The First Test Tube Baby at 40

Whether you can conceive naturally or get help from fertility specialists, hopefully the end result is a healthy baby, 40 weeks later. But how does a fertilised egg turn into a baby? Chris Smith went to see expert in human development at Cambridge University’s Gurdon Institute Azim Surani, who was doing his PhD with IVF pioneer Bob Edwards 40 years ago...

Azim - I remember the day when Louise Brown was born. I was actually on holiday in Cornwall, and I heard the news and I sent a telegram to Bob congratulating him.

Chris - No email in those days?

Azim - There was no email in those days so I had to send him a telegram.

Chris - Let’s go right back to the beginning of the life process which begins with sperms and eggs. So what is special about those two cell types that makes it possible for them to give rise to an embryo and then a foetus and a baby?

Azim - The egg and sperm only contain half the number of chromosomes, so they only have half the information for making a whole organism. And you need to fertilise an egg so that you have both sets of information from father and mother; that’s when the process of development can start.

Chris - How does the egg “know” it’s been fertilised?

Azim - Well, at fertilisation there are changes in the levels of some chemicals like calcium in the egg, and that actually starts the process of early development. That’s when the egg starts to divide and starts to develop further.

Chris - If you’ve got millions and millions of sperm competing to fertilise the egg, why is just one successful?

Azim - Yes, this is actually very important. Because what happens at fertilisation is as soon as one sperm enters the egg there are changes in the membrane of the egg which prevents further sperm from getting in. This is actually very important because you need exact numbers of chromosomes from each of the parents. If you have too many from the father then the process of development will go array.

Chris - So sperm gets into the egg, triggers this change in the membrane preventing any other sperm getting in. It then gives its genetic cargo to that egg so we’ve now got a cell with, hopefully, a complete assemblage of chromosomes - 23 pairs of chromosomes. Then what happens?

Azim - This is the point when the egg starts to divide, and it divides into two cells first. Then it continues to divide as it travels down the fallopian tube and enters the uterus, and, as it divides, the cells continue to multiply. They go through a number of divisions until the embryo reaches about 60 to 100 cells.

Chris - What’s special about that number?

Azim - Basically, there are two sets of cells: there are cells on the inside, which are called the inner cell mass cells which are going to give rise to the embryo, and then there’s the outer shell of cells which will give rise to the placenta.

Chris - So we’re at this stage where we have a ball of cells inside a ball of cells. The ball round the outside is going to be the bag that the baby develops in and the placenta that connects it to its mum. But how does that ball of cells in the middle turn into something we would recognise as a developing baby?

Azim - Well, one of the early things that happens is that the embryo starts to look like a sheet of cells, and at one end of the embryo you start to form a little structure called the “primitive streak.” Here the cells start to enter into the primitive streak and they go inside, and those cells are eventually going to give rise to the structures which we recognise as the internal organs eventually, and then it starts to be recognised as a developing foetus.

Chris - So cells are flowing in from the outside into the inside? It’s almost like inflating itself with more of its own cells and it creates that population of cells inside itself which they they're destined to become the internal organs and so on?

Azim - Yes. These cells, they start to become more specialised, as the embryo develops, becomes three dimensional, and it starts to be recognised as a foetus.

Chris - But then what happens next to actually turn this very primitive, very tiny, one millimeter structure into something which would resemble a baby?

Azim - The key aspect that occurs from then onwards are increasing numbers of cells and also increasing complexity of the developing internal organs.

Chris - By which time are all the major organs developed - things like the heart, brain, face, eyes? When are all the major things made and when are they present by?

Azim - The early stages of organogenesis are occuring between day 28 and 35 days of human development. This is when all the rudimentary organs are already formed, so all the basic structures start to get established by this time, and then thereafter there is tremendous growth of the embryo as development progresses.

Chris - Are we comfortable that the manipulations that are being done on sperms, eggs, and embryos to do things like IVF don’t have consequences for the health of that individual?

Azim - From all the experience we have had from all the IVF babies that have been born there is, at the present time, no clear evidence that there is an impact of IVF. Now we have to remember that Louise Brown is 40 years old, so it’s still quite early days. So I think it’s something that we should actually keep an eye on, to see if there are very long term consequences of IVF.

Chris - But at this stage we’re not aware of any?

Azim - There have been a number of experiments that have been done to test if there have been any effects of manipulation of the eggs and sperm in culture. But so far the majority of the evidence is that there’s no potential impact of manipulation of eggs and sperm in culture.

Chris - And last Azim, after you returned from your holiday having sent that telegram to your supervisor, Bob Edwards, what happened next?

Azim - I came back to Cambridge and we had a lot of celebrations. A lot of champagne was drunk I have to say.

What actually happens in the lab in a fertility clinic? Chris Smith met embryologist Adam Burnley at Bourn Hall, the clinic set up by Bob Edwards, Jean Purdy and Patrick Steptoe following their success creating Louise Brown. Adam explained the IVF process at the clinic; and for all cases, his first job is to assess fitness of the father’s sperm...

Adam - We’re looking for numbers of sperm, how well those sperm are moving, and the sort of abnormalities within the sperm.

Chris - I’m looking at the computer screen. That’s someone’s sample as seen down the microscope. Talk me through what’s on there.

Adam - What the software associated with this equipment does is identify the sperm heads. So anything of that size and shape it will track individually and it will work out how quickly that sperm is moving forwards, whether it’s moving at all, and will give us a precise number of sperm so that we can base our treatment recommendation on that, on the results.

Chris - How do you then make a judgement about the most effective way to treat that patient based on what you see here?

Adam - We take what the World Health Organisation call a normal sample parameters, so a certain number of sperm, the type of motility. And if the sperm parameters are above those, or what we would call a normal sample, we might just want to mix sperm with eggs and let the sperm fertilise those eggs on their own. If the parameters fall lower than those, we might decide that we need to inject sperm individually into eggs to enable those to fertilise and to create embryos.

Chris - What happens next?

Adam - We’ll go through to the lab and where the theatres are and I’ll try and explain what happens.

The female patient will need some preparation before they come in for an operation to harvest any eggs, and what that involves is stimulating the patient with fertility drugs which makes them hopefully produce more than the usual one egg per cycle.

Chris - And that happens in here? This looks a bit like an operating theatre.

Adam - We have an anaesthetic machine if necessary. A scanning machine so that when the surgeon’s doing the collection they can see the patients ovaries on a screen and therefore they can use a metal needle attached to a probe to suck out the eggs from each of the follicles. And depending on how many follicles that patient has grown in response to the fertility drugs, hopefully we should collect a corresponding number of eggs from those follicles.

Chris - How many eggs do you get from someone for each cycle like that?

Adam - The average number of eggs that we collect from patients is about ten, but some patients will get one egg collected, some patients will stimulate much more and get 30 or 40 eggs collected. And as the doctor is doing the egg collection we’ll let them know how many eggs they’re collecting. They’re put into a culture media which keeps them at the optimal conditions until we’re ready to do either IVF or the injection of sperm.

Chris - If you decide to go down the route of what they call ICSI (Intracytoplasmic Sperm Injection), which is why it gets called ICSI I’m guessing…

Adam - Yes.

Chris - ... where you are literally injecting a sperm into an egg. What happens then and where do you do that?

Adam - Do you want to come through here and I’ll show you where we perform that procedure.

What we’ll have to do before the ICSI procedure is to assess how many of the patient’s eggs are suitable for that procedure, and usually we find 80 percent will be. What we then do is, under a high power magnification, we have to select an individual sperm, immobilise that sperm by hitting it on the back of the neck with a needle, and we then inject that sperm into each of the suitable eggs. We hope that about 70 percent of those eggs that have that procedure will fertilise.

Chris - And hopefully, by that stage, the person has a reasonable prospect of getting a fertilised egg. What do you do then?

Adam - We’ll want to culture those and grow them for a few days until the embryo reaches the appropriate stage for us to select the most likely one that we think is going to implant.

Chris - So it takes about five days before you’re in a position to put the developing embryo back into the woman?

Adam - Yes, that’s right. The embryo when it gets to about day five become what we call a blastocyst, so its cells have different functions within the embryo, and the embryo needs to do that in order to implant.

Chris - This is one of the incubators: it’s got a series of drawers on the top I can see you’ve been putting some of the dishes, which have got the developing embryos, in. The amazing thing is there is a huge screen on here and we can see embryos developing. I can see cells dividing and you’re watching these things in almost real time.

Adam - Yeah, that’s right. This is relatively new technology in that in normal incubator conditions you would look at your embryos once a day; whereas this is taking a picture of the embryo every five minutes so we can review its development to see whether the embryo’s followed the right patterns of development.

Chris - This one’s just gone from 1 cell, to 2 cells, 4, now we’re at 8, 16, that’s amazing!

Adam - Yeah.

Chris - That’s a human developing?

Adam - Yeah. And to see it happen in that time lapse quick play is an amazing thing really. You can watch five days of development in two minutes.

Chris -  I wouldn’t get any work done if I worked in this lab because I’d be stuck here watching this.

Adam - An amazing bit of technology really.

Chris - You would be able to tell from those pictures what one looks promising and what one’s not going to make the grade, can you?

Adam - On day five, we look at all the embryos, see which one has developed to the best stage, but then we can review the footage of that embryo developing and possibly deselect or select embryos to transfer based on that information.

Chris - This person here’s got quite a lot of embryos cooking. You’re going to be able to put how many back into that person and what do you do with the rest of them?

Adam -  Okay. Well, the law allows us to put either one or two embryos back depending on their circumstances. If the patient then has other embryos which have reached the right stage we could possibly freeze surplus embryos, which means the person could come back if they’re not successful.

Chris - How do you get that back into the woman?

Adam - We have to pick the embryo up in a really tiny amount of culture media in what we call a transfer catheter, a sterile floppy plastic tube which is attached to a small syringe. Take it through to the surgeon who has the patient prepared for the transfer and he will feed the soft catheter through the cervix directly into the uterus, press the plunger on the syringe, and the embryo or embryos will be deposited in the uterus in the right place.

Chris - Does the lady have to lay there with her legs in the air for hours on end?

Adam - Not any more. It used to happen but not for a long time.

Chris - You used to do that?

Adam - Yeah. A patient would sit for three or four hours sometimes either in bed or with their legs up in the air. The fear being that the embryos would drop out.

Chris - Drop out?

Adam - Yeah. But a lot of studies have shown that it is absolutely not necessary. The embryo transfer procedure means you can walk down to theatre, have your transfer. The whole process takes about 15 minutes and then you can go home and resume your normal life and hope for the best.

Chris - And what’s the soonest you would know if it’s worked?

Adam - Really the earliest is about a day 18 home pregnancy test all the patients do.

The process of fertility treatment is an emotional, financial and physical rollercoaster. Katie Haylor spoke to Jackie Stewart - an independent counsellor who supports patients going through IVF at Bourn Hall...

Jackie - I think it’s important to include any form of counselling for people’s psychological and emotional journey. So there are two types of counselling really: implications counselling is for anybody undergoing donor treatment or surrogacy, and then there’s support counselling or therapeutic counselling which involves supporting a person’s feelings through this journey.

Katie - Can you give me an idea of some of the emotional problems someone might experience having fertility treatment?

Jackie - Not everybody experiences what I’m going to tell you, especially if it works first time. Having said that, if they come back for more treatment and it doesn’t work they can start to experience some of the effects.

They may start to experience the effects of something that is likened to a grieving process because there is a feeling of a sense of loss. The further down the line that you get with treatments not working, the harder the impact, higher the anxiety, the stress levels will start to come up.

Katie - Of course, no-one has fertility treatment in isolation from the rest of their life. You’re still going on doing your day-to-day things. You might have a job, you might have caring responsibilities. Can the stress of fertility treatment trickle into other aspects of your life and how do you deal with that?

Jackie - It can be overwhelming; it affects every part of your life. The longer you’re in it, the harder it gets. Stress and infertility can’t be separated so it affects working capacity. Sometimes people keep it to themselves completely; they have little or no support. Other times, companies are very good and they do share it with family and friends but it’s a very individual thing. It’s hard to talk about because it’s a private matter and so just understanding and acknowledging people’s feelings can really help.

And often, men and women cope differently. I’m generalising, of course, but when you’ve got two different coping mechanisms in a partnership, that can sometimes isolate people from each other. So it’s helpful to come and talk to a councillor or talk to other people through a support group and to understand that your feelings are very normal. The point of counselling really is to support your feelings, help you to find ways through the treatment, help you to cope better so that you feel less overwhelmed.

So there are coping strategies, there are lots of websites and networks, books, support group. There are ways of helping a person to feel less alone with this and that’s the whole point really, and to feel reassured that there’s a way through it.

Katie - Can you tell me a bit more about implications counselling?

Jackie - For the majority of people there is a gap between having your own biological child and moving on to using donor gametes. They may need just a short space at least to consider the implications of that and what that means to them. How will the partner feel about that? When would they tell their child? How will they tell their child? How will they support their child if the child wants to find out more about the donor? All the legalities of that. There are so many implications.

Katie - Obviously, the best case scenario is to end up with a successful pregnancy and a healthy baby or multiple babies. That doesn’t happen for everyone. How do you come to terms with that?

Jackie - If you’re trying to decide to end treatment, that’s one of the hardest decisions you’ll ever make, so it’s really important that you reach out for some support. And it could be that you decide to move on to another form of parenting, which is absolutely wonderful and there’s lots of support there. But for those people that have been through this process, and maybe it’s been an arduous time for them, they need more support and lots of understanding.

This is a stressful situation that you’re going through so what I would say is to not be too hard on yourself and be compassionate to yourself. You are a patient, and what would you be saying to say a best friend if they were going through this? That it might have been a long held dream so to just give yourself permission to do or not do things, you know? There are people around you that actually are really waiting to help but they just don’t know how to, so if you can just be clear with what you might need from people and then communicate that.

For more information: 

http://fertilitynetworkuk.org/for-those-trying-to-become-parents/information

https://www.hfea.gov.uk

https://www.bournhall.co.uk/news-events/fertility-support-group

http://www.surrogacyuk.org

https://www.adoptionuk.org

Research scientist Kay Elder started working at Bourn Hall in the 1980s. Kay took Chris Smith through her collection of memorabilia documenting the story of how Bob Edwards, Jean Purdy and Patrick Steptoe made IVF happen...

Kay - “It’s a girl; here she is the lovely Louise. The first “test tube” baby is born and medical history is made as a mother’s dream comes true.”

Chris - We’ve got the original press cuttings when the Daily Mail, which is dated Wednesday July 26th, 1978 cost the princely sum of 8 pence!

In order to arrive at this day, with the birth of Louise Brown, where did the story begin and how long had they been working on this in order to achieve the birth of Louise?

Kay - The story began when Patrick and Bob Edwards met at a meeting at the Royal College in London on February 28th, 1968. Bob had had visions of what he wanted to achieve in terms of fertilising human eggs in-vitro and he needed the help of a clinician. Patrick immediately understood what the goal was and they decided to begin collaborating.

Chris - What was Patrick’s contribution then that caught Bob’s eye?

Kay - The development of what we now call keyhole surgery - laparoscopy - which is now commonly used in all different fields of medicine. But in the 1960’s, it was yet to be developed and Patrick heard about this technique that was being pioneered and he developed his own expertise by practicing in the postmortem room.

Chris - So he’s developing this technique to look inside tummies. What’s the relevance of that to fertility treatment and fertility research?

Kay - Patrick could see by looking inside tummies what the problem was. Some women had tubes that were blocked so that the egg could not pass into the womb. He could see abnormalities in the pelvis, he could see if there were bits of fibrous tissue adhesions.

Chris - Why was Bob interested in that?

Kay - Because he had spent many years working on looking at the development of eggs. They decided to start collaborating. Patrick was based up in Oldham near Manchester. Bob was based at his lab in the University of Cambridge. When Patrick was ready to do a laparoscopy, Bob and Jean would load up the car with microscopes, test tubes, culture medium, and drive up there. And when Patrick was able to recover eggs they put them into culture, looked at them under the microscope and watched to see if an embryo would develop eventually.

Chris - The patients who were undergoing this - what was then an experimental procedure - these were women who were hoping that they would have a baby through this sort of approach?

Kay - Definitely.

Chris - So they were willing to take part in these sorts of studies. So what did they then do in order to achieve in-vitro fertilisation?

Kay - They had to work out how to recover the eggs. They had to work out how to manage them, how to look after them, how to nurture them. What kind of culture conditions, the temperature, the gas. And once they were certain that the eggs appeared to be normal they started fertilising them.

Chris - But that’s still eight years before these headlines we have on these newspaper cuttings in front of us. So what happened over eight years? Why did it take so long from having embryos to having a baby?

Kay - Really everything that’s now taken for granted in IVF treatment they had to work out from scratch. Getting the hormones exactly right at the time that the eggs were collected and when the embryos were put back.

Chris - Looking at some of these other cuttings the reception wasn’t all positive though was it? Again, this is a Daily Mail editorial you’ve got here:

“Amid the rejoicing there are those who shiver involuntarily, where, they ask, is all this going to end?”

Kay - The teams themselves were an incredible set of extraordinary individuals. They were always very positive and very optimistic. They were quite certain that what they were doing was correct.

Chris - But you had people like James Watson. On the scientific stage, this guy has enormous credibility and he’s saying this is a bad idea?

Chris - You’d think then that having achieved this world first, things must have taken off! They must have then had people biting their arms off to do work. Is that what happened?

Kay - No. There was so much controversy and criticism that between 1978 and 1980 they had nowhere to continue working. And it took them two years to raise sufficient capital venture funding to open a private clinic because they eventually realised that this was their only option. They had hoped to have funding from the NHS, from the MRC, but the atmosphere in those days, thanks to people like James Watson and Max Perutz, was so negative, their only option was to open a private clinic.

Chris - And actually, that led to the purchasing of where we’re standing now, which in Bourn Hall. They bought that and moved in here in what, 1980?

Kay - September, 1980.

Chris - What were the other major developments along the way that have helped to keep Bourn Hall ahead and have helped to keep your success rate at what it is? Because it is one of the most successful clinics the country has.

Kay - Well, the first transition really started in 1984 when an expert ultrasonographer by the name of Jill Williams came over from California and started using ultrasound to measure the growth of the little follicles that contain the eggs.

Chris - This is physically looking inside the woman at the development of the egg that you’re going to harvest, or eggs you're going to harvest?

Kay - That’s right. Jill started by monitoring just by putting an ultrasound probe on the lady’s tummy and looking at the follicles, looking at the ovaries to see how they were doing.

And then the next thing that happened was a doctor by the name of Rajat Goswamy came in 1985 and started trying to recover eggs using ultrasound guidance instead of opening up for a big operation like laparoscopy. By 1986, we were using ultrasound guided egg collections, vaginal ultrasound, which is what everyone uses nowadays. So that was a major transition.

But another major transition was the discovery by two of our scientists here at Bourn Hall, Colin Howells and Mike Macnamee, that patients who had high levels of a particular hormone LH in their urine were less likely to get pregnant than those who had lower levels at specific times during the cycle, and this led to the use of drugs that would suppress the hormone cycle that elevates LH. That made it easier to programme and regulate when the eggs could be collected.

Chris - When did the atmosphere and the perception of the work that was being done here at Bourn Hall switch from one of being shivers going down people’s spines and scepticism to one of positive reception?

Kay - That really took quite some time. I think things started to shift when Dame Mary Warnock led a committee to look into the ethics of IVF. In fact, I think we were probably the first clinic in the world who had our own ethical committee.

Katie Haylor asked GP Sarah Smith what advice she would give to people thinking about thier fertility...

Sarah- I think once you’re over the age of 25 your fertility does start to decline, and once you’re over 35 it declines even more quickly, so I think don’t leave it too late. Do if you’re having problems come along and see us and talk about it. We can refer you. You can have tests done. I did read one statistic of ladies who are married over the age of 40, 4 in 10 will get pregnant but 6 out of 10 can have problems, so leave it too late and do think about all your options. Stay safe, have safe sex, and just a healthy lifestyle to maximise your fertility.