11 February 1991: with an enthusiasm and energy that might have surprised those that did not know her well, Professor Joy Delhanty flew around the door of the microscope room of the Galton Lab with a big smile.
'Did it work?'
The challenge had been to try and get a clinically robust preimplantation genetic diagnosis (PGD) protocol (to determine sex in a single cell) effective and reproducible in eight (rather than the usual 24) hours... It had worked.
Eight hours was essential as the then 'window of diagnosis' for PGD – basically to return the result within one working day so that the embryo could be transferred in the same menstrual cycle as the egg collection.
The background to this research was that the, much-fanfared, Nature-published PCR sexing protocol for the world's first PGD just did not work at all well. Trying to amplify a Y chromosome DNA repeat, and then rely on visualising a band in an agarose gel to tell whether a cell was male or female was (with the benefit of hindsight) not the best of ideas.
As Joy knew well, sometimes PCR just does not function (even today) but especially so in the late 1980s when you've tried to place a single cell in a regular Eppendorf tube using a home-made glass pipette. False negatives were inevitable and frequent. Similarly, if any male was within 50 miles of the lab (I exaggerate), contamination (a false positive) was equally likely.
Joy's concept had been carefully to splat a single embryonic nucleus on to a glass slide and then use fluorescence in-situ hybridisation (FISH) with X and Y specific probes in different colours to visualise the cells and chromosomes directly. Using a Y chromosome probe alone had a similar problem to that of the PCR approach (too many false negatives). Using the X chromosome alone on the other hand, we actually made a new discovery. We serendipitously found that the phenomenon of mosaicism (some normal and some abnormal cells in an embryo) was commonplace in humans; the scientific community has been discussing it ever since.
Nonetheless, we often had false positive 'XX' cells (probably tetraploid male) and that would not suffice as a diagnostic test. Joy's 'red-green-blue' approach however not only visualised the cell directly, not only had inherent, independent confirmation (X and Y chromosomes separately) but also detected sex chromosome abnormalities at the same time. There are more up to date protocols these days of course but, if all you wanted to do was sex a single cell, this protocol could still be used today, such was its robustness. The protocol and, more specifically, its interpretation, was archetypal Delhanty: straightforward, visual, unequivocal and direct.
By the end of the week, we were running clinical cases and many couples at risk of transmitting sex-linked disorders benefitted.
The rest is history.
In point of fact, FISH might have been the original PGD protocol were it not for the fact that Joy was meticulous in her approach. The Y chromosome FISH protocol was equally as good as the new PCR (less prone to false positives in fact) but not nearly as 'whizz-bang' and, hey, cytogenetics was not very trendy in those days. As a 'true blue' cytogeneticist, she was ultimately proved right however and, as a result, we treated patients with the first-ever cytogenetic PGD. The BMJ picked it up, as did BBC news and we were all on the telly. Joy was quite the publicist when she needed to be.
Joy was deep, there is no doubt. She was serious, considered and so very, very quiet. Silences between the sentences of a conversation were commonplace and, when on the phone, could be quite disconcerting. But that was just her character, she was simply thinking and considering her next response, she did not waste words. On the other hand, she was clearly passionate about her science, would fiercely support her students and staff and she created an environment of discovery and learning, the like of which you don't always see in labs today.
Indeed, there was much 'joy' in her lab, she was rarely demonstrative, but always managed to create a buzz around her, while looking on with some bemusement at the dynamic environment for which she was responsible.
Joy allowed her PhD students to make their own mistakes, picking up the pieces when necessary. She got us around the world to speak about our research at conferences. She got us published. I also felt the enormous pride of being asked back to UCL by her to be an external examiner both for MSc and PhDs. Such is her legacy, not only her academic 'children' but also the 'grandchildren' (students of her students) – a phrase that she didn't care for. There are even a few great-grandchildren out there now.
There are many lessons that we, her students, learned from her, I paraphrase them here in the hope that she would not feel them 'overly sensationalised':
• Just do it. There is no good research unless you get on with it. • Keep it simple. Joy was never comfortable public speaking, given her inherent shyness. Overcoming this however, her research talks were sublime, measured, clear and full of good science. • Take your opportunities. Science is not always linear, planned and structured. Most of us often had a couple of projects on the go at any one time and were encouraged to take the new opportunities that they presented. • Always give credit. There are few parts of academia that raise the hackles more than authorship and it's sometimes amazing, in hindsight, to realise how she would go out of her way to make sure that credit was properly attributed. • There is nothing more important than your team. She empowered us, she showed us the way and then she watched with pride as we spread our wings. • Be a teacher. Many of us were given the opportunity to give lectures and teaching in her practical classes, which we benefitted from enormously. • Publish and publicise. We did, and many of us continue to do so.
Joy was one of the original cytogeneticists.
Starting in 1956 and staying loyal to UCL until the end, she entered the field just at the time that the first determination of the correct human chromosome number was uncovered. She described the first human triploids; a discovery that led to the realisation that triploidy is one of the leading causes of pregnancy loss, providing reassurance to many thousands of couples that suffer first-trimester miscarriage.
She also has a whole body of work in the molecular cytogenetics and molecular biology of cancer, particularly colon cancer, where there are a number of 'firsts' in her CV. Perhaps her greatest contribution however is the seminal work that tells us that the human embryo is not quite as it appears in the textbooks. A uniformly diploid number of 46 chromosomes in each and every cell is not the norm. Like Joy herself, early developing humans are complex, fluid and dynamic. Yes, dynamic, not in an overt way, but dynamic nonetheless. We will surely miss her.
This article was originally published in Bionews.