 Without further ado, let's move on to our next talk. Hacking human fetuses and here to present Dr. Aaron Hefley. Hi everyone, thanks for coming. My name is Dr. Aaron Hefley. I am an OBGYN physician from Phoenix, Arizona recently relocated to Sacramento, California. And my talk today is on hacking human fetuses. I guess a quick disclaimer, I'm not really a biohacker. I'm not a clinical researcher. I'm an OBGYN in practice who enjoys having these kinds of conversations with my colleagues to talk about the cutting edge science that will eventually be translated into actual interventions and treatments that I can offer my patients. So I like reading about these things. I like talking about these things, but I'm not in the lab working on these things as some of the other people you've heard speak today might be. But I hope that there are plenty of people in the audience who are, who can be inspired by some of these conversations to help advance the science. So again, in the future, there are more things I can offer my patients to help them. So just kind of a brief overview of what I hope to cover today. Just starting with this concept that human reproduction, really reproduction or sexual reproduction is an imprecise vulnerable process and we can exploit it. There are outside influences that can alter the way that an organism develops permanently or temporarily. We've long known this by observing the effects of charlatans, harmful chemicals, things that can influence the process. And so by studying the way that the process of human development can be negatively impacted, we can maybe find ways to intervene in a positive way. First to treat diseases to correct genetic problems and then hopefully maybe in the future to actually enhance human development and create better babies. Last year I gave a talk on pre-implantation genetic modification of human embryos and kind of where we are at in the science with that. So far we've been able to modify human embryos to correct genetic diseases, in particular fallacymias, blood disorders that can be fatal. There are a lot of ethical concerns with that. But there are a lot of practical issues with implanting that corrected embryo and developing it into a fully formed pregnancy and then developing it into a healthy baby. We've not yet really done that yet. But just to touch on genetic modification. So genes are the portions of DNA that encode proteins. These proteins are critical to processes and development. If you are lacking a gene for a protein, if you have an aberrant gene for a protein or that you create a harmful protein or a structurally deformed protein, you're not going to get the normal process of development, which can cause problems and diseases. These genes can be mutated. These mutations can be passed on. And we can also manipulate them in a lab to create new mutations. Epigenetics is kind of broadly the other processes outside the actual encoded DNA that influence the way that your DNA is kind of translated into these proteins and then the way it works in your body. So this is a way to turn genes off and on. Sometimes these processes are physiologic. You want them to happen. You want certain genes to be active at certain times in development and not active at other times in development. Sometimes you want them to be turned off or on depending on the environmental conditions. So for example, if there's a certain fuel that's very prevalent in the environment, you might want to upregulate the production of an enzyme that will metabolize that particular fuel and then turn those genes off again when that fuel is absent in the environment because it's just a waste of your biological resources to produce the things to metabolize that fuel when it's not there. And then they can occur kind of by exposure to harmful things in the environment that can turn off and on genes, which is one way that cancer can occur. It's also critical to understanding this process is understanding maternal fetal physiology. So the embryo grows and develops inside the uterus and there's a barrier between the fetal organism and the maternal organism at the placenta. And the placenta enables diffusion and transport of different substances critical for the development of the fetus without an actual mixing of maternal and fetal blood. There isn't really a combining of the blood, but the blood of the mother and the blood of the fetus come into close enough contact through this membrane that they can exchange nutrients, gases, waste products, hormones, things that can influence development. This is a nice timeline of fetal development that shows you how different organ systems are developing at different periods during the pregnancy. Early on you have a zygote where you've combined the maternal and the paternal DNA and you start out just with rapidly dividing cells that are all pluripotent stem cells. These cells can turn into any critical cells in the body. So if you take one out at this stage in development, you don't really hurt the organism as a whole. Any of the remaining cells can continue to divide and eventually differentiate into the organism. But before differentiation has happened, you can remove cells or damage cells and it's not really going to affect the organism as a whole. So that's the stage where we're doing the pre-implantation genetic modification of embryos. Over time they start to differentiate into different organ systems and then things get a little bit hairier. Early on and really throughout the entire pregnancy, even into childhood and really up until your mid-20s, your brain and your neurologic system is maturing and developing. But some of your other organ systems or functional systems are only really developing for a very brief window during that period. And so any harmful alterations or positive manipulations we can do is going to occur just during that really short period. After that, you're not going to be able to influence the system quite as effectively or potentially at all. And the most critical phase in development of these organ systems and morphological structure of the fetus is in the first eight weeks. So one unfortunate part of that is that many women don't even know that they're pregnant until a lot of these organ systems have already started to develop and potentially been irreversibly damaged. So touching again on irreversibly damaging these systems, we understand a lot of this process by studying the effect of teratogens. So teratogens are substances that act in specific ways on these developing organ systems to interrupt the normal process of growth and development. And when that process is interrupted particularly in those early stages, you can have critically damaging deformations of the fetus, interruptions to the organ systems. But again, that is dependent on when in the pregnancy you're exposed. And so if you're exposed to a certain substance that really only affects the heart, if you're exposed to it outside of the window of development for cardiac development in the fetus, it may not really have an effect. There are some substances that can affect many different organ systems, but because those organ systems are maturing at different stages in development, you might not affect all of them depending on when you're exposed. And then, of course, there's a kind of a dose response influence too. So sometimes small amounts aren't really going to cause a problem, but very large amounts might. And just, you know, teratogens can include medications we give people on purpose. They can include illicit substances, radiation, infections, maternal health problems, nutritional deficits. Anything that either takes away something that's critical to development, adds something that's going to harm development, changes that process of translating the DNA into the critical proteins, etc. So going back to this chart, you can see that, for example, if somebody is exposed to something that acts on the teeth very early in development, you might not actually see problems with the teeth. But at that stage, kind of at eight weeks and beyond, you might actually see those problems. One thing to point out is very, very early in pregnancy, we have something called an all or nothing phenomenon. That means that during this pluripotent stem cell stage, if you're exposed to a teratogen, it's either not going to cause a problem at all, or it's just going to cause a miscarriage. You're not going to have these kind of structural problems. It's either the blow was just too great for the organism to continue, or you're not going to see an effect. The undamaged cells are able to recover and continue to proceed with the pregnancy. I'm going to touch on some famous teratogens. So alcohol is probably one that everyone knows, you know, pregnant women shouldn't drink alcohol. Alcohol can affect the way your pregnancy develops. Well, we really, I mean, this is a question I get all the time as an OBGYN. Is this really true? Can I really not drink at all? Can I drink one glass of wine a day? How much alcohol is safe in pregnancy? We know that women who are alcoholic sometimes have babies with this fetal alcohol spectrum disorder, fetal alcohol syndrome, which is kind of a constellation of symptoms. Alcohol can affect pretty much all the organ systems. We don't know all the specific pathways involved in this effect, but you get kind of facial features like small eyes that are wide set, a smooth upper lip, thin lips, neurologic problems, mental retardation, etc. Behavioral problems later in life. Again, we know that women who drink really heavily in pregnancy are at risk for this happening. Some women who drink really heavily in pregnancy don't have this happen at all. We know that if you don't drink any alcohol, there has been no case of fetal alcohol syndrome in people who don't drink at all during pregnancy. Somewhere in between is probably the safe level of alcohol to consume, but nobody can tell you what that is. And nobody is willing to perform those studies to give pregnant women varying amounts of alcohol to see who has a jacked up baby and who doesn't. So what I can say is that I would be an irresponsible OBGYN if I stood up here and tried to tell you that there is any safe level of alcohol to consume during pregnancy. However, as adults with free will and personal responsibility can make their own decisions, I can say that some observational studies have shown that there are probably no ill effects consuming 7-9 alcoholic beverages a week in pregnancy. There's a great article, it's called Do's and Don'ts of Pregnancy Missing Facts. You can look it up if you want to learn more, but just to throw that out there. Another really famous example of a teratogen is Thalidomide. Thalidomide was a medication used for various things, but ended up actually being recommended and prescribed. I think it was available over the counter for women in pregnancy to treat morning sickness. If you've ever been pregnant or know anything about it, you might know that morning sickness really affects women for the most part during that first trimester. So during that really critical stage of organ development, women were taking this medication to help with their morning sickness, and then they had all of these babies with like flipper limbs who didn't develop their arms and legs properly. So it was pulled off the market and generations of children grew up with this problem. We didn't know for a really long time exactly how this was caused. There was some theorization that it disrupted kind of the blood vessel development to the limbs. Recently it looks like it was probably this critical protein involved in limb development that the medication caused to be degrade too quickly. So it just wasn't around in the fetal circulation long enough to do its job and enable the limbs to develop the way they were supposed to. Diathylsobestrol DES, it's really well known kind of in my circle because it causes reproductive tract anomalies. So if you see a woman with like this narrow T-shaped uterine cavity, it's very likely that she was exposed to this compound in utero. This was another one that was actually prescribed to women in pregnancy because it was supposed to help prevent miscarriages and other sort of pregnancy complications. In addition to reproductive tract abnormalities, the children who were exposed to this in utero are at higher risk for reproductive cancers. One really interesting thing about this is we found that it's probably through those epigenetic changes that this medication was causing those effects. So altering kind of the way that the DNA was processed and transcribed and translated into proteins. And this effect, this epigenetic effect actually seems to be able to pass down to future generations. So if my mother had taken diathylsobestrol at her pregnancy and I inherited these, or not inherited, but I had these epigenetic changes that were caused by her taking this medication and I get pregnant, I might actually pass those changes down to my offspring who would have the same problems. Torch infections, you probably have heard of this before. So these are just a kind of a set of infections or viruses that you can acquire during pregnancy that can cause different problems with fetal development. Most of them will cause like some of the same symptoms like enlarged organs, rashes, bone and teeth problems. Depending on when mom's exposed to pregnancy, these can cause either kind of these structural problems with the way the fetus develops or they can cause life-threatening infections of the fetus at birth. One of the newest ones, Zika virus, that's recently been added to the list of torch infections causing microcephaly, so small fetal heads. We don't yet know kind of what the long-term effects of that are. It's too new. And maternal diabetes is this one that's becoming more and more of a problem for my field as more younger women are developing diabetes because of the obesity epidemic and more older women who are already more susceptible to diabetes just from age are having babies later in life. Maternal diabetes can cause a whole host of problems for the infant. Most commonly it ends up being hypoglycemia at birth. So being exposed to high levels of blood sugar in utero, the fetus overproduces insulin once they're born and they are not exposed to this high blood sugar environment anymore. They're producing too much insulin. It drops their blood sugar to critically low levels. We can correct that pretty easily and then you'll need to see if we know what's going to happen. However, there are some critical structural problems that can occur, particularly heart defects and then coddle regression syndrome, which causes mermaid baby syndrome essentially where the entire lower body fails to develop properly. And this is a fatal structural problem with the fetus. All right. So again, by studying some of the effects of these teratogens on how the process of fetal development can be interrupted and manipulated we can look for ways that we can intervene in positive ways. And there are a couple ways that we could potentially get these chemicals or molecules or whatever it is into the fetal environment. Again, remembering that one way, of course, is if mom ingests something it might cross the placenta depending on what it is, how big it is, how lipophilic it is. So transplacental is kind of the oldest way we've been able to do this. But I've had some conversations over the past year with some colleagues about some really exciting other ways we're trying to introduce things into the fetal environment to help prevent and cure genetic diseases and other ways to just manipulate development. One is direct injection into the amniotic fluid. So the fetus is constantly swallowing amniotic fluid and it gets into the lungs and it gets into the gut and the fetus pees it out. So if it's in the amniotic fluid it's going to be taken into the fetus and then it's actually another one is direct injection into the fetus usually through the umbilical cord. Again, transplacental just means that when mom takes something it's going to go into mom circulation and at that barrier in the placenta it's going to cross over into fetal circulation. We've used this for a long time to treat certain conditions in the fetus. For example, fetal arrhythmias. So we can give mom a cardiac medication like digoxin or sotolol or flecanide and that will cross into the fetal circulation and help treat the fetal arrhythmia. As you can imagine though, because it's also in mom circulation these medications are going to affect mom too. So fortunately for something like this, usually we're giving low enough doses that mom doesn't have too many problems but this could potentially be a challenge when we try to treat other things in the fetus just by giving mom a medication. Thyroid problems is another one but typically in those situations mom also has a thyroid problem so you're really just kind of treating both at the same time. Fetal tumors, so you can actually give mom chemotherapy to treat. Usually it's like a rhabdomyosarcoma kind of tumor in the fetus and that can regress during fetal development so that when the baby is born the tumor is much much smaller or potentially gone and that can just make it easier to operate on if necessary. And then we've long given steroids for fetal and maturity so if we suspect a baby is going to be born premature we can give the mother an injection of steroids that will accelerate fetal lung development so that if indeed the baby is born premature that can help it have fewer respiratory complications at birth. So intrauterine injection, again you can directly inject with a needle kind of through mom's abdomen into the uterus into the amniotic cavity these molecules or proteins or other substances that might influence the process of fetal growth and development. Kind of the inspiration for this whole talk was a New England Journal of Medicine article about prenatal correction of excellent typo-hydratic ectodermal dysplasia which is a mouthful but essentially this is a condition where the fetus has a genetic disorder that prevents it from being able to develop sweat glands. So it lacks the ability to create this critical protein that causes differentiation of sweat glands and the baby is born with no sweat glands. And when the baby is born with no sweat glands it can't regulate its temperature and is at high risk of morbidity and mortality from high fevers. So they have found actually two different strategies for this. They can either inject kind of like a recombinant protein that gets taken up or they can inject like immune molecules that will attach themselves to the receptors that trigger this pathway. Both of those have been tried and seem to be effective for like triggering this pathway in the fetus that they then develop sweat glands even though they lack the gene required to produce the protein to have that happen on its own. And then intra-embilical injection is again direct injection into the fetus through the umbilical cord. We've used this for a long time to treat fetal anemia. If mom creates immune cells that attack the fetal blood cells you can have a potentially fatal anemia in the fetus. And we found that doing injection or blood transfusions through the umbilical cord can actually treat that and help kind of sustain that pregnancy. It's incredibly dangerous to stick a needle into the umbilical cord. It has a very high mortality rate for the fetus. We would only do this in situations where it looks like this is your last shot. This baby is going to die if we do nothing and this is the one thing we might be able to help it with. But recently we have found that you can inject stem cells into the umbilical cord of babies with osteogenesis imperfecta. So that's brittle bone disease. These kids are highly susceptible to fractures and in the most severe forms they are developing fractures in utero. So in the uterus they can't survive labor. Every time the uterus contracts it just crushes their tiny frail skeleton and they're still born. So this has been used and has been shown to actually reduce not only the fractures that the fetus undergoes in the uterus but also reduces fractures in childhood as well. And then they've used blood and bone marrow transfusions in the fetus to treat certain forms of thalassemia. So like a hemoglobin disorder. Alright, so we've looked at these processes. We see kind of how they're affected by things in the environment or things that we ingest. We've been trying to kind of utilize that to treat diseases where we can when we understand the whole biologic process is involved and the pathway is involved. The next step is can we potentially use this in the future to create enhanced offspring? So right now we have a baby that we know is going to have a problem. Can we bring it to baseline? Next step is can we bring it from baseline to above that? Just theorizing a couple different ways that maybe this could happen by discussions that depends on lit review. Cognitive function would be fantastic, right? If you could ingest something and know that your baby's going to be born smarter or with better memory. Now, we know that things that women take during pregnancy affects the brain development and the way that the neurological pathways are wired in their fetus. So we see this with fetal alcohol syndrome. We see this with opiate addiction. We even see this with SSRIs. So a medication that pregnant women take for depression, those babies are known to have different wiring of their brains. They don't respond to pain in the same way as babies who weren't exposed to these things in utero. We also know that certain substances can affect adult cognitive performance. I don't think we know of any substances that when you take them during pregnancy, they rewire your baby's brain in a way to make it smarter or have better memory or have better neurological performance. But that has to exist out there, right? You have to think that if we have so many different things we can take during pregnancy to mess that up, we have to be able to mess that up in a happily accidental way that actually creates a kind of better process. Again, I would be a really irresponsible OBGYN if I stood up here and encouraged pregnant women to just take stuff and see what happens. And if you can identify that substance that you can ingest during pregnancy that creates smarter babies, but again, it's got to be out there. Bone development is another one that we might be able to influence in a positive way to create structurally stronger skeletons. So bone morphogenic proteins induce bone production. They specifically, BMP2, causes stem cells to differentiate into osteoblasts, which are cells that produce bone or lay down bone structure. It's been used in healing of fractures to help accelerate that when you've broken a bone and trying to replace the bone and make it stronger. Is there an opportunity to manipulate that system during fetal development to kind of lay down more bone in that stage that would improve your ability to regenerate bone throughout your life? Bone is remodeled constantly throughout your entire life. It's remodeled in utero. You know that the fetus kicks and moves around. They found that that process actually encourages bone development and strengthening during pregnancy as it does, you know, people do weight-bearing exercise, just deva fasciuprosis, et cetera. So in addition to those things, if we can trigger these cells to lay down more bone, maybe we can create stronger skeletons. Muscle development is another one that's turned a lot of promise. So yeah, so there are actually genetic disorders that cause babies to be born with a lot more muscle mass. We've also found that in fetuses with growth restriction, they don't develop the same density of skeletal muscle tissue as a normal healthy developing fetus. And this has been shown in animal models where we can, at the right time in development, infuse these growth factors and additional amino acids into the amniotic fluid that we can bring these fetuses that would have had a lower than normal density of skeletal muscle tissue up to kind of a baseline normal level. This is really important because at birth, you have pretty much all of the, like, myosates you're going to have. The increases in muscle mass over your lifespan is more due to hypertrophy or enlargening of these fibers than it is creation of new muscle tissue. So if there's a way we can take that one step further, even, and instead of bringing these, like, small babies up to a normal level of muscle density, but actually kind of increased muscle density, then you could have these super strong children. Vision is another system that I'm sure we would love to be able to enhance and that has shown some early research promise. We have found that, again, at the right stage in development when the eye is developing, if you inject a certain viral vector, it will target those developing eye cells. And we don't really know what to do with that yet, but we know that we can, like, get these stem cells into the eyeball structures. There's hope that this will be used to help correct congenital vision problems and also help delay or prevent just your normal age-related deterioration and vision. So your peak visual acuity is somewhere around 12 to 13 years old. So I think pretty much everyone here, sorry, you're already past your prime vision. But if we could maybe prevent that to generation or even take it a step further and enhance vision, we're able to target some of those rods and cones. If we can manipulate those in certain ways, we might be able to see a wider spectrum. There are already people out there who, like Pap and Stance of Genetics, can see a broader range of colors than the average person. Maybe at some point we would be able to influence things so that everyone can see all of those colors. And lastly, oxygenation. So this is one of those epigenetic processes that you produce different types of hemoglobin during different stages of your life. So as a fetus, you produce this fetal hemoglobin that has a higher affinity for oxygen. It's important because you want the fetus to be able to pull that oxygen away from the maternal blood, so it has to have a higher affinity for oxygen than the maternal blood. So the oxygen circulating through the maternal blood comes close to that membrane and the fetal hemoglobin attracts it and holds on to it more. There are people who have, genetically, this persistence of fetal hemoglobin into adult life. So typically a couple weeks or months after you're born, whatever process happens in your body, that gets switched off and you start producing the adult form of hemoglobin. But there are people who persistently produce the fetal form. That doesn't seem to have any deleterious effects for them. It doesn't really necessarily seem to have any benefit that we know of as of yet. However, in people with like sickle cell anemia, if they have sickle hemoglobin and persistent fetal hemoglobin, it prevents some of the ill effects of the sickle cell. St. Frithalisemia. And then another kind of promising field with regard to increased oxygen carrying capacity is looking at populations who live at high altitudes. And now a lot of this is going to be kind of natural selection over millennia of living at these higher altitudes, but not all of it. Populations living in like the Andes, mountains, the Himalayas, even like Leadville, Colorado, they found that some of these people who were in utero, so like just stated, at a higher elevation, respond differently even to going kind of like up and down from higher to lower elevation than somebody who was born at lower elevation. So everybody here, if you go to a higher elevation, your body's going to undergo some changes to increase the oxygen delivery in your body. But if you were born at a higher elevation, live at a lower elevation and go back to a higher elevation, the way that you respond is going to be enhanced compared to somebody who wasn't born in that sort of environment. So the better we understand some of these processes and how they're turned on and off and how they were affected in utero might enable us to do this at any elevation. So challenges to implementation. Again, nobody's going to approve a randomized controlled trial for this. Many ethical concerns in general with just manipulating a fetus. There are so many things that could go wrong with it. You know, in any system like this, we might be targeting one process and have no idea what effects we're going to have on a different process. There are so many uncontrollable variables. So, you know, every single maternal fetal unit is going to be different in regard to mom's genetics, the fetus' genetics, the environmental exposures, mom's metabolism, mom's nutritional status. All of these things are going to really influence the way that any medication or substance that we administer to this system is going to be expressed, which then affects reproducibility. So if I find something that works in on one patient, I'm not necessarily going to be able to give that to anybody else. So what's the utility at that point? And of course I talked about intended effects. So with that, I think I will open it up to questions, comments. I'd love to hear from people who are doing other kinds of research or have heard of other kinds of research that might be utilized in this way in the future. And one question? Two questions. All right. Do you want them to come to the microphone? I have a question regarding the first segment of your discussion. When the woman is pregnant, I guess typically are the genetic testing, isn't it done after 12 weeks or before 20 weeks or something like that? And do you imagine that in the future we would have, or do we already have testing that enables us to see deformities and disease at a much earlier week, time period for the fetus? So it depends on what it is. We do have something called cell-free fetal DNA testing, which is kind of like a standard at this point. And you have to know what you're looking for. That's sometimes the problem, is that if you know that there's a certain genetic mutation that is going to cause a problem and you know that the parents carry this in their bloodline somewhere you can look for it, the difficulty is if it's something that we don't quite know what causes it, or we didn't know that these parents were at risk to look for it, you're not necessarily going to see it. But yeah, we can do... It's kind of close to the end of the first trimester. Unfortunately, a lot of... There's just not enough circulating material in the maternal blood before that when the embryos are so tiny. But some of it we can diagnose very early on, and that's kind of the hope that if we can diagnose it early on, we can fix it, also with ultrasound. So sometimes you can see physiological defects that we hopefully would be able to then treat at some point in the future. I mean, right now, if I get a DNA test result or a genetic testing result on the fetus and I know there's going to be a problem, it's a lot of like, well, we can terminate now or we can wait and see what happens. And if this pregnancy survives to birth, then we'll see how severe the problem is and then we can see whether or not we can treat it. At this point there's so, so little we can do during pregnancy to help. Discussed. If the baby has a problem, give the mom meds or if they both have problems and help them both. But what if the mom needs the heart medication? How does the baby or the fetus handle that? Sure. We'll monitor it. A lot of the time that seems to go okay, actually. You know, mom needing a heart medication doesn't seem to have too many deleterious effects on the fetus. We do carefully monitor maternal-feel heart rate and just kind of adjust the medication to find that kind of sweet spot balance. For other things that we know that trading mom might cause problems for the baby, one thing that comes to mind immediately is like intractable seizures. So we know that giving mom seizure medication can cause certain defects in the baby. Interestingly, women with seizure disorders during pregnancy about like a third of them will get better and have fewer seizures or no seizures. A third of them, like there won't really be any change and a third of them will be much, much worse. And so, for the most part, you just have like a discussion with your patient about what's your risk tolerance level. You know, if your seizures are just getting so bad, we need to treat you and keep you alive. Like your baby's not going to live if you don't, right? So, yeah, I mean, absolutely. It just depends on what the disease is, what the medication will do. And some of them, depending on what it is, if you can refrain from taking a medication for the first trimester and be okay during those critical stages of organ development, giving it to you later in pregnancy probably won't cause as much of a problem. All right, well, I mean, I'll be sticking around here for a little bit if anyone else wants to talk about anything. Thank you so much for your attention.