The New Prospective Parenthood: When Does More Info Become Too Much?
Obstetric ultrasound of a fourth-month fetus.
Peggy Clark was 12 weeks pregnant when she went in for a nuchal translucency (NT) scan to see whether her unborn son had Down syndrome. The sonographic scan measures how much fluid has accumulated at the back of the baby's neck: the more fluid, the higher the likelihood of an abnormality. The technician said the baby was in such an odd position, the test couldn't be done. Clark, whose name has been changed to protect her privacy, was told to come back in a week and a half to see if the baby had moved.
"With the growing sophistication of prenatal tests, it seems that the more questions are answered, the more new ones arise."
"It was like the baby was saying, 'I don't want you to know,'" she recently recalled.
When they went back, they found the baby had a thickened neck. It's just one factor in identifying Down's, but it's a strong indication. At that point, she was 13 weeks and four days pregnant. She went to the doctor the next day for a blood test. It took another two weeks for the results, which again came back positive, though there was still a .3% margin of error. Clark said she knew she wanted to terminate the pregnancy if the baby had Down's, but she didn't want the guilt of knowing there was a small chance the tests were wrong. At that point, she was too late to do a Chorionic villus sampling (CVS), when chorionic villi cells are removed from the placenta and sequenced. And she was too early to do an amniocentesis, which isn't done until between 14 and 20 weeks of the pregnancy. So she says she had to sit and wait, calling those few weeks "brutal."
By the time they did the amnio, she was already nearly 18 weeks pregnant and was getting really big. When that test also came back positive, she made the anguished decision to end the pregnancy.
Now, three years after Clark's painful experience, a newer form of prenatal testing routinely gives would-be parents more information much earlier on, especially for women who are over 35. As soon as nine weeks into their pregnancies, women can have a simple blood test to determine if there are abnormalities in the DNA of chromosomes 21, which indicates Down syndrome, as well as in chromosomes 13 and 18. Using next-generation sequencing technologies, the test separates out and examines circulating fetal cells in the mother's blood, which eliminates the risks of drawing fluid directly from the fetus or placenta.
"Finding out your baby has Down syndrome at 11 or 12 weeks is much easier for parents to make any decision they may want to make, as opposed to 16 or 17 weeks," said Dr. Leena Nathan, an obstetrician-gynecologist in UCLA's healthcare system. "People are much more willing or able to perhaps make a decision to terminate the pregnancy."
But with the growing sophistication of prenatal tests, it seems that the more questions are answered, the more new ones arise--questions that previous generations have never had to face. And as genomic sequencing improves in its predictive accuracy at the earliest stages of life, the challenges only stand to increase. Imagine, for example, learning your child's lifetime risk of breast cancer when you are ten weeks pregnant. Would you terminate if you knew she had a 70 percent risk? What about 40 percent? Lots of hard questions. Few easy answers. Once the cost of whole genome sequencing drops low enough, probably within the next five to ten years according to experts, such comprehensive testing may become the new standard of care. Welcome to the future of prospective parenthood.
"In one way, it's a blessing to have this information. On the other hand, it's very difficult to deal with."
How Did We Get Here?
Prenatal testing is not new. In 1979, amniocentesis was used to detect whether certain inherited diseases had been passed on to the fetus. Through the 1980s, parents could be tested to see if they carried disease like Tay-Sachs, Sickle cell anemia, Cystic fibrosis and Duchenne muscular dystrophy. By the early 1990s, doctors could test for even more genetic diseases and the CVS test was beginning to become available.
A few years later, a technique called preimplantation genetic diagnosis (PGD) emerged, in which embryos created in a lab with sperm and harvested eggs would be allowed to grow for several days and then cells would be removed and tested to see if any carried genetic diseases. Those that weren't affected could be transferred back to the mother. Once in vitro fertilization (IVF) took off, so did genetic testing. The labs test the embryonic cells and get them back to the IVF facilities within 24 hours so that embryo selection can occur. In the case of IVF, genetic tests are done so early, parents don't even have to decide whether to terminate a pregnancy. Embryos with issues often aren't even used.
"It was a very expensive endeavor but exciting to see our ability to avoid disorders, especially for families that don't want to terminate a pregnancy," said Sara Katsanis, an expert in genetic testing who teaches at Duke University. "In one way, it's a blessing to have this information (about genetic disorders). On the other hand, it's very difficult to deal with. To make that decision about whether to terminate a pregnancy is very hard."
Just Because We Can, Does It Mean We Should?
Parents in the future may not only find out whether their child has a genetic disease but will be able to potentially fix the problem through a highly controversial process called gene editing. But because we can, does it mean we should? So far, genes have been edited in other species, but to date, the procedure has not been used on an unborn child for reproductive purposes apart from research.
"There's a lot of bioethics debate and convening of groups to try to figure out where genetic manipulation is going to be useful and necessary, and where it is going to need some restrictions," said Katsanis. She notes that it's very useful in areas like cancer research, so one wouldn't want to over-regulate it.
There are already some criteria as to which genes can be manipulated and which should be left alone, said Evan Snyder, professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford Children's Health Research Center in La Jolla, Calif. He noted that genes don't stand in isolation. That is, if you modify one that causes disease, will it disrupt others? There may be unintended consequences, he added.
"As the technical dilemmas get fixed, some of the ethical dilemmas get fixed. But others arise. It's kind of like ethical whack-a-mole."
But gene editing of embryos may take years to become an acceptable practice, if ever, so a more pressing issue concerns the rationale behind embryo selection during IVF. Prospective parents can end up with anywhere from zero to thirty embryos from the procedure and must choose only one (rarely two) to implant. Since embryos are routinely tested now for certain diseases, and selected or discarded based on that information, should it be ethical—and legal—to make selections based on particular traits, too? To date so far, parents can select for gender, but no other traits. Whether trait selection becomes routine is a matter of time and business opportunity, Katsanis said. So far, the old-fashioned way of making a baby combined with the luck of the draw seems to be the preferred method for the marketplace. But that could change.
"You can easily see a family deciding not to implant a lethal gene for Tay-Sachs or Duchene or Cystic fibrosis. It becomes more ethically challenging when you make a decision to implant girls and not any of the boys," said Snyder. "And then as we get better and better, we can start assigning genes to certain skills and this starts to become science fiction."
Once a pregnancy occurs, prospective parents of all stripes will face decisions about whether to keep the fetus based on the information that increasingly robust prenatal testing will provide. What influences their decision is the crux of another ethical knot, said Snyder. A clear-cut rationale would be if the baby is anencephalic, or it has no brain. A harder one might be, "It's a girl, and I wanted a boy," or "The child will only be 5' 2" tall in adulthood."
"Those are the extremes, but the ultimate question is: At what point is it a legitimate response to say, I don't want to keep this baby?'" he said. Of course, people's responses will vary, so the bigger conundrum for society is: Where should a line be drawn—if at all? Should a woman who is within the legal scope of termination (up to around 24 weeks, though it varies by state) be allowed to terminate her pregnancy for any reason whatsoever? Or must she have a so-called "legitimate" rationale?
"As the technical dilemmas get fixed, some of the ethical dilemmas get fixed. But others arise. It's kind of like ethical whack-a-mole," Snyder said.
One of the newer moles to emerge is, if one can fix a damaged gene, for how long should it be fixed? In one child? In the family's whole line, going forward? If the editing is done in the embryo right after the egg and sperm have united and before the cells begin dividing and becoming specialized, when, say, there are just two or four cells, it will likely affect that child's entire reproductive system and thus all of that child's progeny going forward.
"This notion of changing things forever is a major debate," Snyder said. "It literally gets into metaphysics. On the one hand, you could say, well, wouldn't it be great to get rid of Cystic fibrosis forever? What bad could come of getting rid of a mutant gene forever? But we're not smart enough to know what other things the gene might be doing, and how disrupting one thing could affect this network."
As with any tool, there are risks and benefits, said Michael Kalichman, Director of the Research Ethics Program at the University of California San Diego. While we can envision diverse benefits from a better understanding of human biology and medicine, it is clear that our species can also misuse those tools – from stigmatizing children with certain genetic traits as being "less than," aka dystopian sci-fi movies like Gattaca, to judging parents for making sure their child carries or doesn't carry a particular trait.
"The best chance to ensure that the benefits of this technology will outweigh the risks," Kalichman said, "is for all stakeholders to engage in thoughtful conversations, strive for understanding of diverse viewpoints, and then develop strategies and policies to protect against those uses that are considered to be problematic."
Pioneering XPRIZEs, Longevity and Mindset with Dr. Peter Diamandis
XPRIZE founder and chairman Peter Diamandis launches XPRIZE Healthspan at an event on November 29.
A new competition by the XPRIZE Foundation is offering $101 million to researchers who discover therapies that give a boost to people aged 65-80 so their bodies perform more like when they were middle-aged.
For today’s podcast episode, I talked with Dr. Peter Diamandis, XPRIZE’s founder and executive chairman. Under Peter’s leadership, XPRIZE has launched 27 previous competitions with over $300 million in prize purses. The latest contest aims to enhance healthspan, or the period of life when older people can play with their grandkids without any restriction, disability or disease. Such breakthroughs could help prevent chronic diseases that are closely linked to aging. These illnesses are costly to manage and threaten to overwhelm the healthcare system, as the number of Americans over age 65 is rising fast.
In this competition, called XPRIZE Healthspan, multiple awards are available, depending on what’s achieved, with support from the nonprofit Hevolution Foundation and Chip Wilson, the founder of Lululemon and nonprofit SOLVE FSHD. The biggest prize, $81 million, is for improvements in cognition, muscle and immunity by 20 years. An improvement of 15 years will net $71 million, and 10 years will net $61 million.
In our conversation for this episode, Peter talks about his plans for XPRIZE Healthspan and why exponential technologies make the current era - even with all of its challenges - the most exciting time in human history. We discuss the best mental outlook that supports a person in becoming truly innovative, as well as the downsides of too much risk aversion. We talk about how to overcome the negativity bias in ourselves and in mainstream media, how Peter has shifted his own mindset to become more positive over the years, how to inspire a culture of innovation, Peter’s personal recommendations for lifestyle strategies to live longer and healthier, the innovations we can expect in various fields by 2030, the future of education and the importance of democratizing tech and innovation.
In addition to Peter’s pioneering leadership of XPRIZE, he is also the Executive Founder of Singularity University. In 2014, he was named by Fortune as one of the “World’s 50 Greatest Leaders.” As an entrepreneur, he’s started over 25 companies in the areas of health-tech, space, venture capital and education. He’s Co-founder and Vice-Chairman of two public companies, Celularity and Vaxxinity, plus being Co-founder & Chairman of Fountain Life, a fully-integrated platform delivering predictive, preventative, personalized and data-driven health. He also serves as Co-founder of BOLD Capital Partners, a venture fund with a half-billion dollars under management being invested in exponential technologies and longevity companies. Peter is a New York Times Bestselling author of four books, noted during our conversation and in the show notes of this episode. He has degrees in molecular genetics and aerospace engineering from MIT and holds an M.D. from Harvard Medical School.
Show links
- Peter Diamandis bio
- New XPRIZE Healthspan
- Peter Diamandis books
- 27 XPRIZE competitions and counting
- Life Force by Peter Diamandis and Tony Robbins
- Peter Diamandis Twitter
- Longevity Insider newsletter – AI identifies the news
- Peter Diamandis Longevity Handbook
- Hevolution funding for longevity
XPRIZE Founder Peter Diamandis speaks with Mehmoud Khan, CEO of Hevolution Foundation, at the launch of XPRIZE Healthspan.
Hevolution Foundation
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.
Important findings are starting to emerge from research on how genes shape the human response to the Covid virus.
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. “But 99 percent of people who get it will never see the inside of a hospital for COVID-19,” she says. “They are home, they are not interacting with the health care system.”
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didn’t have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were “more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant,” she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And “for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time,” says Hollenbach. “This T cell response is very early in infection and ramps up very quickly, even before the antibody response.”
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. “It gives us an opportunity to think about whether this might be a vaccine design strategy.”
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that “CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections,” says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which “is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared.” Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they don’t start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, “Virus replication in the male lungs was negatively associated with testosterone levels.”
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, “One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing” CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that “it probably is much better to inhibit the enzyme” produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. It’s also uniting different fields of science into a new, collaborative approach they’re calling “infection endocrinology,” she says.