Medscape One-on-One With Howard Jones, MD: IVF Past and Present in the Light of the Nobel Prize

Eli Y. Adashi, MD; Howard W. Jones, Jr., MD


October 13, 2010

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Eli Y. Adashi, MD: Hello. I am Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One. Joining me today is Professor Howard Jones, Jr., whose vision and leadership gave rise to the first test tube baby in the United States. Our topic, the just-announced award of the Nobel Prize in Medicine to Professor Robert Edwards for the development of human in vitro fertilization, more commonly known as IVF. Welcome.

Howard W. Jones, Jr., MD: Thank you. I'm delighted to be here.

Dr. Adashi: It's plain wonderful to have you with us.

Dr. Jones: Thank you.

Dr. Adashi: And what a great day it is. Is it all smiles and no regrets?

Dr. Jones: Well, I think there is a regret. There is a regret that this should have happened 15 years ago at least, because many of [Edwards'] friends did what they could to persuade the committee to make such an award some 15 years ago. It's been an up and down thing, and it looked like it was a dead issue. Then suddenly this happened.

Dr. Adashi: I suppose the fact that Dr. Steptoe could not be included in the award is another unfortunate outcome, perhaps, of the delay.

Dr. Jones: The rules are that they award it only to living people, so I think that's the explanation. I expect that the committee was sensitive to the opposition to IVF, and that is probably what caused the delay. That opposition has been very formal with the Roman [Catholic] church, informal in some other areas. Nevertheless, I suspect, although I don't know this for a fact, that the Nobel committee has been intimidated by this opposition and maybe decided to do this knowing that Bob wasn't really well and that if it were ever going to be done that it had to be done now. This is supposition on my part, but I believe it.

Dr. Adashi: When did you first meet Dr. Edwards, and how did your interactions with him evolve over the years?

Dr. Jones: Well, do you want the long story or the short story?

Dr. Adashi: We'll take both.

Dr. Jones: I met Bob first in 1965 at Johns Hopkins in Baltimore. It was a result of the fact that he got the idea that in vitro fertilization could be applied to the human. It had been described in the rabbit just 5 years before. He was a geneticist, basically, in mice, but was interested particularly in the genetics of reproduction.

When this information came along about in vitro fertilization being successful in the rabbit, he worked with animals, and then so thought, well it could be done in a human. But he was frustrated by the fact that he couldn't get any human eggs in Cambridge. He had had a few, and the few that he had were obtained by a gynecologist by the name of Molly Rose, who was working in London and who happened to have been the deliverer of some of his children when he was working in London. And so with this contact, he got, I believe it was 5 eggs over a period of some months, and it made him frustrated.

He wrote a letter to a friend of his at Hopkins, Victor McKusick, who was a geneticist. They had this in common, had met at international meetings, and he asked Victor if he were to come to Hopkins would it be possible for him to have some human eggs. Victor telephoned me and said he had this letter and would there be any chance of giving Edward some eggs if he were to come to Baltimore. I replied that, yes, I thought this was possible, and the reason for that was that at that time, the standard treatment for a condition known as polycystic ovarian disease was wedge resection of the ovary. We were doing 2 or 3 of those a week, and it occurred to me that we could just give him part of the ovary that we removed, and he could get the eggs from that. That was the basis for extending the invitation to Bob to come, and he came in the summer of 1965, and during that summer, he attempted to fertilize human eggs in vitro. Shall I go on?

Dr. Adashi: Did you have other professional interactions with him, beyond national meetings and the like, along the lines of developing IVF, shall we say?

Dr. Jones: Do you mean subsequent to the meeting at Hopkins?

Dr. Adashi: Subsequent to the 60s, yes.

Dr. Jones: Well yes, I did. Actually, I think we had a warm friendship. I had an open invitation to come to where they were working in England, and we took advantage of that on a number of occasions. When he would be in this country, he would stop by, and so we had a good exchange. I always regarded him as good company and nice to be with.

Dr. Adashi: What can you tell us about Dr. Patrick Steptoe and his role in making Dr. Edwards' vision a practical reality?

Dr. Jones: Patrick Steptoe was a clinician, an obstetrics/gynecology specialist, and was an innovator. He held a post of consultant in a town of Oldham in England, which was near Liverpool. This was about 150 miles, I think, from Cambridge. Patrick Steptoe introduced laparoscopy into the United Kingdom.

Dr. Adashi: Could you briefly describe the technique?

Dr. Jones: Yes, laparoscopy at that time was the introduction of a telescope, if you will, through a small incision in the umbilicus, in the navel, and with that, one could observe the pelvis in a very unique and special way.

Dr. Adashi: This is so-called band-aid surgery?

Dr. Jones: Yes, that would be band-aid surgery to be sure. It was when Patrick Steptoe was describing this technique at a meeting in London that Bob happened to be attending that it occurred to Bob, well, I wonder if that could be used to harvest eggs. So Bob made contact with Patrick after that meeting, and they agreed to collaborate. That's how they got together -- Patrick being the clinician who retrieved the eggs, which at that time had to be done [with the patient] under general anesthesia using laparoscopy, and Bob was basically the laboratory person who worked with the eggs when they were given to him.

Dr. Adashi: It seems fair to say that IVF would not have happened in the absence of this collaboration between a scientist and a physician.

Dr. Jones: I think it's true to say that's the case. Now, it may have happened later by other people if [Edwards and Steptoe] hadn't been the ones who did it, but they had the idea and they deserve the credit. There's no question about that in my mind, anyway.

Dr. Adashi: History tells us that the 1978 birth of Louise Brown, the first ever IVF baby, followed the transfer of a single 8-cell embryo. In retrospect, what were the odds of that happening given the technology of the day?

Dr. Jones: I'm not sure I can give you a good mathematical answer to that, but all I know is that they had been trying for a number of years. He had done at least 200 attempts before this happened, so at that time, it was 1 in 200.

Dr. Adashi: Had a single embryo been transferred today, what live birth rate might we anticipate?

Dr. Jones: I think with a random selection as we do, even with the best of intentions with a microscope, we're talking about a 30% chance.

Dr. Adashi: In general, today, how does IVF compare with natural fertility in terms of the outcomes of conception?

Dr. Jones: Interestingly enough, natural fertility is an inefficient process. You wouldn't believe that, considering all the people in the world, but the truth of the matter is that every time the sperm and egg meet, there is only about 1 chance in 4 or 5 that a pregnancy and a live birth will occur. There's a big age spread, and the figure I just gave you is an average one for all ages. Reproduction becomes inefficient starting very early. Everything is downhill from about 25 on, but the curve really takes a dip in the 30s, and by the time 40 comes along, the curve is pretty flat. The figures I'm giving you are average figures. Therefore, when you try to do IVF, you are grafting an inefficient process on an inefficient process.

On an egg-to-egg basis, we recently actually reviewed this matter, and I can give you a figure based on over 50,000 mature eggs in our own program, and it turns out that only 1 in 20 of those eggs, as harvested, results in a live birth. On an egg-to-egg basis, as I've said before, you have a very inefficient process on an inefficient process, and that's why IVF is so difficult to do.

Dr. Adashi: For the individual patient in the United States, in the best possible clinic, what is the best pregnancy rate?

Dr. Jones: Well, again, this depends on the cause of the infertility, and it depends, above all, on age. There's a little message here, if a message is suitable, which is that in couples thinking about pregnancy, remember the clock is ticking and the curve is downhill.

The results are very much age related, but overall these days, it depends on the number of fertilized eggs that are transferred. This is a very key issue, so there are a lot of variables and the figures that I give you may not apply to an individual case. As reported in the national data these days, we're dealing with a 30% pregnancy rate for each try. We also have the chance of freezing unused fertilized eggs now so that they can be subsequently used. So if you're talking about the pregnancy rate from a single egg harvest, it would be higher than the figure that I presented, maybe by 8% or something like that.

Dr. Adashi: In the 32 years since the introduction of IVF, have we uncovered any unforeseen, indeed, unintended consequences for either the mother or the child?

Dr. Jones: I think the principal unintended consequence was multiple [births]. This is a result of the inefficiency of the process so that to overcome this inefficiency, more than a single egg has been transferred. Of course, most twins and most triplets, fortunately, are perfectly [healthy]. But there is no doubt that as you go up in numbers, the consequences for the child become more and more troublesome, so that if we could somehow or other do away with multiple [births], that would be a mighty step in the right direction.

Dr. Adashi: Are we moving in a reasonable way would you say?

Dr. Jones: Yes, there is a strong movement to resort to single-embryo transfers in certain circumstances. The rest of the world does a little better than the United States with regard to that. That revolves around the insurance coverage of IVF. In a good many European countries, IVF is covered as part of the national health system, so they are, therefore, able to transfer smaller numbers [of eggs]. The example I use often on that is Belgium, where in, I think, it was in '03 by royal decree, it was decided that you could have as many IVF attempts as necessary, up to 6, but the insurance coverage would work only if you did a single embryo transfer if you were 35 years old or less. If you look at the data, it is interesting that the triplets essentially disappeared. The [rate of] twins, instead of running around 25% or 30%, as they do in most countries, dropped down to about 5%, and most of those were from people who were older than 35, where more than one was put in, as allowed by the insurance program.

The United States, unfortunately, does not have general insurance coverage, so we do not have any laws that govern IVF. The number [of embryos] to transfer is entirely on a volunteer basis, but is usually regulated by, or influenced by, guidelines that are put forward by the American Society for Reproductive Medicine. I think you could make a case for saying that those guidelines maybe are not as strict as they should be in terms of a single embryo transfer. You could also make the case that even the guidelines as they exist probably are not followed very rigorously across the country, so that the multiple pregnancy problem, I think, is something we need to work on and solve.

Dr. Adashi: It sounds like the Belgians have come up, given their very special circumstances, with a policy that is both responsible and generous.

Dr. Jones: And good medicine.

Dr. Adashi: And good medicine. What future innovations do you foresee for IVF?

Dr. Jones: I think we have a lot of work to do. We certainly need to somehow or other identify the fertilized egg with neonatal potential.

Dr. Adashi: In other words, identify the embryos that will actually take and survive.

Dr. Jones: That will take and, furthermore, after taking, survive, because there is a loss during natural pregnancy, and of course that applies to IVF as well. That is associated usually with abnormalities of the conceptus, so that we need to somehow or other be able to identify prior to transfer by a noninvasive means a fertilized egg that has neonatal potential.

Dr. Adashi: Survivability through birth and beyond.

Dr. Jones: Absolutely right, and that has been worked on quite a bit, and the current approach to that is the use of genetic markers of various kinds -- "omics" of all sorts-- proteomics and the like, and it's a little too early to say whether that's going to work. We can say that it is not going to be easy, because the variables are so many that they are very difficult to count. This is a work in progress, and that is a major thing that we need to get after.

Dr. Adashi: So a search for a biomarker is on?

Dr. Jones: A search for a biomarker is on in many centers.

Dr. Adashi: Were it not for IVF, human embryonic stem cell research would not have been possible. In your personal estimation, will the recognition of IVF as a Nobel-worthy discovery impact the swirling controversy in this arena that we are currently witnessing?

Dr. Jones: I would certainly hope so, but I am not sure that it would because the opposition, as I mentioned before, is centered around the Roman [Catholic] doctrine, but joined in by many other people, who I guess we would call conservatives. It's unlikely that a single prize will sway that very much, although it will probably push it a little bit. I think we're going to have to deal with the opposition by demonstrating that it works. That's what's happened with IVF, because the opposition to IVF has faded through the years -- not disappeared. but faded. I believe the reason for that is that IVF works, and as soon as stem cells work, I think the opposition will tend to disappear, but we're not there.

Dr. Adashi: So without getting into the merits of the arguments, a deliverable would go a long way toward mitigating the debate.

Dr. Jones: I think that's right, sure.

Dr. Adashi: IVF has all but vanquished barrenness, as we knew it. What do you say to those who argue that infertility is not a disease?

Dr. Jones: I can make a case for saying that it is not a disease. I think it's a symptom, like pain. Pain can be caused by many things. Infertility can be caused by many things. I am aware that the American Society for Reproductive Medicine (ASRM) has said that it is a disease, but it's a matter of defining what disease is. I like to think of it as a symptom, because a symptom can be caused by a variety of diseases, and in that respect, maybe we're quibbling with words, but nevertheless, that's my view.

Dr. Adashi: Yes. Dr. Jones, though a month or two early, may I wish you an absolutely wonderful 100th birthday.

Dr. Jones: Thank you, but you know I've had 100 birthdays.

Dr. Adashi: How is that?

Dr. Jones: How is that? That is because we don't count the most important birthday in our lives, and that's the real birthday. If you add that, I've already had 100 birthdays, but I haven't lived 100 years.

Dr. Adashi: Point well taken. From all of us at Medscape, we thank you for your outstanding contributions to the field of IVF, to women's health, and to medicine overall.

Dr. Jones: Thank you, Eli.

Dr. Adashi: On this note, a sincere thanks to our viewers for joining us for this special Medscape One-on-One. Until next time, I am Eli Adashi.


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