Terra Sigillata

Have you ever taken one of the now-over-the-counter heartburn relief remedies like Tagamet, Zantac, or Pepcid?

How about the beta-blocker atenolol (Tenormin) or metoprolol (Lopressor) for antihypertensive therapy, or the original less-selective beta-blocker propranolol (Inderal) for migraines, presentation anxiety or stage fright?

Sir James Black - David Levenson Rex Features.jpgIf you answered yes to either question, you owe a debt of gratitude to Sir James Black, the Scottish physician who left us earlier this week at age 85. The best obituary I have seen memorializing Sir James comes from the UK Telegraph.

Black was called the father of analytical pharmacology and was said to have relieved more human suffering than thousands of doctors could have done in careers spent at the bedside. Certainly, no man on earth earned more for the international pharmaceutical industry.

Yet though he became joint winner of the Nobel Prize for Medicine in 1988, Black derived little personal financial benefit from his discoveries. Among businessmen he had a reputation as an irascible maverick and this prickly independence, combined with an antipathy to big institutions, led him to flounce out of jobs whenever he felt corporate short-sightedness was getting in the way of research.

Others can be read at The Independent, The Times, The Guardian, The Scotsman, and BBC News.

It is rare for a scientist to discover one drug that makes it to market. Sir James not only led the discovery of two major drugs, propranolol and cimetidine. As if that were not enough, each drug was a “first-in-class” agent, the first approved drug that acts via a novel mechanism of action.

Sir James was trained originally as a physician and cardiovascular physiologist and then wisely teamed with medicinal chemists to make his discoveries. Hence, most scientists refer to Black as a pharmacologist. He was the consummate physician-scientist.

A native of the coal-producing region of Fife in Scotland, Sir James earned his medical degree from St. Andrews in 1946. Sir James split his career almost equally between pharmaceutical companies and academia, unusual for a scientist of his generation but provided a combination of experiences the facilitated his drug discovery efforts. He spent the last part of life and career at University College London.

His methodological claim to fame was to discover drugs not by random screening but by careful structural design based upon known stimulatory molecules, or agonists.

The discoveries
For propranolol, Sir James seized upon the 1948 landmark work of Raymond Ahlquist at the University of Georgia who used a series of ligands that bound to adrenergic receptors to subdivide these in to alpha and beta receptors (Am J Physiol 1948; 153:586-600 – Citation Classic reflection here). Most naturally-occurring adrenergic chemicals such as epinephrine (adrenaline) and norepinephrine (noradrenaline) bind somewhat non-selectively between α and β receptors but Ahlquist demonstrated that a compound called isoprenaline or isoproterenol selectively stimulated adrenergic effects on the heart (the increase heart rate and force of contraction) while having little effect on adrenergic receptors on constriction of blood vessels. The former effect is due to β receptors while the latter is due to α receptors. These receptors were subsequently divided into subtypes based on chemical and molecular biological studies.

Black reasoned that one could make structural modifications of known stimulatory molecules to create similar compounds that instead blocked those receptors. That is how he developed propranolol as an antihypertensive and antiangina drug in the late 1950s. We did not know until 1967 that there were at least two classes of β receptors: β1 and β2. Propranolol is relatively non-selective for these two. More modern beta-blockers for cardiac indications are more selective for β1 receptors.

Sir James similarly attacked the issue suppressing gastric acid secretion by recognizing from physiology that this process was stimulated by histamine. We know that histamine causes blood vessel dilation and “leakiness” that results in swelling of our mucous membranes and general misery during allergy season. The drug diphenhydramine (sold as Benadryl in the US), blocked the effect of histamine on mucous membranes but had no effect on gastric acid secretion. Black worked with chemists to modify the structure of histamine to block gastric acid secretion with little effect on other effects of histamine. This work led to the discovery of cimetidine, the first selective histamine H2 antagonist.

For these two discoveries, Sir James shared the 1988 Nobel Prize in Physiology or Medicine with Gertrude Elion and George Hitchings for their discoveries of several anticancer and antiviral compounds. Regular readers will know that Gertrude Elion is one of my personal heroes. Interestingly, Elion and Hitchings also did their work at a pharmaceutical company, Burroughs-Wellcome (swallowed up by Glaxo followed by SK&F), and also based their first anticancer drugs on endogenous compounds, nucleotides.

The Nobel Prize website features Sir James Black’s autobiography, upon which some of the obituaries were based. Nobelprize.org also has a nice 16-minute interview with Sir James from 2001 where he shows both his humility and charm.

Personal reflections
I was very fortunate to hear Sir James speak at my 1985 graduation from the Philadelphia College of Pharmacy and Science, a few years before he won the Nobel. At the time, I was doing my internship at the US side of SmithKline & French, the same company where Black had designed and developed cimetidine in the UK. I recall being struck by his urging that we graduates continue to conduct research for the sake of advancing the base of knowledge rather than necessarily focusing on creating a saleable product.

Sir James had become concerned that universities had then started becoming much like businesses increasingly focused on producing revenue-generating intellectual property. His concern was that universities were no longer valuing solid basic research and contended that the business of drug discovery is best left to businesses. He used as an example, that also shows up in his 2001 Nobel interview, that Ahlquist’s basic physiology research in academia provided the knowledge base for Sir James to design propranolol. Today, drug companies are even further outsourcing their research and development efforts, emphasizing the need for academics to continue basic research.

The commencement address by Sir James has stayed with me and impressed upon me the value of purely basic research – in the intervening years, I’ve been surprised by how the most seemingly esoteric work with worms and marine creatures has led to new drugs while so-called targeted therapies and drug discovery efforts have been less than successful.

Sir James remained active until his recent illness. He is a co-author on a 2010 paper assessing a cholecystokinin-2/gastrin antagonist for gastric cancer and he wrote a 2009 review reflecting on clinical trials of gastrin antagonists against pancreatic cancers.

I did not come to know him personally but one can learn the measure of a man by his writing. In his autobiography at Nobelprize.org, Sir James wrote of his first wife:

I met Hilary Vaughan at a Student Ball in 1944 and we married in the summer of 1946, as soon as I graduated. I joined the Physiology Department under Professor R.C. Garry in October 1946 and Hilary, completing her degree in Biochemistry, was the best student I ever had. Had she chosen a sectarian approach to study she would have become a visible star but her eclectic pursuit of knowledge and her unwavering support for her family led her to study law and choose poetry as a distillate of her wisdom. Intellectually she was the most exciting person I have ever known and, quite simply, the mainspring of my life until she died in 1986.

Sir James was loved by his many students and colleagues. One of these is physiologist and pharmacologist Richard A. Bond at the University of Houston College of Pharmacy. I met Bond during a seminar visit to Houston in 2002 and he mentioned being engaged with Sir James regarding his recent work in paradoxical pharmacology, examining how β2 agonists used to treat asthma can trigger asthma attacks – a very timely topic given the recent regulatory warnings on long-acting beta agonists (LABAs).

Bond’s friendship with Sir James grew to the point that he wrote the obituary (PDF) for his colleague on the website of the British Pharmacological Society. Bond also posted this personal reflection (PDF) on Sir James that speaks volumes of the man and his priorities:

In the mid 1990′s I was walking with Sir James at a scientific congress in San Diego. A very distinguished scientist approached us and said, ‘Jim, I need 30 minutes of your time to discuss some things with you’. To which Sir James politely replied, ‘of course, please have your secretary contact my office and we will schedule it’.

We walked along for another ten steps or so, and a frightened and awestruck student approached us and quietly mumbled, ‘Sir James, would it be possible to have 5 minutes of your time to show you my data?’ Sir James simply put his arm around the student and said, ‘Why don’t we have lunch?’

That story has forever affected my attitude about how important students are.

The following information has also been posted at the British Pharmacological Society webpage:

His wife and family welcome all wishing to attend his funeral service. The service will be held at St Colomba’s Church of Scotland, Pont Street, Knightsbridge, London SW1X 0BD on Monday 29 March at 11am

If you would like to send us your reflections or memories of Sir James for inclusion in an online book of remembrance, please email them to Hazel O’Mullan (hom [at] bps [dot] ac [dot] uk)

Addendum: At In the Pipeline, pharma medicinal chemist blogger Derek Lowe has a post and interesting comment thread on Sir James as well.

Comments

  1. #1 awb
    March 28, 2010

    I had no idea. Thank you.

  2. #2 Abel Pharmboy
    March 29, 2010

    Here’s a link to more British press that has come out since with colleagues elaborating on the impact of Sir Jame Black’s discoveries:

    http://www.timesonline.co.uk/tol/news/uk/scotland/article7078238.ece

    For example,

    Beta-blockers were swiftly taken up for use on people suffering angina, heart disease and hypertension. Their success is writ large in mortality figures for coronary heart disease, which show that in 1978, in the UK, it killed 255 of every 100,000 men aged 35-74. That figure had plummeted to 65 per 100,000 by 2007.

  3. #3 thomas
    April 5, 2010

    Some of these figures are perhaps amplified a bit by the occasion. Surely it doesn’t take anything away from Sir James’ very real accomplishments to point out that a four-fold reduction in CHD mortality needs a whole lot more than beta-blockers.

    Even if one believed that a normal blood pressure attained with a beta-blocker was as safe as the same blood pressure attained by non-pharmacological means, and even if everyone was treated, the mortality rate would only go down by roughly 30% for the typical 10/5mmHg reduction in blood pressure.

    There have been reductions for multiple reasons in both incidence and case fatality for CHD over this time period. The MONICA project is trying to estimate and disentangle these contributions.

    It’s also interesting to note that of the other major classes of antihypertensive drugs, thiazide diuretics came about serendipitously from failed attempts to design better carbonic anhydrase inhibitors, and ACE inhibitors were developed in imitation of a protein in the venom of a South American snake. [I don't know the history of angiotensin receptor blockers and calcium-channel blockers, which may well have been developed in a way closer to Black's approach to beta-blockers]

    I loved the story about making time for the student, though.