Hermann (“Hugh”) Blaschko (1900 – 1993)

Introduction

Among the architects of metabolic pathways, the names Knoop, Warburg, Meyerhof, and Krebs are well known. Here we focus on Hermann “Hugh” Blaschko, whose name may be less well known, but whose work on the synthesis and degradation of catecholamines set the foundation for countless, game-changing therapeutics throughout the 20^th and 21^st centuries (Fig. 1).

Figure 1:

Dr. Hermann “Hugh” Blaschko (left), best known for elucidating these four steps of catecholamine biosynthesis from the amino acid tyrosine (right). Adapted from Reference 3.

Research on the chemistry of life thrived in Germany at the beginning of the last century. It started, however, in France, and was subsequently pursued in Britain and in the United States by refugee scientists when German universities and academic medicine came under ideological massacre in the 1930s. Blaschko’s life was profoundly affected by the circumstances of his time. It also remains a challenge to separate his personal life from his life as a medically trained scientist because these two lives were so closely intertwined. Here we make a brief attempt to do so.

Like his peers, Blaschko was one of the many German-born and German-educated, refugee scientists in the first part of the last century[1]. The fortunate ones among them found opportunity in adversity. In addition, as shown in the examples of Blaschko, Krebs and many others, the circumstances eventually resulted in a unique amalgamation of two cultures (the British and the German) within each person. However, Blaschko’s discoveries in the field of catecholamine metabolism which unequivocally shaped the course of metabolic, cardiovascular, and neurological medicine were all made in England. To this day, the degradation and synthesis of catecholamines remains an active field of research.

Vita

Hermann Felix (called Hugh) Blaschko was born in Berlin in 1900, the same year his friend Hans Krebs (the first author`s mentor) was also born. Both were born into large, highly educated, German, Jewish, middle class families. Blaschko and Krebs first met when they were medical students in Freiburg im Breisgau, and became life-long friends. It was through Krebs that the authors got to know Blaschko. “We still lived in Victorian times” Blaschko often joked. Queen Victoria died in 1901.

Blaschko attended medical school in Berlin and in Freiburg, where he graduated in 1922. He then moved to Göttingen for his clinical training before moving back to Berlin to join Otto Meyerhof’s lab. Like Krebs, Blaschko spent his formative years in the presence of academic teachers who had made important contributions to the physiology of neurotransmission and metabolism. In recollections from his student days, Blaschko often mentioned Otto Loewi, Otto Meyerhof, Edith Bülbring, and Karl Lohmann. Loewi had demonstrated the principle of neuroendocrine transmission in the isolated frog heart, Meyerhof had unraveled the interconnected reactions of the glycolytic pathway, Bülbring became the “mother of smooth muscle physiology,” and Lohmann discovered ATP, the energy currency of the cell. In short, in the 1920s, acquisition of scientific knowledge made quantum leaps in Germany, in parallel with a vibrant cultural scene, before the fatal turn of events in 1933, which started with the dismissal of anyone with a Jewish background from Public Service jobs, including University appointments, and which ended with the Shoah. The darkest chapter in German history.

Returning to the time before 1933 Blaschko’s background also had much to do with his scientific outlook and research interests. In Germany a century ago, there was a distinguished tradition that linked clinical medicine and bench research. Blaschko’s career exemplified this translational form of research. In his autobiographical notes[2], Hugh Blaschko wrote about the significant milestones in his development as a scientist, and provided a perspective of his own research in a broad context.

In addition to Blaschko’s peers and mentors in the scientific community, Blaschko’s family left a significant footprint in the academic and scientific community, and this unique upbringing greatly impacted his path to academic medicine. His father, Alfred Blaschko, was a well-known dermatologist and engaged social reformer. Berlin has named a street after him (Blaschkoallee). One of Hugh’s sisters was a physician, while the other was married to a physician. Blaschko’s family was large, and his many cousins were prominent figures in various sectors of academia, commerce, and social activism.

The 1930s was a time of political polarization in Germany, culminating in the collapse of democracy and the persecution of people of Jewish heritage. Many Jewish writers, scientists, artists, and intellectuals suffered heinous oppression and death at the hands of the National Socialist regime, while others fled the country. Blaschko’s migration in May of 1933 from Germany to England was a rational and life-saving decision. The transition to England seemed seamless due to his prior exposure to British culture and science, which came about through his six-year “apprenticeship” (post-doctoral fellowship in today’s terms) in Otto Meyerhof`s laboratory. It was in 1929 that Meyerhof sent Blaschko to work with his colleague A.V. Hill at University College London. Hill was the other leading muscle physiologist at the time, with whom Meyerhof had shared the Nobel Prize in Medicine in 1922. In 1930, after a year in Hill’s lab, Hugh returned to Germany, only to leave again for Britain, when the Nazis came to power. At first he continued assisting A.V. Hill until 1934. At Hill’s recommendation, Blaschko joined Sir Joseph Barcroft’s physiology department in Cambridge. Here, some of his best work took place. In 1944, Blaschko moved to Oxford on the invitation of J.R. Burns, the Professor of Pharmacology. Blaschko remained in Oxford until he died, nearly 50 years later.

In later years, Blaschko came to regard his decade in Cambridge as the most productive period of his life. With great pride, he used to mention cheerfully that five of his former students in Cambridge went on to win the Nobel Prize (personal communication). One of them, Fred Sanger, even won the prize twice. Blaschko was a prolific experimental biochemist, and just like his close friend Krebs, his many discoveries resulted from his use of manometry to study enzyme-catalyzed reactions. Blaschko’s passion for catecholamine metabolism persisted throughout his life. In his last paper, written in 1988, he describes an effective precursor for noradrenaline and a lifesaving treatment for patients lacking an essential enzyme, dopamine-β-hydroxylase. In short, his commitment to scientific advancement remained active throughout his whole life.

The Story of Catecholamine Metabolism

Blaschko’s fundamental discoveries deal with the metabolism of catecholamines and may be grouped into three major themes: 1) The inactivation of adrenaline. 2) The pathway of catecholamine synthesis. 3) The secretion of adrenaline from the adrenal medulla[2]. The degradation of adrenaline was Blaschko’s first major discovery. Prior to his findings, scientists assumed that autooxidation was the mechanism of degradation within the body. Blaschko, however, proposed that there is a biological system that is responsible for degrading adrenaline. Using animal tissue extracts incubated with adrenaline in a Warburg manometer, Blaschko measured that adrenaline activity ceased when one molecule of oxygen per molecule of adrenaline was consumed. He noticed that the biological system was thermolabile and non-dialyzable, signifying that an enzyme was responsible for the inactivation of adrenaline[2]. He thus discovered monoamine oxidase, the cornerstone for treating both depression and Parkinson’s disease.

1. In 1942, Blaschko contributed his second, and perhaps most important, discovery by outlining the biosynthesis pathway of catecholamines[3]. Using human kidney extracts, he observed the highly specific activity of L-dopa decarboxylase and postulated that this enzyme is involved in an intermediate reaction between the synthesis of adrenaline from tyrosine. Linking his experimental findings together with findings by others, Blaschko accurately outlined the steps of catecholamine biosynthesis: 1) introduction of the second phenolic hydroxyl group to tyrosine. 2) decarboxylation of L-dopa. 3) introduction of the side chain carboxyl group to dopamine. 4) N-methylation (Fig 1)

In 1953, Blaschko contributed key findings to the storage and release of adrenaline form the adrenal medulla. Blashcko performed differential centrifugation of cattle adrenal medulla and conducted a series of pivotal experiments. He found that the majority of catecholamines in chromaffin cells are stored in granules resembling mitochondria, and he proposed that there is a specific mechanism for their release.

The synthesis of adrenaline from tyrosine, starting with the hydroxylation of tyrosine followed by the modification of two more intermediates, is perhaps Blaschko’s best-known work (Fig. 1). The importance of this short pathway is on par with longer metabolic pathways, like the glycolytic pathway (Meyerhof) or the citric acid cycle (Krebs). He was the first to describe the sequential synthesis of a set of ubiquitous receptor ligands, which govern the function of living cells, playing an integral role in the function of heart muscle, smooth muscle, and nerve cells. Blaschko’s elucidation of the biosynthesis and metabolism of catecholamines is therefore a classic in the application of biochemical methods for solving pharmacological problems. Blaschko writes: “In biochemical pharmacology, catecholamines have long occupied a position of particular interest. One remarkable feature of these amines is that they have been on the scene for a long time and that during that period they have always presented aspects of both scientific and clinical importance. Also, they were the first paradigm of chemical messengers that reached their targets by two distinct routes: By the bloodstream, as hormones, and by local release, as neurotransmitters”[3].

Blaschkòs work was reported in a series of single or two-author papers in Nature and other high-profile journals at the beginning of his career. Towards the end of his scientific journey, Blaschko again published many single-author papers, placing his discoveries into perspective[4]. Considering the limited technology at the time of his discoveries, Blaschko’s work is even more impressive, consisting of novel hypotheses that were vigorously tested in technically and intellectually creative ways.

Friend to many

While Blaschko made a profound mark in the world of medicine, he also deeply impacted many people throughout his journey. At the time when political intolerance began to disrupt academic work in Germany, Blaschko was welcomed in England by A.V. Hill and friends. Initially, he helped A.V. Hill to establish a society, now called the Society for the Protection of Science and Learning, that was founded in the wake of the forced exodus of scientists from Germany. A decade after arriving in England, Hugh Blaschko married Mary Black, whom he had met in Oxford. Their home provided hospitality to colleagues, students, their families and visitors from around the world. The last author was very fortunate to be able to play his sister`s beautiful Blüthner grand piano which had been transported from Berlin before the outbreak of war. After one such occasion, Hugh – then in his nineties –remarked that the music had brought back memories of his sister and had made him feel happy. Kind words that will never be forgotten. His active interest in research and the personal investment in people performing research at the bench continued up until the month he died. Hugh touched the lives of many people throughout his life, and his reach spanned many generations and corners of the globe. We are convinced, were Mary and Hugh be alive today, their house would always be open, providing warmth and kindness to whoever may show up. After Blaschkòs death, the University of Oxford established a Blaschko Visiting Research Scholarship through a benefaction from his widow.

One interesting attribute of Hugh`s was his photographic memory. Once he had read a scientific paper, he could recall every detail many years later. He even remembered telephone numbers without writing them down. Surely, Hugh would have embraced the internet, and we can only ponder what other discoveries he would have made with the world’s information in the palm of his hand!

The general sentiment of Hermann Blaschko is well-reflected in a tribute by Professor A. David Smith, then chair of the Department of Pharmacology at Oxford: “Hugh seemed to me to be a very contented man in the 35 years I had the privilege of knowing him. In his scientific life he had managed to satisfy his curiosity many times and had revealed nature’s secrets; I think he was also content because throughout his life he had been able to help his fellow human beings in many ways. Probably what gave him the greatest joy were the successes of his scientific family” [5].

Summa:

Hermann Felix Blaschko (1900 – 1993) was a physician-scientist of great distinction whose prolific career spanned a period of enormous political upheaval. As a person, Blaschko is remembered for his kindness, modesty, and discipline. His research provided the basis for the pharmacological treatment of common cardiovascular, neurological and psychiatric disorders. His contributions to medicine continue to help people every day, and his life-story is an inspiration to many. For interested readers, we recommend the comprehensive biography of Hugh Blaschko published by the Royal Society[6].

Main Discoveries.

• The degradation pathway of catecholamines

• The storage and secretion of adrenaline from the adrenal medulla

• The biosynthesis pathway of catecholamines