UCSF home page UCSF home page About UCSF UCSF Medical Center
UCSF navigation bar
photos

In Memoriam

Antony F. McDonagh, Ph.D.

September 30, 1938 – October 22, 2012

Antony McDonagh

Photobleaching of bilirubin on cloth (Tony McDonagh, ca. 1975)

The cotton shirt worn by the leaping buffoon was dyed yellow by immersion in a saturated solution of bilirubin in 0.05M Tris buffer, pH 8.5. After being washed (buffer, distilled water), wrung (manually), dried (high-vacuum) and pressed (warm iron), selected areas were exposed to midafternoon sunshine through plate glass for about 4 hours. Covered areas (dark on the photo) remained bright yellow; exposed areas became almost white. The photograph was made through a blue lens filter. (McDonagh AF, Palma LA. Mechanism of bilirubin photodegradation: role of singlet oxygen. Fogarty Proceedings No. 35. Chemistry and Physiology of Bile Pigments (April 1975), P. D. Berk, N. F. Berlin, eds. DHEW Publication No. 77-1100, pp. 81-86.)

Our friend and colleague, Tony McDonagh, was born in the north of England, near Manchester. His grandparents on both sides were among the Irish who migrated to England after the mid- 19th Century potato famine. Tony’s parents grew up poor, without an opportunity for higher education, which made his father ambitious for his children. All four went to university. Tony, the second oldest, was a wayward student during his first year but re-grouped, achieving Honors in Chemistry. He then went to the U.S. for a PhD in organic chemistry at Vanderbilt University, after which he returned to England for three years as a postdoctoral research assistant with Prof. Raymond Bonnett at Queen Mary College, University of London. It was Bonnett who introduced him to the colorful world of tetrapyrroles, a group of chemicals that includes heme (the red of hemoglobin), chlorophyll (the green of photosynthesizing plants), and bilirubin, the yellow of jaundice. The most pressing clinical question of the day involving bilirubin was neonatal jaundice, which in some infants resulted in permanent brain injury, a condition known as kernicterus. Premature babies were most at risk, because their liver was immature and not yet fully capable of conjugating and excreting bilirubin. Exposure to light brought down the level of jaundice, but the mechanism was unclear. Fear that the degradation products could be as toxic as bilirubin itself led many centers to employ exchange transfusion to keep the blood bilirubin below the danger zone while waiting for the liver to mature.

Tony’s initial studies in London, 1966-69, concerned the role of active oxygen and light on bilirubin degradation in the test tube. The work caught the attention of Rudi Schmid, who a few years earlier had founded the Gastrointestinal Research Unit at the University of California, San Francisco (UCSF). Rudi had made his name initially by demonstrating that water-soluble bilirubin was a glucuronide conjugate. Although biochemistry was the new science of the day, Rudi saw chemistry as still required for work at the cutting edge. He recruited Tony as the person to provide it, and his enthusiasm for this initiative was boundless. In the months prior to Tony’s arrival in 1971, many a lab discussion was concluded by his stating “Tony McDonagh will solve this”. This went on for several months, a period that in the lab became known as Waiting for McDonagh.

Tony’s space needs were modest, but absolute control of ambient light was essential for studying light-induced events. There was no convenient dark room, so Tony designed a tent-like structure made of blackout curtains, erecting it in a back corner of the lab. The work behind the curtain, being invisible, took on a certain aura. However, all became clear with Tony’s initial presentation of his research-in-progress. The experiments were novel, cleverly designed and carried out with meticulous technique. Moreover, Tony was eager to share his knowledge and collaborate with his biologically and medically oriented colleagues. He played a vital role in the Gastrointestinal Unit, impacting on virtually every member of the group, not insisting on publication credits in return for advice -- just making organic chemistry real and relevant, much as Rudi had envisioned.

Tony’s seminal discovery came during his first years in San Francisco and illustrated yet again that chance favors the prepared mind. At a Gordon Research Conference on tetrapyrroles in the mid-1970’s, one of the speakers was his old mentor, Ray Bonnett. The topic was the chemical properties of unconjugated bilirubin. Although bilirubin’s structure predicts ionizable groups and therefore water solubility, the molecule in fact is minimally soluble in physiological media. Bonnett pointed out that bilirubin is not planar (as commonly depicted). Rather, its two halves are free to rotate around the central carbon. He postulated that rotation allows formation of internal hydrogen bonds, which would neutralize the ionizable groups and account for the lipophilic character of the pigment. Bilirubin glucuronide is water-soluble, because conjugation interferes with hydrogen bonding. Listening to the talk, Tony had the brilliant insight that light energy might disrupt the hydrogen bonding, creating – at least, transiently – a hydrophilic form of bilirubin that would be taken up by the liver and excreted like the glucuronide conjugate. Back in the lab, he produced the evidence for this idea in elegant detail, characterizing the postulated photoisomer not only in the test tube but also in vivo. For the latter, he used the Gunn rat, which lacks bilirubin glucuronyl transferase, has high levels of unconjugated bilirubin from birth and exhibits neural deficits – in short, an animal model for neonatal jaundice and kernicterus. Tony showed that the Gunn rat exposed to light has ‘photobilirubin’ in its plasma, which the liver takes up and excretes into bile. In bile, the photoisomer reverts spontaneously to native unconjugated bilirubin. The work provided the scientific basis for phototherapy as a non-toxic remedy for neonatal jaundice. Its clinical impact has been enormous, allowing many thousands of premature babies with an elevated bilirubin to be spared the risks of exchange transfusion. Tony’s contribution to the field of neonatology was recognized in many ways but most recently with a Neonatal Landmark Award, which he received at the annual meeting of the American Academy of Pediatrics in New Orleans, a few days before he unexpectedly passed away.

Tony was an inspired teacher. For nearly 15 years starting in the late 1970’s, he gave the lectures on heme synthesis and bile pigments to first-year students of the Schools of Medicine and Pharmacy at UCSF. His goal was to convey the fascination of tetrapyrrole biology in a way that would engage students of widely varying background who moreover were already saturated with information. He decided on a multi-media approach combining light, music, live animals and assorted high jinx. The idea of using music was not accidental. Tony’s interest in music was linked to his first efforts in science, which consisted of making a radio that could pick up 1950’s broadcasts of the American armed forces network. He wanted to hear jazz and early rock and roll that were not available on BBC. He was a good pianist, favoring rags and boogie, ready to perform whenever a piano was at hand.

His lecture approach was avant garde, coming well before digital slides; the preparation was lengthy and meticulous. For the initial talk on heme, he had a series of slides showing its step-by-step synthesis. As befits a molecule described as the origin of life (because of its oxygen-binding function), Tony synchronized the slides to the portentous opening of Richard Strauss’ Also Sprach Zarathustra (familiar also as the music for Kubrick’s 1968 film, 2001:A Space Odyssey). In the lecture on bilirubin, one of his props was a Gunn rat (see above). At the start of the talk, Tony put the animal on a counter in the front of the lecture hall and invited it to jump through a small metal hoop. The rat seemed stunned into immobility and only quivered on all fours. Tony explained that a high circulating bilirubin had affected its motor function. He then put the rat back in its cage under a light and invited his audience to keep an eye on it while he talked. The next 40 minutes were a brilliant exposition of bilirubin toxicity and phototherapy. He then removed the rat from underneath the light and again presented it with the hoop. Clearly there was no discernible effect of its exposure to light. Tony gave the rat half a minute to do something. Then, feigning impatience, he picked it up and dumped it through the hoop, apologizing for bringing a substandard animal that apparently was a little under the weather. It was pure theater in the service of a complex and important story. The students found it riveting. Many times over the years that he gave the talks, Tony was nominated for best lecturer in a first-year course. More astonishing, the same students returned in significant numbers the following year to catch the performance again. Some even brought dates. It made for a packed lecture hall.

Tony’s exuberant teaching style (see Figure) extended to his writing. He kept files of bilirubin esoterica gathered from every conceivable source. He did the same for porphyrins and related topics, weaving the material into his papers, which at the same time are models of clarity. Lycanthropy became an interest because of stories in the popular press (far-fetched, needless to say), which claimed that the vampire and werewolf legends were based on actual people afflicted with porphyria. This and other apocrypha are covered in a 1998 review of porphyria that he co-authored with one of us (1).

Tony’s fun included pranks albeit the sophisticated variety. In the late 1970’s while he was working on photobilirubin, others were carrying out studies of bilirubin glucuronidation both in San Francisco and New York. The two groups were locked in combat over their theories and findings. This played out at annual meetings of the American Association for the Study of Liver Diseases, where research presentations on this topic took the form of offensives and counter-offensives. It was a source of much amusement for Tony, who like many bystanders failed to see the reason for so much heat. At one of the meetings, he decided to submit a satirical abstract, purportedly co-authored by both camps, giving the principals transparent pseudonyms and composing some scientific gibberish for the text. It was the practice in those days to publish all abstracts, so Tony’s appeared and was widely enjoyed. Rudi Schmid was not amused, although eventually he relented. In the same vein, Tony’s favorite gift for friends was often a wind-up mechanical toy that he would find on a trip, usually in Asia. The toys were typically small and intricate, with movements that were unpredictable and hilarious. Some were displayed in his office along with shamanistic relics and bezoars. The collection included a “boxing nun” with aggressive arm action and a mischievous, come-hither facial expression.

Tony never married and had no children but was a family man. He was interested in the children of his friends, happy to be an honorary uncle when given the opportunity. Similarly, he was very pleased that his work meant something for families with jaundiced newborns. For a number of years he starred at the annual Christmas party of the Gastrointestinal Unit, which featured the small children of the faculty, trainees and staff. He played Santa Claus in a red suit and beard, handing out gifts to the kids. When that was over, he would shed the costume and move to the piano for holiday music, occasionally drifting into a boogie version of “The First Noel”. For most of his life, he was far from England but always in touch with his siblings and proud of them. His older sister, Pat, studied at Manchester University and the Sorbonne. She is a well-known fashion designer based in Toronto. Tony’s younger sister, Bernadette, became head of St. Dominic’s international school near Lisbon, Portugal. The last of the four, Michael, earned a business degree in London, went initially into advertising, then moved to the music sector, first with record companies, then bands. He lives in London and credits Tony for seeding his interest in music.

Also celebrating the memory of Tony McDonagh is a host of friends, who not surprisingly represent a spectrum. Some did science with him while others did music, traveled or jogged with him (running was another of his passions). For the most part, these were distinct groups of individuals with not much crossover. What they had in common was Tony, and to a person they will miss his original mind, his collaborative spirit, his eclectic interests and, above all, his generosity and loyalty.

Tony’s discovery of bilirubin photoisomerization and, in the same decade, elucidation of the enzymatic conversion of heme to bile pigment by the Schmid group seemed at the time to be the final chapters of the bilirubin story, leaving only minor cleanup. Just when many thought it safe to move on to other areas, however, Tony and colleagues at UC Berkeley showed that this yellow ‘waste product’ is also a powerful endogenous antioxidant (2), opening up an area of research that remains very active. In one of his last reviews, Tony covers this as well as several other active issues in bilirubin biology (3). It’s a forward-looking paper, written with Tony’s signature clarity and flair. Sadly the person who was best prepared to provide the answers is gone. We await his successor.

References

  1. McDonagh AF, Bissell DM. Porphyria and porphyrinology – the past fifteen years. Seminars in Liver Disease, 1998;18:3-15.
  2. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043-6.
  3. McDonagh, AF. Controversies in bilirubin biochemistry and their clinical relevance. Semin Fetal Neonatal Med 2010;15:141-7.

Achnowledgment:

We are grateful to Michael Mcdonagh for sharing information on Tony's formative years and his family.

D. Montgomery Bissell, MD
Averil Ma, MD
Division of Gastroenterology, Department of Medicine, UCSF

Maria Almira Correia, PhD
Department of Cellular & Molecular Pharmacology, School of Medicine, UCSF