Cell. Mol. Life Sci.

64 (2007) 2181 – 2188

1420-682X/07/172181-8 Cellular and Molecular Life Sciences
DOI 10.1007/s00018-007-7230-8
 Birkhuser Verlag, Basel, 2007

Memories of a Senior Scientist

Biological Redox Systems and Oxidative Stress*

H. Sies

Institut f
r Biochemie und Molekularbiologie I, Heinrich-Heine-Universitt D
sseldorf, Universittsstrasse 1,

Building 22.03, 40225 D
sseldorf (Germany), Fax: +49 211 811 3029, e-mail: [email protected]

Received 9 May 2007; accepted 10 May 2007

Online First 14 June 2007

thrust in the advance of knowledge. Research fields

centered around cellular redox systems, oxidants and
antioxidants, and the concept of oxidative stress. A
noteworthy aspect is the global network of scientists
joining in these endeavors worldwide.

My recent account on How I became a Biochemist

started out saying that, “as my own path in the world of
science unfolded, I noticed the wonderful interplay of
choice between a kaleidoscopic array of options and
what might be called a prepared mind” [1]. The story
began at Goslar, where I was born in 1942, and at the
nearby city of Seesen on the Western rim of the Harz
mountains in Northern Germany, where I grew up and
went to school, not far from the university town of
Gçttingen. The first noteworthy point there was the
wonderful first-grade elementary school teacher,
Georg Henkel (then 28, now 86 years old and a good
friend), who early on instilled enthusiasm in nature
and engendered self-confidence in our own capabil-
ities. So, one of the roots of the prepared mind was laid
Figure 1. out early. Following a great time of adolescence and
subsequent university studies at T
bingen, Paris and
Munich [1], the experimental work for the M. D.
Abstract. This account revolves around fascination dissertation (no biochemistry curriculum as yet avail-
and excitement with science. Early curiosity and able) was performed at Marburg and Munich under
fortunate opportunities can lead to a satisfying career. the guidance of my academic teacher, Theodor
The privilege of performing basic research in bio- B
cher. The topic was on steady-state relaxation
chemistry and molecular biology at a university kinetics of the enolase reaction, one of the glycolytic
coupled with teaching motivated students and work- reactions catalyzed with high capacity, the measurable
ing with dedicated co-workers makes for sustained deviation from thermodynamic equilibrium becoming
a suitable measure for metabolic throughput, basically
an application of simple first-order kinetics to a
* Dedicated to my wife, Nancy (Ph.D., UC Berkeley) complex biological system [2].
2182 H. Sies Biological Redox Systems and Oxidative Stress

Postdoc Time with Theodor B
cher at on one of his visits, and after appropriate control
Ludwig-Maximilians University, Munich experiments and extensions, this was published in the
then new FEBS Letters [7].
Following a two-year period in clinical medicine,
notably in internal medicine with H. E. Bock at
T
bingen, postdoc activities started back again at Research at the Johnson Research Foundation,
the Institute of Physiological Chemistry at the Lud- Philadelphia
wig-Maximilians-University at Munich, headed by
Theodor B
cher, himself a student of Otto Warburg at Brit invited me to join for further work at the JF in
the Kaiser-Wilhelm-Institut f
r Zellchemie in Berlin- Philadelphia, even together with my great technician,
Dahlem. Work from the outset was on biological Annegret Marklstorfer, nee Conze (sadly deceased at
redox systems, and “
ber die katalytischen Wirkungen the Djerba terrorist blast attack a few years ago).
der lebendigen Substanz” by Warburg and “Wege des These were great times at the JF (see a superb account
Wasserstoffs in der lebendigen Organisation” by of the atmosphere then, written by Angelo Azzi whom
B
cher and Klingenberg [3] were cherished reading. I first met at those days there [8]), a close relationship
I was associated with Bolko Brauser, a pioneer in developing with Nozomu Oshino, who had joined
organ absorbance spectrophotometry, and by combin- from Ryo Satos lab in Osaka with his wife Reiko.
ing fiber optics techniques with the use of the Working with isolated mitochondria, Alberto Boveris,
hemoglobin-free perfused liver we were able to coming from Andres Stoppanis group in Buenos
generate excellent signal/noise optical absorbance Aires, looked at hydrogen peroxide production under
difference spectra from a 3 – 4 mm thick lobe of rat different states of respiratory activity. Hydrogen
liver [4]. In combining absorbance with surface peroxide metabolism in mammalian organs was
fluorescence techniques, the way was opened to written for Physiological Reviews [9]. It took a while
noninvasive redox titration. The cytosolic NADH/ until we got the article together, and for the current
NAD+ system was interrogated with stepwise younger reader it might be interesting to note that we
changes in the lactate/pyruvate ratio, whereas the did real cut and paste, i.e. scissors and glue, to
mitochondrial NADH/NAD+ system was poised and compile the more than 550 final references together.
titrated by the ß-hydroxybutyrate/acetoacetate ratio, We had about ten or even more versions going
allowing direct measurement of localized redox between Philadelphia, Buenos Aires and Munich,
potentials and nucleotide binding constants [5]. We and I remember typing on my small Olivetti type-
also looked at the redox state of the mitochondrial writer during summer vacation at the Etang de Berre
cytochromes in the intact organ and the terminal near Marseille, while others were windsurfing. Well,
oxidase of the drug metabolizing system, cytochrome the Johnson Foundation and the great personality of
P-450 [6]. The latter coincided with the early days of Britton Chance left its mark, and I am overly thankful
the drug-metabolism field, and at a workshop at for the good fortune of having been part of it.
Konstanz in 1968 I met Lars Ernster and Sten Longlasting friendships developed, cooperations
Orrenius from Stockholm, forming the basis of a were started, and future generations of students
life-long friendship. This whole research area was such were fostered.
a delight of congenial colleagues, including Ron
Estabrook, then still at the Johnson Research Foun-
dation at Philadelphia, and Herbert Remmer from Research Group at Munich: Glutathione and
T
bingen University, who had discovered the induc- Hydroperoxide Metabolism
tion of the drug metabolizing system by phenobarbi-
tal. The Habilitation thesis was written in 1971, entitled
My own niche in the redox field opened when one Das Peroxysom im Hepatozyten, and a review article
evening at the basement lab in Munich I decided to appeared in 1974 [10]. Leopold Floh, then at
look at yet another extramitochondrial pigment, the T
bingen, being one of the early students in the
peroxisomal hemoprotein, catalase. Britton Chance newly established curriculum of biochemistry, was
had described catalase Compound I in 1947, and working on the enzymology of glutathione peroxidase,
zeroing in on its peak in the dual-wavelength mode at an enzyme yet to be fully appreciated. He had seen our
640 – 660 nm, I infused ethanol at low concentration as papers on NADPH redox states in the perfused liver,
one of the hydrogen donors: gosh, it worked! This was and suggested to check whether glutathione disulfide
the discovery of steady-state hydrogen peroxide was in fact produced at the time NADPH was
production by a mammalian organ, a slightly heretical oxidized, which it did. Albrecht Wendel, a doctoral
thought at the time. Discussing it with Britton Chance student of Flohs, joined the boat, and we had great
Cell. Mol. Life Sci. Vol. 64, 2007 Memories of a Senior Scientist 2183

times along glutathione research. Two international Linke was the core technician, keeping things running
conferences on glutathione, one at an exquisite villa at when I was out of town. We also had exciting Fasching
T
bingen [11], the other at the Reisensburg castle (Carnival) feasts in the spring, sometimes even too
near Ulm [12] testify to this, with the Kosowers, Alton exciting.
Meister and Sir Hans Krebs attending, as well as us At Munich, interest in oxygen-related topics flour-
junior people who were just starting out in research. ished, and on one memorable day in 1977 we founded
Sir Hans, a former postdoctoral associate of Otto the Munich Oxygen Club in the Max-Emanuel-Brew-
Warburg, after his retirement at Oxford University, at ery, a group of colleagues that made their name in the
age 67 had started a whole new line of research in field in the decades to come: Erich Elstner, Manfred
redox states together with Derek Williamson and Saran, Wolf Bors, Hans Nohl, Peter Eyer and many
Patricia Lund at the Radcliffe Infirmary, and many of others.
his papers were close and complementary to our own The main research support came from the Deutsche
interests in redox titrations. I had seen him as a student Forschungsgemeinschaft, B
cher had taken initiative
first at the 1963 Lindau Meeting of Nobel Prize to found the Sonderforschungsbereich 51, entitled
Winners, and now as a young colleague met him at a “Biochemie und Molekularbiologie in Mnchen”,
workshop at Royaumont Castle near Paris in 1973 including members from university (Feodor Lynen)
(where I also first met Joseph Tager from Amsterdam, and from the Max-Planck-Institute as well as the
a genuinely pleasant person and colleague), then also Diabetes Institute in Schwabing (Otto Wieland).
at the Fall Meeting of the Gesellschaft f
r Biologische Young researchers got their first independent projects
Chemie at D
sseldorf in 1974. This was my first-ever and profited from interdisciplinary cross-fertilization
visit to D
sseldorf, a university having just grown out (one of them, for example, was Robert Huber, Nobel
of the Medical Academy. My talk was in a session Prize 1988 for chemistry). A highlight was the annual
chaired by Sir Hans, and the work was related to retreat to Lake Tegernsee near the Alps, called
glutamine metabolism, which had been carried out Symposium Gentianum, named appropriately for
largely by Dieter Hussinger, one of my first doctoral the location at the place where Enzian Schnaps was
students at Munich. The talk ended, and Sir Hans, in (legally) distilled.
his low voice, said that he recalls having done a similar
experiment in 1935! This taught me the lesson to go
back to read the literature consisting of more than just D
sseldorf University: The Institute of Physiological
the past couple of years. Chemistry
We became personal friends, paying mutual visits to
him and his charming wife Margaret at Oxford As it goes in German academia, a time comes to
(including a punting spree) and to Munich (I vividly wander off: I was appointed Full Professor (Ordinar-
remember a party in our small apartment with Feodor ius) at the Department of Physiological Chemistry I at
Lynen and Otto Wieland concentrating on a bottle of D
sseldorf, starting in the fall of 1979. Wolfgang Staib,
Chivas Regal), and having long walks and discussions chair of the Department of Physiological Chemistry
at the Aberdovey beaches in Wales or in the Alps. His II, had things covered well regarding faculty matters
wonderful sense of humor is most memorable, Sir and teaching arrangements, and he gave valuable
Hans having been a most unassuming personality, administrative advice, so luckily I could concentrate
always curious to find out something new; a wonderful on building a research group more or less from scratch
experience. with almost no eclipse from the move. One first area
Work was going well, with great young medical was redox cycling and thiol redox state, working with
students joining. One of my best early students, as Regina Brigelius, and there was an early review on
already mentioned, was Dieter Hussinger. This is quinone redox cycling together with Hermann Kap-
how I recruited him: in a written exam for the second- pus [13]. Enrique Cadenas from Buenos Aires had
year medical students, he had finished way before joined as Humboldt Fellow, and with Armin M
ller
everyone else and started smoking his pipe, so we got and Peter Graf we looked at a new selenoorganic
into talking… The first postdocs from abroad joined compound, carrying the order number (Prfzahl) PZ
the team: Karen Moss from Brian Chappells group in 51, brought to us by Erich Graf and Mike Parnham
Bristol was the first Humboldt Fellow of many to from the Nattermann company at nearby Cologne.
come, Theo Akerboom joined from Tagers group in This compound, later known as Ebselen, exhibited
Amsterdam, and there was a flurry of international glutathione peroxidase-like activity, and we shared
meetings (at one stage in the cytochrome P-450 string this whole topic with Albrecht Wendels group in our
of meetings, Judd Coon from Ann Arbor sighed: “Ive joint glutathione-oriented research, resulting in sev-
got to fly home to pick up some more slides…”). Ingrid eral papers published in Biochemical Pharmacology
2184 H. Sies Biological Redox Systems and Oxidative Stress

(our first one, [14]). Low-level (ultraweak) chemilu- fact of flying the plane as a private pilot or whether it
minescence detected by red-sensitive photomultipli- were our research results: Tamara and Franklin were
ers or later on by a Germanium diode detecting in the impressed (a scientific advisory board was around as
near-infrared at 1270 nm, was a means to study singlet well, by the way), and I was asked to join NFCR as a
oxygen chemistry and biochemistry. This noninvasive Project Director, being funded generously for basic
technique allowed us to obtain novel insight into the research, starting from 1984, from 2000 onwards as an
biology of electronically excited states. It was a great NFCR Fellow, now under the leadership of Franklin
pleasure to interact with Giuseppe Cilento and his Salisbury, Jr. and Sujuan Ba. This wonderful instru-
group from Sao Paulo and with Waldemar Adam from ment of research support, based on initial trust, and
W
rzburg on electronically excited triplet carbonyls. with very little bureaucratic strings attached, certainly
Many co-workers from the Institute at D
sseldorf and has contributed enormously to productivity in our
visitors from abroad made this a very lively time, group. This is an appropriate place to express my
including Herbert de Groot and Thomas Noll, special- sincere gratitude.
izing on hypoxia and lipid peroxidation, Heribert
Wefers on menadione redox cycling, Theo Akerboom
on glutathione disulfide and glutathione S-conjugate Society for Free Radical Research (SFRR)
transport, and Gianna Bartoli from Rome on gluta-
thione (GSH) release, Jos Estrela from Valencia on Trevor Slater from Brunel Unversity at Uxbridge,
calcium transients during drug metabolism, Denis United Kingdom, and his associate Robin Willson
Crane from Brisbane on coenzyme A mixed disul- were instrumental in founding the Society for Free
fides, Gail Gurtner from Baltimore on pulmonary Radical Research in the U.K. in 1982 (Fig.2). Trevor
vasoconstriction by arachidonate metabolites, Fran- linked up with Hermann Esterbauer from Graz,
cisco Romero from Valencia on glutathione compart- Austria, and Mario Dianzani from Torino, Italy, and
mentation, Toshihisa Ishikawa from Sapporo on Mario Comporti from Siena, Italy. Being part of this
cardiac glutathione S-conjugate transport, Raj Sohal group, I enjoyed the scientific colleagiality and open
from Dallas on pentane production and aging in the interchanges in these early days. This wonderful spirit
housefly, Dieter Hussinger then from Freiburg on filtered down through the whole field worldwide, and
pyruvate dehydrogenase and on glutamine metabo- still today the research field on free radicals and
lism, Jim Kehrer from Austin on ischemia/reperfu- related topics is characterized by a friendly and
sion, to name a few. Peter Graf was an excellent generous atmosphere.
technician in many of these projects. The Third Biennial Meeting of SFRR was held at
D
sseldorf in 1986, a highlight in the field as well as for
us. I had just published the book “Oxidative Stress”,
National Foundation for Cancer Research (NFCR) with the definition of this term and of the concept in
the Introductory Chapter [15], and a larger article on
At these bustling times, on the other side of the the biochemistry of oxidative stress [16].
Atlantic an exciting organization had come into being:
in 1973, Franklin Salisbury, a Washington-based
lawyer, and his wife Tamara had founded what was Oxygen Club of California (OCC)
known to be the National Foundation for Cancer
Research, NFCR. The co-founder was Nobel Lau- Lester Packer (Fig. 2), from the Department of
reate Albert Szent-Gyçrgy, based at Woods Hole, Physiology at UC Berkeley, had also been at the JF
Massachusetts. A major reason for establishing NFCR with Britton Chance, and his extraordinary person-
was to provide research funds to enable Szent-Gyçrgy ality and enthusiasm to start new research made his
and scientists from all over the world to do basic group a center in free radical research, based meth-
research in the cancer field, the motto being Labo- odologically on electron spin resonance techniques,
ratory without Walls. It was an extremely fortunate utilized by John Maguire, Rolf Mehlhorn and Alex-
event that I was invited to present our research at the andre Quintanilha. NFCR had a superb meeting at
1983 NFCR meeting at Montecito, California. Many Berkeley, topped by a boat ride in San Francisco Bay. I
of those present (Fig. 2) have made fundamental remember vividly the radiant Tamara Salisbury and
contributions in the decades to come. Later that year, the scientific director, ex-Surgeon General of the
Franklin and Tamara had a small meeting at Braun- army, Charles Pixley, stepping off the boat after a great
lage in the Harz Mountains in Germany, and I flew a party. The Packer lab also was active in teaching, in
small Cessna plane to a nearby grass airstrip to join particular a well-attended class on aging, together
there for presenting our results. Whether it was the with a neuroendocrinologist, Paola Timiras. In 1984/
Cell. Mol. Life Sci. Vol. 64, 2007 Memories of a Senior Scientist 2185

Figure 2. National Foundation for Cancer Research (NFCR) Research Conference at Montecito, CA, 11 – 12 February 1983. Front row
(from left): Harold Schwartz, Lester Packer, Franklin Salisbury, Albert Szent-Gyçrgy, Trevor Slater, Patrick Riley, Hermann Esterbauer.
Second row (from left): Keith Ingold, Bill Pryor, John Ward, Rolf Mehlhorn, Helmut Sies, Alexandre Quintanilha, Norman Krinsky, Peter
Gascoyne, Bruce Demple, Martyn Smith, Robin Willson.

85, I took a sabbatical with Bruce Ames at the degree also by industry. Genuine scientific interest
Department of Biochemistry at UC Berkeley in was expressed by colleagues coming from industry,
Barker Hall, closely working together also with Lester illustrated by the fact that several of the Lifetime
Packer and Martyn Smith. My work was on the OxyR Members of OCC are from industry, for example
regulon, and we noticed that deletions of this regulon Manfred Dunker from the Henkel Company.
led to enormously augmented spontaneous mutations,
whereas strains overexpressing OxyR had consider-
ably less mutations than controls. Singlet Molecular Oxygen
These days laid the foundation for much of the
subsequent development: Lester Packer founded Singlet oxygen as an electronically excited state is
what is now known as the Oxygen Club of California important not only in photooxidations but also in
(OCC), www.oxyclubcalifornia.org, cherished for its chemiexcitation, i.e. excitation without light energy.
great Biennial World Congress, held at the Fess Parker We used the thermodecomposition of an endoper-
Doubletree Hotel at Santa Barbara. These meetings oxide to generate singlet molecular oxygen at a
also extended to other sites, e.g. to Cadiz, Spain, and controlled rate, enabling us to study singlet oxygen
Alba, Italy, as well as to Portland, Oregon, in joint chemistry in biological settings. Paolo di Mascio in his
meetings with the Linus Pauling Institute headed by dissertation work studied the reaction of the endoper-
Balz Frei, a former associate of Bruce Ames. Not oxide of 3,3(1,4-naphthylidene) dipropionate
enough: Gordon Conferences were inaugurated, on (NDPO2) in detail, examining the dimol photoem-
Oxygen Radicals, on Nitric Oxide, and on Carote- ission at 634 nm and 703 nm as well as the monomol
noids, with Lester Packer and Norman Krinsky emission at 1270 nm [17]. We looked at DNA single-
(Fig. 2) being in the forefront. Many of these meetings strand breaks in plasmids in work by Heribert Wefers,
were sponsored by NIH and other government together with Dietrich Schulte-Frohlinde from the
agencies, by Unesco, WHO etc., but to a considerable Max-Planck-Institute for Radiation Chemistry at
2186 H. Sies Biological Redox Systems and Oxidative Stress

M
lheim. With Steen Steenken from the same In- ultraviolet light-induced erythema in humans, and
stitute, Wolfgang Schulz and with Paul Devasagayam, with Willi Stahl several studies on the concept of
visiting from the Babha Atomic Research Institute at nutritional protection against skin damage from sun-
Mumbai, India, the molecular aspects were studied in light were performed (see [19]).
a detailed fashion. Likewise, mutagenicity of singlet
oxygen was studied in a mammalian SV40-based
shuttle vector in joint work with Carlos Menck from Peroxynitrite, Nitric Oxide, Selenium
Campinas, Brazil, and Alain Sarasin from Paris.
The biology of peroxynitrite, a product of nitric oxide
and superoxide, became a research topic after Joe
Carotenoids: Lycopene Beckmans pioneering paper. We noted that ebselen,
the GSH peroxidase mimic, reacted with peroxyni-
Unlike the enzymatic defense against hydroperoxides trite, in studies with Hiroshi Masumoto from Tokyo
as effected by catalase and GSH peroxidases, there is and Wim Koppenol from Zurich. Karlis Briviba and
no known enzymatic defense against the short-lived two other young colleagues from the former Soviet
singlet oxygen. Linus Pauling in the 1930s had noted a Union, Victor Sharov and Ivan Roussyn, embarked on
role of carotenoids in singlet oxygen quenching, various aspects of defense against peroxynitrite. Not
utilizing the extended system of conjugated double- only ebselen, but also glutathione peroxidase protect-
bonds to dissipate the energy to the solvent as thermal ed against peroxynitrite, exhibiting peroxynitrite
energy, leaving the molecule intact. Thus, carotenoids reductase activity. Other selenoenzymes such as
would serve like an enzymatic catalyst. Interested in selenoprotein P or thioredoxin reductase as well as
biological defense against singlet oxygen, we exam- tellurium compounds displayed this activity, with
ined various classes of compounds and found that Gavin Arteel from Chapel Hill and the doctoral
lycopene, the red pigment occurring in the tomato, students Darius Buchczyk and Ronald Tamler being
was the most efficient singlet oxygen quencher, with instrumental in these studies. The field of selenium
the second-order rate constant being near the diffu- compounds developed rapidly, as reviewed together
sion limit [18]. with a Humboldt fellow from Bangalore, Govind
Wihelm (Willi) Stahl joined the group in 1990, Mugesh, and in joint work with Claus Jacob these
establishing carotenoid analysis, the basis for a long- topics were extended into protein chemistry. Annika
term development. Specific patterns of cis-trans Assmann found that selenomethionine oxide was
isomers of lycopene and ß-carotene in human serum readily repaired by glutathione, opening the attractive
and tissues were described, and first steps into the field strategy of channeling protein oxidation to a readily
of human nutrition were taken: Uptake of lycopene repairable site, selenomethionine, thereby protecting
was found to be greater from processed than from less well repairable aminoacid sidechains in proteins.
unprocessed tomato juice or from tomato paste than A new field opened with emerging knowledge on
from fresh tomatoes. Lycopene came to be a bio- signaling cascades. Stefan Schieke demonstrated that
logically important carotenoid for the human. Bio- activation patterns of mitogen-activated protein kin-
kinetics, the application of pharmacokinetic principles ases elecited by peroxynitrite were attenuated by
to micronutrients, vitamins and trace elements, is selenium supplementation of cells in culture.
important in assessing the function of compounds
occurring in minute amounts.
Carotenoids and their stimulatory effect on gap- Signaling, Aging Research
junctional intercellular communication was a topic
of interest. 4-Oxoretinoic acid generated from can- Beate Meier made the pioneering observation that
thaxanthin was stimulatory, as were a number of human fibroblasts release reactive oxygen species in
synthetic carotenoids. Synergistic antioxidative ef- response to interleukin-1 or tumor necrosis factor-
fects of lycopene and lutein were observed in mem- alpha [20] and in response to treatment with synovial
branes, and divergent optimum levels of lycopene, ß- fluid from patients suffering from arthritis. These
carotene and lutein in cells were identified. We observations provided a bridge between biochemistry
consider the latter observation of general interest and immunology, which received considerable atten-
with regard to the large human antioxidant trials, tion subsequently.
noting that those employing higher doses in the Lars-Oliver (Ole) Klotz and his team in the lab
human intervention studies provided rather negative dissected the pathways of quinone-induced signaling,
results, contrary to expectations: Paracelsus was right! which involves the epidermal growth factor receptor
Dietary tomato paste was found to protect against as a common mediator [21]. Peter Brenneisen and his
Cell. Mol. Life Sci. Vol. 64, 2007 Memories of a Senior Scientist 2187

group examined factors generated and released by trations of circulating bioavailable plasma nitric oxide
tumor cells, acting on gap junctional communication [25]. Interestingly, the vascular effects apply not only
between human fibroblasts. Klaus-Dietrich Krçncke to conduit arteries but also to microcirculation as
analyzed the role of nitric oxide in zinc-finger-depend- revealed in a noninvasive study on human skin.
ent transcription. Thus, the exciting emerging aspects
of signaling pathways and mechanisms were ad-
dressed. What makes you senior?
Cristina Polidori from Perugia, Italy, joined for work
on the topic of aging research, having access to The wonderful essence of life as a university research-
centenarians. The basis for identifying profiles of er and teacher is that there is always the exciting next
antioxidants in human plasma was worked out [22]. question and, fortunately, there is the enthusiastic
Aging research has advanced in several directions. We next young student taking up what previous research
worked on human skin, particularly on the effects of had unraveled, eager to comprehend the problem and
ultraviolet radiation, in joint work with Jean Krut- the techniques to solve the problem. It is a great
mann, in the framework of a core grant (SFB) of the privilege to be part of this, and to be supported by
Deutsche Forschungsgemeinschaft, “Molecular and funds from trustful taxpayers and other sponsors. One
cellular mediators of exogenous noxae”, initiated finds that peers spend their time reviewing the work
together with the chair of dermatology, Thomas for publication, and that there are colleagues going
Ruzicka, in 1995. through the tedious task of arranging scientific meet-
ings which allow direct exchange of results and ideas
long before being published in the scientific journals,
Flavonoids: Cocoa Flavanols and Vascular Responses and that there are well-known researchers taking their
time to help decide on grant applications or fellowship
In 1998, the Institute of Medicine of the National awards. This is all fine, and one can indulge in the
Academies held a meeting of the Panel on Dietary benefits of these services in the scientific community.
Antioxidants (Chair, Norman Krinsky) at Washing- Then, there comes the time of paying back: the
ton, D.C. at which I gave a survey lecture. In the Deutsche Forschungsgemeinschaft asks for help re-
audience there was Harold Schmitz, working at the viewing grant applications and to take part in site-
Hackettstown, New Jersey, facility of Mars, Inc., who visits for larger grants, the Alexander-von-Humboldt
had recently embarked on identifying procyanidins Foundation asks for service as a member of the
and flavonoids in cocoa. We discussed cocoa poly- Selection Committee to help identify top talent from
phenols and research on dietary antioxidants: the around the world for their fellowships, industry asks
beginning of a longterm research relationship. Gavin for advice in their research programs, organizers of
Arteel quickly found that cocoa polyphenol oligomers meetings ask for overview talks or educational
were effective in protecting against peroxynitrite [23]. lectures (as apart from truly research-oriented lec-
(-)-Epicatechin, the flavanol monomer building block tures), universities ask to help found core facilities or
of the procyanidins in cocoa, thus became a focus of to take part in committee work, and the like. Thus, an
interest in our research group. Peet Schroeder found unsuspecting dedicated researcher is exposed to a
that protection by epicatechin was particularly effi- gradual, creeping demand for help, which is not
cient for nitration reactions as compared to oxidation directly addressing the focus of research but reaches
reactions. out somewhat further. Is this what might define
Tankred Schewe, a colleague established in lipoxyge- becoming senior?
nase research, joined the group, and he found that Maybe there could be another angle, slightly more
polyphenols from cocoa inhibit mammalian lipoxyge- biological: a senior scientist could, like a senior
nases at concentrations of physiological interest [24]. citizen, be defined as one of grandfather status:
The efficiency of epicatechin in protection against scientific offspring of ones own students is a highly
peroxynitrite further directed our focus to the vascular satisfactory mark of making one senior. In my case, I
endothelium, and it was fortunate that Malte Kelm at was very fortunate to see several of my former
the D
sseldorf cardiology clinic, an expert on vascular students shape their own careers in science in a highly
endothelial function with emphasis in nitric oxide successful way, generating many scientific grandchil-
research, agreed to join in: the doctoral student dren.
Christian Heiss employed the noninvasive technique Helping organizations flourish is another aspect of
of measuring flow-mediated dilation of the brachial seniority. In my case, it was the Northrhine-West-
artery, establishing that cocoa flavanols exhibit vas- phalian Academy of Sciences, to which I was elected in
cular responses concomitant with increased concen- 1991. Having been active in the Class of Natural
2188 H. Sies Biological Redox Systems and Oxidative Stress

Sciences and Medicine in several types of activity, 7 Sies, H., Chance, B. (1970) The steady state level of catalase
compound I in isolated hemoglobin-free perfused rat liver.
from 2002 I served four years as President of that FEBS Lett. 11, 172 – 176.
Academy and from 2003 onwards as Vice-President of 8 Azzi, A. (2003) How I became a biochemist. IUBMB Life 55,
the Union of German Academies of Science. From 555 – 558.
9 Chance, B., Sies, H. Boveris, A. (1979) Hydroperoxide
2005 onwards, I joined as Member of the Council of metabolism in mammalian organs. Physiol. Revs. 59, 527 – 605.
the Nobel Prize Winners Meeting at Lindau, serving 10 Sies, H. (1974) Biochemistry of the peroxysome in the liver cell.
the most pleasurable task of facilitating interaction of Angew. Chem. Int. Ed. 13, 706 – 718.
11 Floh, L., Bençhr, H. C., Sies, H., Waller, H. D., Wendel, A.,
top young talent from around the world with the eds. (1974) Glutathione. 1 – 316, G. Thieme Publishers, Stutt-
Nobel Laureates. gart.
I close this brief rendition with one thought: the 12 Sies, H., Wendel, A., eds. (1978) Functions of glutathione in
liver and kidney. 1 – 212, Springer Verlag, Berlin Heidelberg
worldwide network of science and its productivity is
New York.
based on a network of individuals, and it is the 13 Kappus, H., Sies, H. (1981) Toxic drug effects associated with
interaction of these scientists and their enthusiasm oxygen metabolism: redox cycling and lipid peroxidation.
which generates the future development. I would like Experientia 37, 1233 – 1241.
14 M
ller, A., Cadenas, E., Graf, P., Sies, H. (1984) A novel
to mention one close personal friend and mentor who biological active selenoorganic compound. 1. Glutathione
had much to do with my own path in the world of peroxidase-like activity in vitro and antioxidant capacity of
science: Gustav V. R. Born, Department of Pharma- PZ 51. Biochem. Pharmacol. 33, 3235 – 3239.
15 Sies, H. (1985) Oxidative stress: introductory remarks. In:
cology at Kings College, London, and later at the Oxidative stress (Sies, H., ed.), 1 – 8, Academic Press, London.
William Harvey Research Institute. Gustav can be 16 Sies, H. (1986) Biochemistry of oxidative stress. Angew. Chem.
called truly senior as scientist, having helped shape Int. Ed. 25, 1058 – 1071.
17 Di Mascio, P., Sies, H. (1989) Quantification of singlet oxygen
scientific careers in all parts of the world, including generated by thermolysis of 3,3-(1,4-naphthylidene) dipropi-
many in Germany, with myself being lucky to know onate. Monomol and dimol photoemission and the effects of
this superbly generous scientist. 1,4-diazabicyclo(2.2.2)octane. J. Amer. Chem. Soc. 111, 2909 –
2914.
The motto I give to new students joining the lab:
18 Di Mascio, P., Kaiser, P. S., Sies, H. (1989) Lycopene as the
“Science is to learn to live with a constant level of most efficient biological carotenoid singlet oxygen quencher.
frustration and enjoy the fascination!” Arch. Biochem. Biophys. 274, 532 – 538.
19 Sies, H., Stahl, W. (2004) Nutritional protection against skin
damage from sunlight. Ann. Rev. Nutr. 24, 173 – 200.
1 Sies, H. (2007) How I became a biochemist. IUBMB Life 59, 20 Meier, B., Radeke, H.H., Selle, S., Younes, M., Sies, H., Resch,
469 – 473. K., Habermehl, G.G. (1989) Human fibroblasts release reac-
2 B
cher, T., Sies, H. (1969) Steady state relaxation of enolase in tive oxygen species in response to interleukin-1 or tumor
vitro and metabolic throughput in vivo of red and white rabbit necrosis factor-alpha. Biochem. J. 263, 539 – 545.
muscles. Eur. J. Biochem. 8, 273 – 283. 21 Abdelmohsen, K., Gerber, P.A., von Montfort, C., Sies, H.,
3 B
cher, T., Klingenberg, M. (1958) Wege des Wasserstoffs in Klotz, L.O. (2003) Epidermal growth factor receptor is a
der lebendigen Organisation. Angew. Chem. 70, 552 – 570. common mediator of quinone-induced signaling leading to
4 Brauser, B., Sies, H., B
cher, T. (1969) Reduction kinetics and phosphorylation of connexin 43: role of glutathione and
content of cytochrome P-450 by application of dual wavelength tyrosine. J. Biol. Chem. 278, 38360 – 38367.
techniques to hemoglobin-free perfused rat liver. FEBS 22 Polidori, M. C., Stahl, W., Eichler, O., Niestroj, I., Sies, H.
Lett. 2, 167 – 172. (2001) Profiles of antioxidants in human plasma. Free Radic.
5 B
cher, T., Brauser, B., Conze, A., Klein, F., Langguth, O., Biol. Med. 30, 456 – 462.
Sies, H. (1972) State of oxidation-reduction and state of 23 Arteel, G. E., Sies, H. (1999) Protection against peroxynitrite
binding in the cytosolic NADH-system as disclosed by by cocoa polyphenol oligomers. FEBS Lett. 462, 167 – 170.
equilibration with extracellular lactate/pyruvate in hemoglo- 24 Schewe, T., Sadik, C., Klotz, L. O., Yoshimoto, T., K
hn, H.,
bin-free perfused rat liver. Eur. J. Biochem. 27, 301 – 317. Sies, H. (2001) Polyphenols of cocoa: inhibition of mammalian
6 Sies, H., Brauser, B. (1970) Interaction of mixed function 15-lipoxygenase. Biol. Chem. 382, 1687 – 1696.
oxidase with its substrates and associated redox transitions of 25 Heiss, C., Dejam, A. Kleinbongard, P., Schewe, T., Sies, H.,
cytochrome P-450 and pyridine nucleotides in perfused rat Kelm, M. (2003) Vascular effects of cocoa rich in flavan-3-ols. J.
liver. Eur. J. Biochem. 15, 531 – 540. Amer. Med. Assoc. 290, 1030 – 1031.

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