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1/ Just finished reading "A Matter of Life", a quick but enjoyable read on the history of IVF= in-vitro fertilization.… #bookreviews #meded
2/ Nowadays IVF is almost routine, and there are million of babies who have been born with it. And yet, in the 40's it was the wild-eyed dream of Robert Edwards, toiling away with rabbit embryos and waking up in the middle of the night to extract mice ova.
3/ Over the next 10 years Robert Edwards built a reputation as a prominent embryologist and dabbled in immunology, but he maintained an interest in human reproduction, and almost as a hobby, collected ova from friendly gynecologists when they would be removing ovaries.
4/ In approximately the same timespan, Patrick Steptoe, an obstetrician-gynecologist practicing in a moderate sized town in England, was perfecting and popularizing the use of laparoscopy in gynecologic procedures.
5/ Laparoscopy involves making a small incision in someone's belly, inflating it with gas, and then inserting a camera and some small surgical tools. This allows for operations with shorter recovery time and less morbidity.…
6/ It doesn't sound super flashy but this opened up a whole slew of diagnostic options for surgeons that were previously too morbid to consider.
7/ Diagnostic laparoscopy is the gold standard for diagnosing many gynecologic conditions- literally peaking in the abdomen so what is going on- and this was a big advance.
8/ - The relevance of laparoscopy to IVF, however, was that it made the retrieval of eggs from ovaries possible. Here is one of the happy coincidences that science history is full of:
9/ Edwards was browsing through random medical journals, as he had the habit of doing, and happened upon an article on laparoscopy by Patrick Steptoe-- which mentions its utility for surgery, diagnosis, and, importantly, for collecting solutions from the Fallopian tubes.
10/ Edwards immediately phoned (subtle example of communication technology accelerating collaboration) Steptoe and told him he was interested in collaborating.
11/ They chat, and Edwards promises to call back but doesn't due to logistical difficulties, and lets the matter sit for a while.
12/ - At a medical conference that Edwards happens to attend six months later he meets Steptoe in person, and they make a good impression on each other. Edwards is impressed by Steptoe's willingness to confront someone who is criticizing laparoscopy, his poise, and his manner.
14/ And maybe some echoes of this:…
the idea that in-person meetings are weirdly important and impactful. @gwern
@gwern 15/ - Thus their collaboration begins. While it necessitates making frequent long drives to Oldham, the excitement of their research drives Edwards forward.
@gwern 16/ Steptoe successfully persuades some of his patients to have intercourse right before other surgeries so that Edwards can retrieve sperm from the Fallopian Tubes.
@gwern 17/ Eventually Edwards, along with Jean Purdy, a research nurse who gradually becomes another central figure in this research during this time period, develop a needle to better extract immature eggs from volunteer infertile women.
@gwern 18/ Jean Purdy is a semi-tragic figure here. For a while her contributions to the research were underappreciated by awarding institutions, though Edwards and Steptoe both repeatedly credited her as a co-inventor in public and privately.
@gwern 19/ Even more tragically, she died very young from malignant melanoma, decades before the Nobel Prize went to Edwards alone (Steptoe had also passed away by then).
@gwern 20/ Back 2 story: They find that patients are very eager to volunteer, even when they know the research won't advance quickly enough to help them. A quote: "We soon discovered that patients needed to be restrained from volunteering too much.
@gwern 21/ Patients would offer themselves for a second laparoscopy or even to come into Oldham General Hospital twelve times a year if necessary! One of our first patients was a dark-haired lady in her late thirties.
@gwern 22/ At her bedside she said to me, ‘Mr Steptoe has explained everything, exactly what is
needed, and I’m glad to help all I can even if, finally, what you manage to do
only becomes valuable to other women."
@gwern 23/ - There follow a whole series of unglamorous steps that brings them ever closer to their dream of in-vitro fertilization, with some small successes and many failures along the way.
@gwern 24/ There's a successfully fertilized egg that grows 9 days in a test tube, a record at the time, and an ectopic pregnancy that, tragically, must be terminated, but provides them with real hope that they're on the right track.
@gwern 25/ Over long years they tinker with the nutrient solution, the surgical procedure to minimize the operation time, the dosage and timing of the hormonal injections women must take at different times, and more.
@gwern 26/ - I was struck by the failures, which would have persuaded many lesser, and perhaps saner, scientists to abandon the project. At some point the prized nutrient broth, painstakingly developed over years of tinkering, stops working, and months are spent trying to recreate it.
@gwern 27/ Then they discover that the hormone injections, crucial to producing many eggs per cycle, interfere with embryo implantation, and they decide to go with natural menstrual cycles, which produce fewer eggs.
@gwern 28/ Many failed implantations later, a patient experiences an ectopic pregnancy, which is a mixed bag of success and failure. The timing of successful implantations was still being worked out at this time.
@gwern 29/ Finally, when Lesley Brown gets pregnant, the team is on the verge of success. Even here, however, they run into a complication.
@gwern 30/ IIUC, Lesley Brown develops preeclampsia, a dangerous condition of pregnancy, and her baby appears to have some IUGR, but after a few rocky weeks, the pregnancy is successful and the baby grows on schedule.
@gwern 31/ When Louise Brown, the first IVF baby, is born, she is the culmination of a 10+ year collaboration.
@gwern 32/ Some "History of Science"/"Progress Studies" @rootsofprogress take-aways: science can take a long time, 10 years in this case; grant-funding bodies have passed on Nobel Prize winning work; ethical concerns shrink with apparent success; serendipity is important; new…
@gwern @rootsofprogress 33/ …technologies can bear unexpected fruit.
@gwern @rootsofprogress 34/ There are some illuminating contrasts to current biomedical research: 1-regulation and oversight seem much looser.
@gwern @rootsofprogress 35/ There's only one mention of an IRB, the one at Oldham, which is made up of physicians and a community member, and is quite supportive of their research in the face of half-true deceptive media coverage.
@gwern @rootsofprogress 36/ Would current research institutions be as supportive of their scientists in the face of outrage? An open question.
@gwern @rootsofprogress 37/ Perhaps more importantly, it seemed much easier to make important discoveries. The low-hanging fruits were everywhere, and ripe for the picking: hormonal regulation of mammalian reproduction, how to induce twin and triplet births in mammals, the appropriate nutrient…
@gwern @rootsofprogress 38/ …solution for growing mammalian embryos in-vitro, cross-species surrogacy with rabbits, and more.
@gwern @rootsofprogress 39/ Before his work on IVF, Steptoe made important contributions to laparoscopy.
@gwern @rootsofprogress 40/ He had learned about it from one of it's early pioneers, Raoul Palmer, and after years of experimenting with it, adopting new technology like a less dangerous lighting system, published a textbook in 1967.
@gwern @rootsofprogress 41/ This technology enabled IVF, since it made possible egg retrieval and embryo transfer, as well as accurate diagnosis of fertility etiology. A new surgical technique enabled a medical advance because of its relative non-invasiveness and speed.
@gwern @rootsofprogress 42/ Innovation has many unexpected sources.
(also, written in @RoamResearch !) #roamcult
funny anecdote: when Robert Edwards first meets his future wife, Ruth, he tells her on their first date about some of his scientific heroes-- Ernest Rutherford and Luke Howard among them. By sheer coincidence, she happens to be related them!
"Ruth was smiling at me faintly.  Perhaps I had been a
bit pompous.  I took the pipe out of my mouth.  ‘I’m the
grand-daughter of Rutherford,’ she said, shattering me.  ‘And curiously, Luke Howard was also an ancestor of mine.’ ‘You’re joking,’ I said.  She was not joking.
The same genes as Rutherford, I thought, my God!
- How could anyone make a pass at a relation of Luke Howard, or at a grand-daughter of Rutherford! Better to return to my night duties with the mice,"

So they only start seeing each other months after that...
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