracellular drug bioavailability: effect of Neutral Lipids and Phospholipids.
      and demonstrated how unbound drug exposure can be used to explain cellular pharmacology and to correct disconnects between cell-based and biochemical assay results.
      • Almqvist H.
      • Axelsson H.
      • Jafari R.
      • et al.
      CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil.
      ,
      • Mateus A.
      • Gordon L.J.
      • Wayne G.J.
      • et al.
      Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery.
      The concept of intracellular bioavailability, and the experimental model developed are currently paving its way into the toolbox of the pharmaceutical industry as a means to quantitate intracellular accumulation unbiased from non-specific membrane interactions.
      The multivariate QSAR modeling and informatics approaches applied in Per’s publications from the late 90s and onwards, in combination with an interest in omics approaches that started with his work on transporter transcriptomics, set the stage for his venture into a new domain in the pharmaceutical sciences—proteomics—during the past decade. Early on, Per collaborated with Yurong Lai and colleagues at Pfizer, Groton to quantitate specific transporters using targeted techniques with isotope-labeled peptides.
      • Karlgren M.
      • Vildhede A.
      • Norinder U.
      • et al.
      Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
      At a research meeting in Greifswald, Germany, another serendipitous meeting at a conference dinner was the starting point for a long-term collaboration with Jacek Wiśniewski at the Max Planck Institute of Biochemistry. Jacek had developed sample preparation methods that enabled reliable label-free, quantitative measurements of protein concentrations across the entire proteome,
      • Wisniewski J.R.
      • Zougman A.
      • Nagaraj N.
      • Mann M.
      Universal sample preparation method for proteome analysis.
      ,
      • Nagaraj N.
      • Wisniewski J.R.
      • Geiger T.
      • et al.
      Deep proteome and transcriptome mapping of a human cancer cell line.
      and Per saw the great opportunities in applying these global proteomics techniques to the different cell models used in his laboratory. With the help of Jacek and a talented team of 5 PhD students and 4 postdocs over the recent years, Per established a state-of-the-art proteomics theme in his laboratory. In this research, Per has explored the value of proteomic analyses in prediction of human pharmacokinetics and presented proteomic data for several tissues, primary cells and cell lines important for drug disposition. This includes primary human hepatocytes which are routinely isolated in his laboratory through a collaboration with the Uppsala University Hospital,
      • Vildhede A.
      • Wiśniewski J.R.
      • Norén A.
      • Karlgren M.
      • Artursson P.
      Comparative proteomic analysis of human liver tissue and isolated hepatocytes with a Focus on proteins determining drug exposure.
      • Wiśniewski J.R.
      • Vildhede A.
      • Norén A.
      • Artursson P.
      In-depth quantitative analysis and comparison of the human hepatocyte and hepatoma cell line HepG2 proteomes.
      • Ölander M.
      • Wiśniewski J.R.
      • Artursson P.
      Cell-type-resolved proteomic analysis of the human liver.
      as well as transporter expression systems,
      • Wegler C.
      • Gazit M.
      • Issa K.
      • Subramaniam S.
      • Artursson P.
      • Karlgren M.
      Expanding the efflux in vitro assay toolbox: a CRISPR-Cas9 edited MDCK cell line with human BCRP and completely lacking canine MDR1.
      and the Caco-2 cell model.
      • Ölander M.
      • Wiśniewski J.R.
      • Matsson P.
      • Lundquist P.
      • Artursson P.
      The proteome of filter-grown Caco-2 cells with a Focus on proteins involved in drug disposition.
      An impressive amount of work was spent to validate proteomic analyses of hepatic tissue samples to ensure accurate quantitation of the proteins important for drug disposition.
      • Wegler C.
      • Gaugaz F.Z.
      • Andersson T.B.
      • et al.
      Variability in Mass Spectrometry-based Quantification of clinically Relevant drug transporters and drug Metabolizing enzymes.
      Several studies from Per’s laboratory have demonstrated the value of proteomic analysis in pharmacokinetic predictions,
      • Ölander M.
      • Wiśniewski J.R.
      • Matsson P.
      • Lundquist P.
      • Artursson P.
      The proteome of filter-grown Caco-2 cells with a Focus on proteins involved in drug disposition.
      ,
      • Matsson P.
      • Fenu L.A.
      • Lundquist P.
      • Wiśniewski J.R.
      • Kansy M.
      • Artursson P.
      Addendum to 'Quantifying the impact of transporters on cellular drug permeability.
      • Matsson P.
      • Fenu L.A.
      • Lundquist P.
      • Wiśniewski J.R.
      • Kansy M.
      • Artursson P.
      Quantifying the impact of transporters on cellular drug permeability.
      • Vildhede A.
      • Mateus A.
      • Khan E.K.
      • et al.
      Mechanistic modeling of Pitavastatin disposition in sandwich-cultured human hepatocytes: a proteomics-informed Bottom-up approach.
      for example a recent study where tissue samples and in vivo pharmacokinetics of several drugs were available from the same individuals.
      • Hjelmesaeth J.
      • Asberg A.
      • Andersson S.
      • et al.
      Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL).
      Using transporter concentrations measured in tissues from each subject, the plasma concentration profiles of rosuvastatin were predicted without any arbitrary scaling factors.
      • Wegler C.
      • Prieto Garcia L.
      • Klinting S.
      • et al.
      Proteomics-informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight.
      This is an important step forward in the field of predictive pharmacokinetics, demonstrating that proteomic data can provide transparent models without the need for ”black box fudge factors”.

      Building an ADME Research Platform

      Per’s continuous contributions to methodological advances in pharmaceutical profiling and preclinical drug absorption studies led to significant interest to collaborate from large pharmaceutical companies, smaller biotechs, and from academic research groups world-wide. To enable such projects Per started working toward establishing a collaboration platform within the Department of Pharmacy. He was inspired by the then recently established Center for Drug Candidate Optimization (CDCO) at Monash University. He visited Monash University in 2003 and had in-depth discussions with Bill Charman and Susan Charman, the driving forces behind the center, around their set-up and business model of CDCO. The Knut and Alice Wallenberg grant which Per received later that year then enabled expansion of his research program into the development of a collaborative platform making use of automated ADME screening assays, including permeability, solubility, metabolism and transporter interactions. Based on the grant, the technology platform was increased and the center came with the possibility to have a full-time employee to manage the center itself, perform outreach activities and also to, together with other resources in Per's groups, run collaborative research projects. In the early days the platform had the tentative name Center of Pharmaceutical Screening and Informatics, and was set up based on the experiences from CDCO at Monash University but adjusted to match the ecosystem and translational research in Sweden at this time. This collaborative platform was then further developed and transformed in 2009 to the Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP).
      Per also joined forces with Annika Jenmalm Jensen and Mikael Elofsson at the Karolinska Institute and Umeå University, respectively, to establish a national platform for chemical biology, probe development and screening—the Chemical Biology Consortium Sweden—in which UDOPP formed one of three nodes. In a parallel initiative, a Swedish center of excellence in the molecular biosciences—SciLifeLab—was established in 2010, initially as collaboration between three universities in Stockholm which a couple of years later expanded to include Uppsala University, subsequently forming a national research infrastructure in the biosciences. As part of this expansion of the SciLifeLab initiative, Per and UDOPP partnered with researchers in medicinal chemistry, biophysics and pharmacology to form a national drug discovery and development platform, which was inaugurated in 2014. UDOPP contributed to the platform as the ADME of Therapeutics (ADMEoT) facility.
      Over the course of UDOPPs 10-year history, the methodological and scientific advances based on Per’s research have impacted more than 200 academic and industry drug discovery projects and resulted in more than 75 publications. The UDOPP team has grown to its current ten members, in addition to Per’s own research group. Throughout this expansion, Per has maintained a scientific interest and provided input on the projects, which have included strategic, long-term academic collaborations—for example that with Thomas Helleday at the Karolinska Institute which has resulted in several high profile publications on drugs for cancer, autoimmunity and viral infections
      • Gad H.
      • Koolmeister T.
      • Jemth A.S.
      • et al.
      MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.
      ,
      • Visnes T.
      • Cázares-Körner A.
      • Hao W.
      • et al.
      Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation.
      —as well as participation in multiple large European Union Innovative Medicines Initiative (IMI) programs such as the European gram-negative antibacterial engine (ENABLE) program and the ConcEPTION consortium which aims to establish safe medications during pregnancy and breastfeeding. Under Per’s leadership as the platform director and scientific lead of UDOPP the platform has, in the hands of platform head Pawel Baranczewski, also contributed to three first-in-human nominations, supported two late (phase 2) clinical trials, and helped establish five drug development partnership agreements between academic and industrial partners.

      International Recognition

      Per’s contributions to the pharmaceutical sciences are well recognized on the international stage. He is a fellow of the American Association of Pharmaceutical Scientists (2001) and the American Association for the Advancement of Science (2016). His impact on the field have also been recognized through honorary titles at the University of Queensland in Australia and at University of Eastern Finland, as well as through awards for meritorious manuscripts in the Journal of Pharmaceutical Sciences (Ebert Prize, 1997 and 2017), European Journal of Pharmaceutical Sciences (2004), and Pharmaceutical Research (2005 and 2011). He has served on the editorial boards of many of the major journals in the pharmaceutical sciences, including the Journal of Pharmaceutical Sciences, European Journal of Pharmaceutical Sciences, Pharmaceutical Research, Journal of Drug Targeting, American Journal of Drug Delivery, Pharmaceutics, and Current Drug Delivery, and between 1998 and 2001 he served as Editor-in-Chief of the European Journal of Pharmaceutical Sciences. The international interest in his research has resulted in more than 300 invited lectures around the world, at scientific meetings and through invitations to academia and pharmaceutical industry throughout Europe, North America and Asia. His first PhD students recall the buzz and interest from industry scientists and academics when presenting posters on the early Caco-2 results at international meetings, and are joined by subsequent generations of his students in their gratitude for benefitting from his large international network—from the casual introductions in a conference hall, to having many of the field’s most impactful scientists visit Uppsala to serve as Faculty opponents on their thesis defenses, or to present at the annual pharmaceutical profiling symposia arranged by Per’s research group. Per also has an extensive track record when it comes to collaboration with global companies, many of these resulting in co-supervised PhD students and postdocs.

      Mentoring

      Over the years, a great number of pharmaceutical researchers and professionals have been guided and influenced through Per’s mentorship, including 33 PhD-level graduate students, 28 postdoctoral and visiting scientists, 16 staff researchers in the Uppsala Drug Optimization and Pharmaceutical Profiling Platform, and close to a hundred Masters-level students. He has, to date, mentored 2 full professors and 8 associate professors.
      An intentional and continuing theme in the research environment that Per has built is the integration of people from different backgrounds (Fig. 4). This includes both diversity in the undergraduate and scientific background of the students and researchers joining his research group - which have included among other pharmacists, chemists, biomedical engineers, physicists, and molecular and cell biologists - and also inviting researchers from around the world in a highly international environment. Visiting students, PhD candidates, postdoctoral and visiting researchers have come to Uppsala University’s Department of Pharmacy from near and far, including Denmark, Finland, Norway, Japan, USA, Canada, Egypt, Australia, Malaysia, Iran, Switzerland, Italy, United Kingdom, The Netherlands, Russia, China, Turkey, Poland, Germany, Spain, and Portugal. Per stressed the importance of scientific internationalism, firstly as a means to excel in research, but also having additional benefits. In his words, ‘we cannot solve all the world’s problems, but this is our small but important contribution toward understanding across cultures and peace’. Having postdocs and guest researchers in the group from the early days has been very successful to facilitate broad research training for the young researchers. This was a unique approach taken by Per in the 90’s, being one of few professors at the Faculty of Pharmacy to have a continuous flow of international postdocs and guest researchers contributing to the research and culture of the group.
      Another aspect that set Per apart from many of his peers has been to use outside expertise to help build a thriving research environment. When his group started expanding around 10 years ago as a result of funding success, the formation of the UDOPP platform, and expanding independent research programs of senior researchers in his group, he brought in a management consultant to organize the administrative work, set priorities and goals–a most unusual step in his environment. With these tools at hand, it was easier to get everyone onboard in the work toward individual and common goals. One important strategic goal that was identified concerned understanding research quality. A common decision was taken to step out of the pharmaceutics box and learn from top scientists publishing in the very best journals. This was cumbersome for some, but Per reasoned that by understanding what it takes to perform the best science using the newest technologies, the PhD students and postdocs would become more attracted by (academic) science. This turned out to be the case and Per takes great pride in that his students nowadays often do not go directly to the pharmaceutical industry after graduating but instead, as a rule, continue to postdoctoral training at prestigious institutes, and that two of his former PhD students were awarded full professorships during the last year.

      Work-Life Balance

      In his off-hours Per has a few recurring themes that occupy his time: good food, good wines, good movies (preferably including superheroes and/or lightsaber fighting), good skiing, and spending as much time as he can with his wife Karin, his daughter Sara and son Björn. On occasion he also enjoys playing a computer game or two, which has been known to result in the weekly research meetings with graduate students to veer off into exposés of how he, during the weekend, conquered the Balrog of Moria. Per is highly competitive in all aspects, which has amused many group members during the retreats where different competitions have been held as recreation. As other group members for sure have been up for the competition, Per is not always leaving the retreats as the winner but still with a smile.
      During the winters he spends as much time as his schedule allows in the Swedish mountains skiing with his family. He also shares the love for the slopes with fellow pharmaceutical scientist Kathy Giacomini, who says the following about Per:
      I am convinced that Per’s entire life follows a Zen Buddhist principle: “How you do anything is how you do everything.” In fact, Per’s leisure time activities reflect his research activities in terms of both their nature and the style with which he pursues them. He and his beautiful wife, Karin, are avid alpine skiers. My husband, John, and I are native Coloradans, and have skied with them for many years. In general, we spend one gorgeous week each winter at a ski resort with the Arturssons. As a group, we have been to many ski areas including Steamboat Springs, Whistler and Val d’isere, and are all hoping for a quick end to COVID19, so we can ski together soon again!
      Now for me, a ski vacation means luxurious spas, manicures and pedicures, retail therapy, outstanding food and wine, and of course, a bit of skiing. For Per, with the exception of the outstanding food and wine, a ski vacation means something entirely different. He, Karin and John cannot wait to find black diamond ski runs, and then ski down them at a fast pace. In fact, Per and Karin often arrive a few days ahead of us, and I am convinced that they arrive early just to find those black diamond runs. On a typical ski day, I like to end early, for example, by 2 pm, so I can relax, shop or even take a nap! Per and Karin literally ski each day until the area closes.
      Now what about his style of skiing? Well, his style is reminiscent of his research, in line with the Buddhist principle, that I am absolutely sure he lives his life by (though I have never asked him). First, he is an outstanding skier. He is not flamboyant, but expertly carves his turns, even on the steepest slopes. He loves a challenge, not only black diamond ski runs, but difficult conditions. He believes that there is no such thing as too much snow, and if it snows at night, he (along with John and Karin) are on the slopes early the next morning to partake in the new challenge. Of course, that’s the day I sleep in! And though he loves good ski equipment, he is ultimately a thinking man, following direction from Warren Miller and Kevin Andrews: “Gotta use your brain, it’s the most important part of your equipment.”
      In the evenings, when the skiing is over, we love relaxing with Per and Karin. Per’s kindness is palpable as he speaks fondly of his students, his friends, his children, his dog, his fancy cars (yes, there is true love there), and indeed his beautiful life in Sweden. To you, Per, and the way you live your life: “How you do anything is how you do everything.”

      Conclusion

      This article aimed to illustrate Per’s defining characters - a curious scientist who deftly moves between disciplines and has continued to innovate, expand boundaries, and profoundly impact the pharmaceutical sciences throughout his career. By integrating techniques and theory from multiple complementary disciplines, he has developed new tools and provided insights that have significantly contributed to today’s molecular and mechanistic approaches to research in the fields of intestinal absorption, cellular disposition, and exposure-efficacy relationships of pharmaceutical drugs. We want to celebrate these important contributions in this special issue of the Journal of Pharmaceutical Sciences in Per’s honor.

      Acknowledgments

      The authors gratefully acknowledge input from Karin Artursson and Peter Edman on the earliest periods covered, and Per himself for many science-related (and–unrelated) anecdotes over the years.

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