HISTORY: Rosalind Pitt-Rivers, the co-discoverer of T3 hormone

The co-discoverers of the T3 hormone (triiodothyronine) in 1952 were

• Rosalind Pitt-Rivers, MD, PhD (London) and
• Dr. Jack Gross, MD, PhD (McGill) from Canada.

 

Rosalind Pitt-Rivers’ early life

Dr. Jamshed Tata, one of Pitt-Rivers’ many co-authors, wrote the Biographical Memoirs of Dr. Pitt-Rivers, in 1994. This work is the main source of this profile.

Tata writes,

When she was about 12, Ros was given a chemistry set by an uncle.

This present proved to be such a great success that she, along with her cousin Ed, the future Lord Stanley at Alderley, was given the stables (presumably part of Alderley) to be used as a laboratory.

The inhabitants of the estate were not only alarmed by the smells that emanated from there but remember at least one explosion that came quite close to a disaster.

Later in life, she told her sister Juliet that this present lay at the origin of her interest in, and life-long love for, chemistry. (p. 229)

Marriage, family and PhD

She married in 1931 to her cousin, Captain George Pitt-Rivers. They had a son, and Rosalind temporarily gave up her desire to pursue her doctorate.

Rosalind’s mother disapproved of their marriage, and their marriage deteriorated within a year after Anthony’s birth.

By 1937, she left their farm and estate, and filed for divorce.

That very year, Rosalind restarted her research career at the Department of Pathological Chemistry at the University College Hospital Medical School, London, where she was mentored by one of her future co-authors, Sir Charles Harington.

She earned her PhD in 1939, and then moved to Harington’s laboratory to work on the biosynthesis of L-thyroxine (T4 hormone).

In 1941 Rosalind and Harington joined the scientific staff at the National Institute for Medical Research (NIMR), the largest unit of the Medical Research Council (MRC) located in London. She remained on staff for 30 years, until her retirement in 1972.

The trauma of World War II

During the Second World War, Rosalind’s career was temporarily diverted toward the war efforts. She worked at a blood transfusion unit, a hospital, and a wartime project to increase milk production from cows.

In 1945 she was placed in an army group in Belgium, where she studied nutrition on prisoners of war.

Rosalind was detained in Belsen concentration camp for three weeks until the Allies liberated it. Tata writes of this episode,

The horror of what she saw there remained strongly etched in Ros’s memory, and on numerous occasions for the rest of her life she recounted her shock at seeing the inmates and witnessing the painful recovery of the fortunate few.

She told her friends that this terrible episode turned her into a heavy smoker, for which she was to pay a high price with her health 25 years later. (p. 332)

The exciting discovery of T3

After the war, Rosalind Pitt-Rivers returned to research, publishing several articles about thyroxine (T4) with Harington and co-workers.

Harington assumed an administrative position, after which Rosalind became independent in her own laboratory. She assisted Harington with his publications while he was busy with managerial duties.

Her laboratory competed with Jean Roche’s laboratory in Paris to identify the various metabolites of thyroxine.

Dr. Jack Gross entered the scene in 1950. As Tata writes,

In the autumn of 1950 a young Canadian anatomist and endocrinologist, Dr Jack Gross, came to the NIMR as a postdoctoral fellow to work with Ros.

Before coming to Mill Hill, Gross had worked in Montreal at McGill University under Professor Charles Leblond, F.R.S., who pioneered with Frederic Joliot-Curie at the College de France the use of radioactive iodine (131-I) in investigating thyroid physiology, particularly the formation and secretion of thyroid hormone.

In Leblond’s laboratory at McGill, Gross had worked on the application of chromatography to the analysis of radioiodinated proteins in human blood following radioiodine therapy for thyroid disorders.

(In the early 1950s, it was common practice to administer very massive doses of 131-I for thyroid gland ablation.) …

Thus Gross came with the best credentials to perhaps the best laboratory in the world working on thyroid hormone chemistry when he joined forces with Pitt-Rivers.

In 1951, Gross and Leblond had described in the plasma of rats given 131-I the presence of an unknown radioactive compound called ‘unknown 1’ that migrated close to thyroxine in two-dimensional chromatography.

Gross had insisted that he and Ros continue this line of work in humans with utmost speed and vigour.

At about the same time Roche’s group in Paris (Roche, Michel, Lissitzky & Michel 1951) had described a deiodinating activity in sheep thyroid gland, thus raising the possibility that the unknown compound could be a less iodinated analogue of T4, possibly triiodothyronine (T3).

Three more papers were published on this subject by Gross and Pitt-Rivers in The Lancet in the four to six months that followed, each within two months of the other (25-27).

The first of these, entitled ‘The Identification of 3:3′:5-L-Triiodothyronine in Human Plasma’ is now history and must surely rank as the most important publication in Ros’ whole career.

Harington’s reaction to the discovery

This anecdote was told by Rosalind herself, in a letter to a colleague thirty years after the event:

When Jack Gross and I rushed into his [Harington’s] room (Fall 1951) and announced that unknown 1 was T3, he remarked

‘Oh, how disappointing’!

(I’m not sure why. Maybe he thought it was a breakdown product of T4 of no significance).

When, two weeks later, Jack and I again rushed into his office with the news that T3 was 3-4 x [times] more active than T4 in the goiter prevention assay, he was overcome with surprise.

The news evidently contradicted his long established beliefs. (Tata, p. 335)

Tata explains Harington’s reaction:

Harington’s scepticism about T3 must have had to do with his failure to detect it in the thyroid gland when, 20 years earlier, he was purifying thyroxine from this tissue. (p. 335)

Rosalind and Jack were incredibly productive over a period of five months as they rushed to prove that it was a hormone equally important as T4.

They had to show that it was synthesized in the thyroid gland and secreted along with T4.

In Gross & Pitt-Rivers’ publications in 1953, they went further than that. They did studies of the potency of T3 hormone in rats, and found that it was 5 times as potent in suppressing goiter (swollen thyroid gland) in rats. They also found that in humans, the effect of T3 on TSH suppression was “several times” more powerful than thyroxine.

They theorized, before there was conclusive proof, that

“triiodothyronine is the peripheral thyroid hormone and that thyroxine is its precursor.”

This intuition turned out to be correct, although it took many decades for the medical establishment to admit it.

It was difficult for many to believe that T4 was only a “pro-hormone” that little to no activity on its own, since T4 was the most abundant product of the thyroid gland.

The discovery of T3 hormone explained some prior research comparing the weaker effect of (levo)thyroxine (L-T4) than animal-derived desiccated thyroid. This reinforced the era’s preference for desiccated thyroid over thyroxine in thyroid therapy.

The comparative research showed that thyroxine lost more than half of its potency by being delivered orally rather than parenternally (i.e. by injection), whereas triiodothyronine retained most of its activity when delivered orally.

Frieden & Winzler (1948) found that parenterally administered desiccated thyroid was about twice as active as thyroxine when assayed by the goitre-prevention test. […]

A relatively small triiodothyronine content in the desiccated thyroid could well account for its increased potency. […] 

Further, these authors (Frieden, Tuckich & Winzler, 1949) showed that natural thyroid preparations given orally retained 70-98% of their potency by injection, while thyroxine retained only half its parenteral potency when given by mouth.

This difference could again be explained, at least in part, by the finding (Table 1) that oral triiodothyronine exhibits 85% of its parenteral activity, while oral thyroxine retains only about 40 % of its parenteral activity.

[Source — Gross, J., & Pitt-Rivers, R. (1953). 3:5:3’-triiodothyronine.  2. Physiological activity. The Biochemical Journal, 53(4), 652–657.

Collegial competition

In 1952, Roche’s group in Paris also published papers on the synthesis of L-T3 from L-T2.

In this way, the two groups confirmed each other’s discoveries.

It appears that Rosalind downplayed the competition between the Paris and London laboratories, presenting them rather as colleagues:

Jack [Gross] and I were in a state of feverish excitement and hardly left the lab. It was probably November 1951.

We went to Paris in December (some sort of chemical meeting) and I was somewhat dismayed by Jack telling Roche’s group that we had identified unknown 1 as T3. (as cited in Tata, p. 336)

It would seem that Jack couldn’t help but reveal this news before their 1952 paper was published, but Rosalind wanted him to keep it secret.

The Paris and London laboratories complemented each other’s work. While Gross and Pitt-Rivers focused on T3 in blood and its activity in the body, the Roche group studied T3 and T4’s biosynthesis and secretion.

Pitt-Rivers and Gross earned prizes as well as royalties from the patent for T3.

Pitt-Rivers was elected as Fellow of the Royal Society in 1954.

From Tata, 1994, p. 346. http://rsbm.royalsocietypublishing.org/content/roybiogmem/39/325

Further scientific exploration

Rosalind subsequently focused on various metabolites of T4 and T3.

She worked on the acetic acid analogues of T4 and T3, tetra- and tri-iodothyroacetic acids (Tetrac and Triac), and early experiments showed that they may have had some milder effects than T3 in animals. However, others were not able to replicate her results until much later.

During her sabbatical year in Boston, she synthesized and tested analogues of thyroid hormone in which bromine and fluorine replaced iodine.

For example, the compound DL-tribromothyronine was found to be effective at treating hypothyroidism (then called “myxoedema”).

However, higher doses of this T3-analogue were required than for levothyroxine, and the preferred treatment at the time was still desiccated thyroid.

Sadly, these aspects of her research have now been largely forgotten.

Pitt-Rivers said of these apparent dead-ends in her research:

The moral of this story has convinced me that it is rash to assume that one is ever at the end of the elucidation of a biological chain of events.

Nevertheless, the relative inactivity of the many metabolites of T4 discovered since T3 makes one wonder whether this story is ended. ( As cited in Tata, p. 338)

Rosalind also investigated how T4 and T3 were transported by proteins in the bloodstream (especially thyroglobulin).

She investigated how the hormones had effects on organs.

She also described the detection of T3 hormone in six thyroidectomized patients treated only with L-T4.

For a while, thyroid science debated whether T3 and T4 were formed by joining T2 and T1, or whether T4 became T3.  Tata said of this debate as of 1994, “Most investigators would now agree that both pathways may operate and that they are not mutually exclusive.”

It was eventually proven that Triac and Tetrac were indeed important in amphibians during metamorphosis, and that they bound to thyroid hormone receptors with greater affinity than T3 and T4 did.

She discovered that in chickens, unlike humans, T3 was equally potent as T4, even though their thyroid hormone receptors preferred T3, as it did in humans.

She used early assay methods to measure the amount of T3 in the thyroid, blood, and various tissues.

Between 1954 and 1964 she continued to publish and co-publish journal articles on thyroid science. Some articles received special mention by Tata:

• ‘What are thyroid hormones?’ – [I cannot locate this; Tata possibly meant Biosynthesis of the Thyroid Hormones, 1960]
• Iodine metabolism in the thyroid gland of the rat, 1962

Her work in the mid to late 1960s focused on another iodine-based biochemical called NIP and a way of measuring anti-DNP sera. She worked with several collaborators to advance this area of organic chemistry.

Apparently her work was so important (paradoxically) that her discoveries outshone her name. Her collaborator, Mitchison, wrote:

One upshot of all this, and it is one by which the lasting importance of this piece of Ros’ science can be judged, is that a whole generation of immunologists happily chat about NIP and NP, without having the least idea of who she was.

And one can peruse the catalogue of Biosearch Inc. of California, who market a range of her compounds, without seeing her name mentioned. That is real fame. (as cited in Tata, p. 342)

Some would beg to differ on that point. How is being unmentioned real fame?

Pitt-Rivers’ books on thyroid hormones

In 1957, Pergamon Press approached Pitt-Rivers about writing a book on thyroid hormones.

Until then the only useful book on the subject was that written by her mentor, Harington, and published in 1933: The Thyroid Gland, its Chemistry and Physiology.

Of course, a lot of research had been done since 1933, not only by Pitt-Rivers but by other thyroid scientists.

She approached her laboratory worker, Mr. Jamshed Tata, who was only 27 years old at the time, and asked him to become co-author.

Their book The Thyroid Hormones (1959) was written in 9 months, and it became the first volume in Pergamon Press’s ‘International Series of Monographs on Pure and Applied Biology’.

Tata boasted that

the book was highly successful, sold out rapidly and has been frequently cited as one of the most authoritative and comprehensive works on this subject. (p. 343)

The team went on to write a second book, The Chemistry of Thyroid Diseases (1960), which was less successful.

Pitt-Rivers then edited the Proceedings of the Fourth International Thyroid Conference in 1960.

Four years later, she co-edited, with W. Robert Trotter, a two-volume work called The Thyroid Gland (1964).

In 1972 she co-authored a memoir of her mentor, Sir Charles Harington.

Her final publication was a co-authored review article titled ‘The effects of drugs on the distribution and metabolism of thyroid hormones’ (1981).

Her character

Excerpts from Tata (1994):

Ros was genuinely interested in the problems, however mundane, of all around her, from janitors to heads of departments.

One was always certain of a sympathetic hearing from Ros and a willingness to help you out of your difficulties.

She had a genuine simplicity and desire to make friends.

When she visited an institution that was new to her, it was never very long before she was on equally friendly terms with director and tea-lady, and knew all about the
family problems of both. (p. 345)

[…]

Her friendliness and informality, devoid of any snobbishness, struck you within minutes of first meeting her, when she would often insist on being addressed as ‘Ros.’

The only person with whom she maintained a degree of formality throughout their association over 25 years was Harington, each addressing the other as ‘Sir Charles’ and ‘Dr Pitt-Rivers.’  (p. 345)

[…]

Harington was a very shy person and not too outgoing in his discussions with
those who were not chemists.

Ros, by comparison, was an extrovert, equally at ease in talking to biochemists, physiologists and clinicians.

There was also her aristocratic background which, besides giving her self-confidence, also helped to liberate her from middle-class inhibitions and concern about status. …

[She had] a freshness of approach, to everyday as well as scientific problems, and an unusual readiness to contemplate new ideas. …

As a scientist, Ros’ greatest love was the laboratory bench. She was truly a single-minded experimentalist who took her science seriously but had fun doing it.

She preferred to tackle problems in small bits, one at a time, and then move on to the next once the results of the first operation were known.

She worked with no more than three or four people at any one time and practised what Bruce Alberts calls ‘small science’.

New ideas, particularly technical advances, fascinated her and she never hesitated in exploiting them for her own work, which is best illustrated by her rapid adaptation of chromatography and electrophoretic techniques in work leading to the discovery of T3 and TBG [thyroxine binding globulin].

Although in her later years she would be classified as an experimental biochemical endocrinologist, she took great interest in the clinical aspects of thyroid gland function and the physiology of thyroid hormones.

She regularly attended meetings where thyroid clinical topics were discussed and had built up strong links with thyroid clinicians. (pp. 340-344)

A final anecdote by her colleague Dr. Cavalieri showed her clinical insight into the manifestations of thyroid disorders:

I remember in particular one of her many visits to my laboratory in the 1970s.

After having a brief chat with one of my colleagues, she drew me aside to suggest that his thyroid function ought to be tested, as she noticed that his voice was more hoarse than she remembered it on a prior visit and he was wearing two ‘woolies’ in September.

The tests confirmed her clinical suspicion of hypothyroidism. (As cited in Tata, p. 344-345)

Honours and awards