To Test or Not to Test: That is The Question with Dr. Nabil Arrach
I had the honor of interviewing Dr. Nabil Arrach, who is a molecular geneticist specializing in embryo testing. He is the CEO and founder of Progenesis and the first scientist to optimize and validate Next Generation Sequencing (NGS) for PGS and PGD, now known as PGT-A and M.
Dr. Aimee: I’m so excited to have you on today to talk about “to test or not to test, that is the question.” Of course, we’re talking about embryo testing.
You founded Progenesis. Tell us about yourself, tell us about your company and what you do.
Dr. Nabil Arrach: Thank you so much for inviting me to your show. I am the founder of Progenesis. We specialize in PGT-A and PGT-M embryo testing. The company was founded in 2015. I was a scientist behind the testing. In 2013 and 2014, I developed the first test that used next generation sequencing. It was the first kind of test to use the latest technology. That was my first step towards starting Progenesis in 2015.
Dr. Aimee: That’s really exciting. You’re on the forefront and you’re the person that we want answering our questions today. Are you ready for this question?
Dr. Nabil Arrach: Absolutely.
Dr. Aimee: I do some weird stuff. I go into elevators and I like to ask people questions. I just walked into an elevator with you, we walked in from the lobby level, and you have from when we get into the elevator until we get to the top of the building to explain to me what PGT is. Go…
Dr. Nabil Arrach: PGT stands for preimplantation genetic testing. Basically, it is a way of assessing embryo chromosomes to select the best embryo for implantation. Embryos that have extra chromosomes or missing chromosomes don’t implant, and if they do, they miscarry, and if they don’t miscarry, they will lead to a syndrome.
Another way of testing embryos is preimplantation genetic testing monogenetic diseases. In this case, what we do is we test the parents to look at what mutation they have, and we look for that particular mutation on the embryos to reduce the risk of having an inherited condition. That could be Cystic Fibrosis or any other syndrome, any other genetic conditions that may impact the quality of life of a child.
Dr. Aimee: Ding. Now we’ve landed on our floor. That was a great answer. Now we got off on our floor and we walk out, and there’s 30,000 people, all fertility patients who really want to know what it truly is, what’s the technology, do you think everyone should test, who should test and why. Just share with our audience some of your thoughts on that.
Dr. Nabil Arrach: That’s really an interesting question. If the patient is 40 years old or younger, and they have three, four, five embryos, I would definitely say test, because when you test you’re choosing the best embryos as far as chromosome composition, so you’re reducing miscarriage and you’re increasing the likelihood of implantation instead of trying three or four transfers.
If you pick randomly an embryo, there is a chance that it could be 50% or 60%, depending on age, or 80% if the patient is 42, likelihood of being abnormal. Instead, you choose the one that is more likely to be normal. By doing that, you are reducing the risk of miscarriage, saving time, so time to pregnancy is shorter. You’re saving cost and saving emotional damages that one would be exposed to if they have to go through a lot of miscarriages.
If the patient is 43 or 44 and has only one embryo to transfer, and I know they have only a 15% or 10% chance of having a normal embryo, that’s a difficult decision. I think from my perspective I will give them the best information that I have on hand — we have tested over 50,000 embryos, so we know what the statistics are — and give them genetic counseling options and the patient will make that decision.
Some patients want to try their luck, so you can’t tell them don’t transfer. You have to just inform them, give them enough information, and let them make the decision.
Dr. Aimee: Great. Thank you for that. Now pretend I’m in the fourth or fifth grade. I don’t know anything about chromosomes, I don’t know anything about genes. You’ve now completely confused me because you’re talking about all this alphabet soup. Can you break down the difference between chromosomes and genes?
Dr. Nabil Arrach: Yes. Look at chromosome as if they were structure, buildings, in which you have genes, the genes are inside a physical structure which is a chromosome. In a normal male, a person has 22 pair of those chromosomes, 1–22, and then they have X and Y because they’re a male. For a female, 22 pair of chromosomes and then X and X.
The genes are just pieces that lie within the chromosome that have a function. That function could be a biological function or it could be a protein or enzyme. It’s a piece of the chromosomes. Not all DNA within a chromosome encode for a function. There are only 20,000 genes within the entire genome. The rest we use to call it garbage DNA, but now we know that it has a lot of functions and regulatory aspects and others.
That’s the difference between a chromosome. The chromosome is the structure, the gene is what is inside a chromosome.
Dr. Aimee: You just mentioned 20,000. That doesn’t seem like a lot. Why can’t we test for things like ADD, ADHD, autism, schizophrenia? I can tell you that for my patients they think that when they’re doing genetic testing of their embryos they’re also screening for these diseases. After they see me, they know that’s not the case, but why can’t we?
Dr. Nabil Arrach: The first quick answer to that is let’s look at how many embryos a common patient will have. If that patient has only two or three embryos, you’re hoping to at least have one to transfer that is chromosomally balanced. If you add more selection to that patient, they’re not going to have a transfer.
I can tell you from looking at a lot of genetic reports, everybody has mutations. Those mutations, sometimes they are called unsignificant impact or unknown impact. I think the first answer would be the more you test, the less likely you will have a transfer. That’s number one.
Number two, if you look at neurological diseases such as autism or schizophrenia, it’s usually a lot of genes. For example, in the case of autism, we have more than 100 genes, at least, that interplay in the cause of the disorder. It’s not always one gene, one effect. It’s multiple genes. It’s a very complex relationship there. What that means is it’s not easy to just test those genes and then find out whether that person may or may not be autistic. You have to just use risk assessment.
We have been looking for genes for autism for many months. There are databases that will tell you gene X, Y, and Z have been linked to autism, but there is no study that really looks at all these genes in combination. So, there is a challenge as far as what we know.
As far as testing, it’s not a challenge in things to test. Testing is pretty easy to design and perform. What is difficult is to know whether that information has a clinical value or not. That’s where we’re learning.
Dr. Aimee: Are you telling me that one day we actually might get there, that we would be able to test for these genes in embryos and give patients this type of information to help make decisions about which embryo to transfer?
Dr. Nabil Arrach: Absolutely. There is no doubt about it. As of now, if we wanted to test for a large number of genetic conditions, we can do it on embryos. We’ve tested embryos on a full exome, meaning all the genes, and I think we can sample about 30%, and now with the technology it is getting closer to 50%. That means you can look at technically 10,000 genes in one embryo.
From a technology perspective, it’s not very difficult to do. It’s just whether you have the right information and the studies to make your call accurate enough for transfer.
Dr. Aimee: Got it. You’ve broken down some big words for us, chromosomes and genes. One word that’s very important for me to make sure my patients to know is mosaicism. I think it’s really important for every patient out there listening to this to know their clinic’s policy for reporting on mosaic embryos and transferring mosaic embryos. What is mosaicism?
Dr. Nabil Arrach: Thank you so much. Mosaicism is like when you’re talking about a mosaic painting, so you have different colors. It’s the same concept. A mosaic embryo is an embryo that has a mix of cells; some cells are normal and some cells are abnormal or have an extra chromosome.
How does it happen? When the egg is fertilized with the sperm, the cells start dividing. In that cell division, chromosomes will duplicate within one cell and then will segregate, they will separate so that two cells will have the same number of chromosomes. That exercise does not always happen accurately, so sometimes you have an extra chromosome that goes to one cell and the other cell has a missing chromosome. Those two cells, if they start dividing, then you’re going to start having a mix of cells that are normal and abnormal. That’s mosaicism, how you define it.
The question is; is it real, does it happen in nature? We have seen a lot of individuals with mosaicism. For example, Trisomy 21, 5% of kids that have Trisomy 21 are mosaic. We have seen mosaicism in miscarriages. There’s a study that I looked at not too long ago with 1,00 patients looking at miscarriage and CVS data, and the estimates for number of mosaicism in that study was about 3.5%. If you look at other studies, it’s about 3%. When we look at our PGT-A data on embryos, we see about 2.5%.
So, differences between laboratories. Some laboratories will report 10%, 15%, 20%, and so you ask yourself how come you are seeing such a difference between two laboratories. The answer to that is it depends on what technology platform they are using and how they are handling that data.
The way I see mosaicism is if you have an embryo at day one with two cells and one of them had what we call a nondisjunction event, basically an error in separation of chromosomes, then mosaicism raises 50%. If it happens in day two, that’s one of four, that’s 25%. The application that labs are using currently don’t detect anything below 20%. What that means is any error that happens in cell division, if it happens after day three, is not detectable anyway. We detect it only when it happens at the very early stage.
That’s in combination with the fact that miscarriages are only 3% to 5% mosaicism rates. I think mosaicism rate reported by certain labs is just inflated.
I have to add to that one more fact. There are no genetic markers that tell you this embryo is mosaic. It’s just an algorithm that labs use to estimate the number of sequences, and based on that it will tell you it is not three copy, it’s not a one copy. Three copy chromosome is trisomy, one copy is monosomy. It’s somewhere between two and three. But that’s just a calculation of numbers, it does not really translate in a biology mosaicism.
To summarize all of that, I think mosaicism is inflated in certain labs. I think it should be somewhere between 2% to 3%. I think most of the time we don’t see it, because people that have mosaicism, 2% or 3%, we would never see it, probably they will be born and you would never know about it. That’s my opinion about mosaicism.
If you have an embryo that is mosaic, you need to have a discussion with the lab, with a genetic counselor, and with your physician, and then come up with a decision. The mosaic calls that we don’t recommending transferring are the syndromic ones, chromosome 13, 18, and 21. Why? Because if they are real, they are more likely to stay and then the likelihood of having a syndrome is higher.
Other than that, we know that monosomies, the ones that are missing a chromosome, are less likely to stay, to implant. If you have monosomies, you have more chance of transfer. The trisomy have more chance of implanting. When you look at miscarriages in general, about 65% of all these embryos that in a normal conception without looking at IVF, 65% of those trisomies are single trisomy.
That’s how I see the decision of transferring an embryo.
Dr. Aimee: I find this extremely helpful and I’m glad that you’re sharing this with us. What is your genetic company’s policy on reporting mosaicism? I know a lot of doctors tell the genetic testing company that they use, “I don’t want to know about it, don’t tell me about it.” Do you automatically tell all of your clients and patients about it, or do you let the doctors opt-in to disclosing this information?
Dr. Nabil Arrach: The physician has the say, whether they want to see mosaicism results or not. If they say, “I don’t want to see mosaicism results on the reports,” then we will report that abnormal. Again, our rate is 2.5%, it’s like in 100 you’re going to find 2 cases.
If the report has mosaic, if it’s a low mosaicism level and the patient does not have any other chance of transferring, if the only embryo they have is mosaic, automatically we enroll them in a genetic counseling session and we want them to go through that exercise of knowing all the risks associated. Then between the patient, the genetic counselor, and the physician there is a decision made there.
Dr. Aimee: ASRM just came out with, I don’t remember if it was a committee opinion or some sort of policy, I should have it top of mind, basically saying that all patients should be told if their physician is not going to report mosaicism to them, they should be told up front. That’s why I do this show and I talk about these kinds of things, because people just don’t know that they need to ask up front before they even do IVF.
I’m passionate about this because I’ve had many beautiful mosaic babies born. My patient population is older, the average patient that I have is between 39 to 41. I take every single embryo seriously and the information that I’m given seriously. These babies are now toddlers and I know they’re doing great. I don’t have the worries about their outcomes because their chromosomes are actually normal. They did CVS, they did amnio, they did carrier types. That’s kind of why I get fired up talking about this stuff. Thank you for sharing that with us.
Dr. Nabil Arrach: Thank you.
Dr. Aimee: People can go online and they Google stuff. I tell patients I’m a lot faster than your Google search, so if you ever have a question about the technology and what it is, ask me.
But people go online and they find this stuff about how abnormal embryos can turn into healthy babies. My theory on that is the likelihood of that happening is so low that it’s close to zero. If someone is transferring an abnormal embryo that turns into a healthy baby, it was most likely mosaic. What is your opinion on that?
Dr. Nabil Arrach: We know that there are certain physicians that in discussion with the patient sometimes they decide to transfer an embryo because that’s the only embryo they have. In our hands, we have not seen an embryo that has implanted that is abnormal. I can definitely understand why certain patients would want to transfer, because they say maybe in case it’s not a fully abnormal embryo.
I think that’s where the relationship with the laboratory has to be really open. Once we have the results and someone asks about the results, we share with them the actual plots, the raw data, and we try to run them through that process. We have scored over 50,000 embryos, so we have lots of experience scoring embryos.
What I can say about PGT-A testing is if an embryo is clearly abnormal, it’s very unlikely that embryo will implant. But if it’s mosaic, definitely it’s an option.
Dr. Aimee: How do you know your testing is accurate? I mean know the answer to this, but I’d love for you to share that with us. How do you know that an abnormal embryo is really abnormal without transferring it?
Dr. Nabil Arrach: First of all, abnormal and normal is a relative thing. It’s euploid, aneuploid, it has 23 pair of chromosome, each one that is reported as normal. Now we have started to change it to euploid or aneuploid, because really there is no such thing as normal. An embryo may carry other modification that may impact the potential of implantation as well that we don’t understand yet.
How do I know it’s chromosomally balanced? I think just looking at all of the data we have. We track the implantation rate, we track the miscarriage rate, we track the delivery rate, and we run quality control and quality assurance on a regular basis, so we understand data. We are data driven.
I think that’s what makes a difference between a good lab and an okay lab, because you can’t just test and send results, you really have to understand what the implication of that testing is in real life, in implantation and all of that. We know exactly what euploid rates are in each age group, based on a very large number of biopsies. I think the quality assurance, quality control, and tracking outcomes is what makes you feel comfortable about the data.
Dr. Aimee: You mentioned testing and how it’s done, and how you actually did one of the first NGS cases on the new platform. What does that mean, what is NGS? How is the testing actually done? Do you use a really strong microscope or a really strong magnifying glass? I’m just kidding. But how do you do it, technically?
Dr. Nabil Arrach: We receive a biopsy. A biopsy of a trophectoderm. So, an embryo will grow until day five or day six, that embryo is a blastocyst. The trophectoderm is an outside layer that will eventually be transformed into placenta.
That trophectoderm is biopsied and we have about five or six cells in general, so we have very little material. That material has to amplify, so we take it to the lab and we put some enzymes and we try to replicate that DNA to a point that we have enough DNA. Then we put a barcode, so every biopsy has a barcode that is associated with a patient for tracking.
Then we read the DNA. When we read the DNA, then we identify what read we have obtained in what region of the chromosome, and we have to assemble that DNA and evaluate chromosome copy. That’s what we report back to the fertility center.
Dr. Aimee: Why does the genetic testing lab matter? I know you brought that up a little bit when you talked about mosaicism. Is there anything else that a consumer or patient should know when it comes to picking a lab that would help them choose?
Dr. Nabil Arrach: Yes. I think a lab should have a geneticist, and I think a lab should have scientists besides the testing personnel. The testing personnel are the clinical laboratory scientists that have been trained to do the test the same way every time, which is great, but testing alone is not enough. You have to have someone behind the scenes looking at the data, trying to figure out if the data makes sense, doing all of the quality control and quality assurance necessary to assure that the data is accurate, tracking outcomes.
For all of that you have to have some geneticists in that team. Not all laboratories have geneticists. Some of them have technicians. You have to have someone who understands genetics. The conception is that the lab has a bunch of technicians and machines that run the test. This is not a blood test that we will enter the data and spill out the results. This is really looking at the data, retesting if necessary, evaluating the data.
It’s like a pathology test when you send a test on a slide and there is a pathologist who is looking at that tissue trying to make a call there. The software will give you a call, but the software is not trained to identify certain things in a result, so that’s where the experience comes in.
Dr. Aimee: Absolutely. What are the testing limitations? How accurate is it? What are the limitations that people should know about?
Dr. Nabil Arrach: The testing limitation is that it does not detect very tiny changes. If the embryo has a mutation, it will not see them. If the embryo has really tiny deletions — when I say tiny, relatively speaking, that is five or six million base — the test will not see it. The test is designed to do a superficial scan on what embryo has potential, what embryo has all of the chromosomes needed for a normal embryo development.
Dr. Aimee: Do you think if we were able to grow embryos out to 15 days and then do a test, would we be able to pick up those really tiny abnormalities that could help patients pick out better embryos for transfer and give them a higher pregnancy rate?
Dr. Nabil Arrach: There are other ways, less invasive, that we are currently working on. One of them is instead of taking a biopsy and just testing it right way, we’ll grow that biopsy for many days and then you sample multiple times. Whenever you see a mosaic result, you can retest again. You have more supply material that has not gone through any modification, just pure cell division. I think that could provide a great alternative as far as improving the test accuracy and also looking for other things that you may be interested in. If at the end you want to see genes, mutations, and more of a high resolution scan, you should be able to do that. I think that’s the direction we’re trying to explore.
Dr. Aimee: You grow the DNA in the biopsy, not repeating the biopsy on the embryo?
Dr. Nabil Arrach: You let the biopsy grow further. What happens is those trophoblast cells will divide and divide. So, instead of relying on three to five cells, now you have hundreds, maybe thousands of cells. You can just take as much as you want, you can take today and tomorrow and the next day if you want. If you have the unlimited supply, you’re definitely going to get a good result.
Also, what seems to be a mosaic result may be corrected over time, because sometimes you may just have a damaged tissue. Over time, if you have more cells coming from the same tissue, you’re going to have more normal looking cells which will correct your call.
Dr. Aimee: Okay. One of the hardest parts of my job is calling people to let them know that their pregnancy tests are negative, especially when they’ve gone through so much work, the process of IVF for embryo creation and then testing, and then a frozen embryo transfer, and all of the stuff in between like implantation testing and ERA testing.
Let’s say you’ve done that. What are some explanations from your point of view as a scientist as to why a perfectly beautiful embryo that has normal chromosomes, and you know what I mean by normal, normal euploid, still doesn’t attach?
Dr. Nabil Arrach: I think as far as we’ve seen the highest implantation rate is probably high 70s, maybe around 80%. You’re talking probably 20% or 30% of non-implantation. I know you don’t like failure of implantation, so I’m going to use non-implantation.
Why? It could be anything. Let’s start with genetics. It could be genetics, because embryos that have normal copy of chromosome are not necessarily competent to implant. They may not be expressing the right genes, or they may have mutations. We don’t know anything about that aspect.
It could be the endometrial tissue. It could be that it doesn’t have the right environment for implantation. You know all the stories about endometrial receptivity and all of that.
It could be the transfer technique. There are so many variables. That’s the thing about IVF, there are so many variables. It is sufficient for one variable to be off and then you don’t have any implantation.
Dr. Aimee: There are so many genes that are needed to be working in order for implantation to occur. There are so many research articles written about the HLA genes and the KIR genes. Why aren’t we able to test those types in genes in embryos to help patients?
Dr. Nabil Arrach: If you remember, I said earlier about extended growth. I think that could also enable us to look at gene expression right before implantation.
I think you’re going to need to study also gene expression within the endometrial tissue to see if you have information on both sides, because the embryo alone is not going to be able to implant if the environment is not favorable. I think it’s going to have to be studying the implantation milia, which is the endometrium, and then studying the embryo ability to implant.
There are many studies and I think it’s wonderful to see some data. I’m sure labs are going to look at that aspect of assessing embryo and potentially assessing endometrium for implantation.
Dr. Aimee: What are some future developments that fertility patients can look forward to that could help them in the future, from a genetic testing standpoint?
Dr. Nabil Arrach: One of them is noninvasive PGT-A testing. We know that a biopsy is not the ideal scenario for testing an embryo, because you have to cut a piece of the embryo, there’s an additional level of stress put on the embryo prior to implantation, so we and other labs are exploring noninvasive PGT-A testing.
There are some challenges. One of them is material contamination, meaning DNA that we see that looks normal is just coming from the accumulative cells that are surrounding the oocyte before fertilization, we see some material contamination. And the consistency is not there. The Y chromosome is slightly weak in terms of detection. So, we’re working on all of these details to optimize the test. There are other companies that are also investing time and money in looking at noninvasive testing.
I think that would be the next step that most labs are focusing on. Then after that is going to be assessing an embryo from many other types of information, not just chromosome copy, but a full scan of an embryo. I think right now the reason why we don’t look at the entire embryo is because it costs more, from a financial aspect it costs more to test an embryo and all of these genes, and we don’t know the implication well. When these two things get optimized, the cost of testing and the information needed to understand the clinical implication, then I think that will be the next step.
Dr. Aimee: I know this sounds scary, guys. I imagine at some point each embryo will have a picture of what your baby would look like as an adult. Don’t you think?
Dr. Nabil Arrach: Yes. It’s not something that we have not thought about. You can imagine a lot of genetic traits are inherited, you look at facial expression, the distance between the eyes, and all the features we see in our eyes, the body type, all of those features are inherited. Science will be able to dissect that information looking at moms and dads or partners, and then estimating that or coming up with possible scenarios in the child.
The other thing I can say is now if you look at all these apps on Facebook and other applications, you can actually by looking at pictures and combining those pictures get a good guess of how the kids would look physically. If you add the genetic components onto that, then you’re going to refine it a little bit more. Whether that is going to be something the patient will go for is a different question, but scientifically, yes, it is possible.
Dr. Aimee: I see a website, EmbryoMatch.com. Where did you meet? We met on EmbryoMatch.com.
Okay. So, we’re almost done with this interview. This has been so great. Thank you for all of the time that you’ve taken to explain all of this stuff for us. I would love for you to just go through real quick euploid rates by age. Can we do that?
Dr. Nabil Arrach: Sure.
Dr. Aimee: Okay. Let’s just start at 45 years old. Blastocyst. What percentage of euploid?
Dr. Nabil Arrach: 45 is probably around 10%. I don’t remember the number exactly, but I can give you a rough number. 45 is probably around 10%.
Dr. Aimee: Okay.
Dr. Nabil Arrach: 43 to 45, within 10% to 15%.
40 to 42 around 20%.
Then below 40, like 38 to 40, we’re talking about potentially 30%.
At 35 to 40, we’re talking about 50% to 60%, in that range.
Under 35, you’re talking about 65%.
I’m just relying on my memory for the numbers, but I may be off by 5% or so.
Dr. Aimee: It sounds about right. Thank you again for all the things that you’re doing to improve pregnancy rates for our patients and all of the research that you’re doing to move the field forward so that my patients can shed less tears and hopefully do less cycles with me. Thank you again for coming on. We really appreciate you.
Dr. Nabil Arrach: Thank you. Thank you so much for the opportunity.
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