If God Hates Abortion Why Do So Many Occur Spontaneously in Humans?

By Fazale Rana – November 25, 2020

A common fundamentalist argument against abortion is that each human being is granted a soul at the moment of conception, and that destroying that “soul” is equivalent to murder. . . However, there’s some serious problems with the logic of ensoulation at the point of conception. The CDC as well as the March of Dimes and several fertility experts have conducted studies to see exactly how hard it is to carry a pregnancy to term. In general, less than 70% of all fertilized eggs will even implant into the mother’s womb causing pregnancy to continue. From there, there is a 25-50% chance of aborting before you even know you are pregnant. So if you look at it from the fundamentalist point of view, all those little souls are being given a home, only to be miscarried before they even know they are alive. Scientific research has compiled the following information about the rates of naturally aborted pregnancies in human beings (or, if you believe everything happens for a reason, pregnancies aborted by God himself).

—RationalWiki, “Spontaneous Abortion in Humans”

Miscarriage and Troubling Questions
Perhaps nothing is more painful and confusing for a woman than when she experiences a miscarriage. My wife and I know this firsthand. Amy’s first pregnancy ended with a miscarriage early in the first trimester. Our joy and excitement were replaced by sadness and an indescribable disappointment. I don’t know if I could ever truly understand how my wife felt then or how she feels now about our loss. We wonder, all these years later, if our first child was a boy or girl. Still, we are so grateful for the wonderful children God did give to us.

Questions surrounding spontaneous abortions and miscarriages are painful, indeed. But they also expose profound philosophical and theological problems with far-reaching implications for the Christian faith. The high rate of spontaneous abortions during human pregnancies raises questions about God’s goodness and also impacts the creation/evolution controversy and the abortion debate.

If human beings are made in God’s image—as the crown of creation—wouldn’t a Creator have designed a less-flawed and error-prone process for human reproduction?
If a Creator made human beings with a soul at the point of conception, why would some of these embryos live, ever so briefly before the pregnancy—and their life—comes to an end?
If a Creator hates abortion, why is the rate of spontaneous abortions so great?
In light of the high rate of spontaneous abortions, why is it so wrong for human beings to voluntarily end a pregnancy?

Without a doubt, these questions represent a serious challenge to the Christian faith. Fortunately, new scientific insights into embryo mortality and the cause of early miscarriages help address some of these challenging and heart-wrenching concerns, even if other questions remain a troubling mystery.

Before we take a look at these new insights, it is necessary to address a broader concern about the consequences of the constancy of nature’s laws and how this feature impacts the incidences of spontaneous abortions.

Consequences of the Second Law of Thermodynamics

Given the complexity of biological systems such as human reproduction, it is unreasonable to think that these processes, no matter how well designed, will perform flawlessly every time. All the more so given the influence the second law of thermodynamics wields.

As a consequence of this law, errors will inevitably occur—at least, on occasion—during all biological processes. Because of the invariance of the laws of nature, the second law is always in operation. Hence, errors will occur during: (1) fertilization, (2) implantation of the embryo in the uterine wall, and (3) placenta formation and embryo growth and development. These errors lead to spontaneous abortions, miscarriages, and stillbirths.

While it is tempting to view entropy (the second law of thermodynamics) in a negative light, it is important to recognize that, if not for entropy, life’s existence would be impossible. Entropy enables metabolism and plays the central role in the formation and stability of cell membranes, protein higher-order structures, and the DNA double helix.

Of course, the unrelenting operation of the laws of nature leads to profound theological and philosophical issues that I have addressed elsewhere. Even if errors are inevitable in biological processes, couldn’t God have somehow designed human reproduction to be less error-prone?

Fortunately, recent scientific insights help address this issue, beginning with a detailed assessment of early embryo mortality.

What Is the Actual Rate of Spontaneous Abortions?

A survey of the scientific literature finds that the reported rates for spontaneous abortions are highly varied. Still, these rates seem to indicate human reproduction is a highly inefficient process with embryo mortality rates:

before and during implantation—as high as 75%
before the first six weeks of pregnancy—as high as 80%
during the first trimester—as high as 70%
before the first 20 weeks—as high as 50%
from fertilization to birth—as high as 90%

But as physiologist Gavin Jarvis from Cambridge University points out, these rates of spontaneous abortions are most certainly exaggerated and find little evidential support. These statistics are based on speculation and imprecise estimates of embryo mortality.¹ In an attempt to remedy this problem, Jarvis carried out a careful reassessment of the published data on embryo mortality.

As part of this assessment, Jarvis concludes that it is impossible to know how many embryos die—or survive—during the first week of pregnancy, from the point of fertilization to the beginning stages of implantation. The earliest point that embryo survival can be realistically studied in a clinical setting is after the first week of pregnancy when the hormone human chorionic gonadotrophin (CG) can be detected. Prior to that point, the rate of embryo loss is merely a guess.

Some biomedical researchers have attempted to estimate embryo mortality during the first week of pregnancy from in vitro fertilization studies. Jarvis argues that these estimates are meaningless. He says it is hard to believe that embryo survival under laboratory conditions would reflect embryo survival rates under natural conditions. In fact, given that in vitro fertilization and subsequent embryo growth occur under nonoptimal, nonnatural conditions suggests that embryo mortality is likely much higher when carried out in the laboratory than when fertilization and early stage embryo development take place in vivo. Jarvis notes, “It’s impossible to give a precise figure for how many embryos survive in the first week but in normal healthy women, it probably lies somewhere between 60–90%.”²

Insight into embryo mortality becomes quantifiable after the first week. As it turns out, about 1 in 5 embryos die during implantation. In fact, in many of these instances the woman would not be aware she was pregnant, because she would not miss her period. Once a woman misses her period, only about 10 to 15% of the embryos die before birth. In total, about 70% of embryos make it to live birth, once implantation commences and the pregnancy is clinically confirmed from CG levels.

As Jarvis notes, “Although we can’t be precise, we can avoid exaggeration, and from reviewing the studies that do exist, it is clear that many more [embryos] survive than is often claimed.”³

Even though the rate of spontaneous abortion isn’t as high as often reported, skeptics still have grounds to question the design of human reproduction, viewing it as an error-prone, flawed process. Yet, new insight into the causes of spontaneous abortions and miscarriages suggests that a rationale undergirds pregnancy loss, especially during the early stages of pregnancy. In light of this insight it appears that spontaneous abortions may be rightly understood as a necessary part of the design of human reproduction.

Why Do Spontaneous Abortions Occur?

Most miscarriages appear to be the result of chromosomal abnormalities. Embryos with damaged chromosomes or an abnormal number of chromosomes often die. Biomedical researchers have discovered that somewhere between 50 to 80% of human embryos produced by in vitro fertilization have at least one cell that displays chromosomal abnormalities. (As mentioned, the statistics for in vitro fertilization are not likely to be reliable measures of naturally occurring fertilization, so we need to be cautious about how we interpret this finding.)⁴ Researchers have also learned that the leading cause of embryo mortality during in vitro fertilization appears to be associated with chromosomal abnormalities.

As I noted, these abnormalities inevitably arise as a consequence of the complexity of human reproduction and the second law of thermodynamics. In light of this inevitability, biomedical investigators now think that spontaneous abortions serve as the means to prevent embryos with chromosomal abnormalities from developing once they begin the process of implantation. By studying the interactions between embryos created via in vitro fertilization with cells cultured from the endometrium (the cell layers that line the uterine wall), investigators have discovered that when healthy embryos are introduced to endometrial cells in a Petri dish, they cluster around the embryo, releasing chemicals that promote implantation. On the other hand, endometrial cells eschew embryos with chromosomal abnormalities, halting the release of chemicals that prompt implantation.⁵ These investigators also discovered that endometrial cells exposed to embryos with chromosomal abnormalities underwent a stress response, whereas healthy embryos activated gene networks in the endometrial cells that led to the production of metabolic enzymes and the secretion of implantation factors. Researchers confirmed this result by exposing the uteri of mice to cell culture media that was used to grow abnormal human embryos and they observed the same response in the mouse cells in vivo as the human cells in vitro.

In other words, it appears as if the endometrium serves as a gatekeeper rejecting embryos with chromosomal abnormalities and embracing developmentally viable embryos. Because the rejection of abnormal embryos happens so early in the pregnancy, most women are unaware that they were pregnant.

Ironically, some researchers believe the widespread occurrence of miscarriages actually led to the success of our species. Compared to other mammals, humans have an unusually high rate of spontaneous abortions (even when we consider Jarvis’s revised estimates). For the most part, humans give birth to a single child that requires nine months of gestation. Other mammals have shorter pregnancies, some birthing litters. For these mammals, a process that allows a few abnormal embryos to grow and develop has relatively little consequences because a significant number of the litter will be healthy. But for humans, allowing a single ill-fated pregnancy to go to full-term is a flawed strategy. As biologist Shawn Chavez notes, “In the case of animals that have litters, maybe they make 10 embryos a month and only eight make it to live birth, but that’s still eight. Whereas we typically can only make one embryo per month, so if it isn’t a good one, maybe it’s better to try again next month.”⁶ Biologist Tim Bruckner makes a similar point. He states, “According to the theory of natural selection, we want to have children that survive infancy and grow up and have children of their own so they can pass on our genes. There’s this idea that human reproduction is inefficient because so many pregnancies are lost, but overall it may have led to the preservation of our species.”⁷

These insights into the cause of miscarriage also contribute to our understanding of infertility. Women with a hypervigilant endometrium may struggle to get pregnant because the endometrium rejects both abnormal and healthy embryos. By the same token, these insights explain why some women are prone to miscarriages. In this case, their endometrium isn’t selective enough, allowing embryos to develop which otherwise “biologically” shouldn’t.

Spontaneous Abortions: A Necessary Design Feature of Human Reproductions

On the surface, the high rate of spontaneous abortions appears to be a flawed design. In reality, this feature of human reproduction reflects an exquisite biological rationale. Though emotionally brutal, miscarriages are a necessary feature of the human reproduction process that arises from the complexity of human reproduction and the second law of thermodynamics. If not for the high rate of spontaneous abortions we would have a reduced likelihood of having healthy children.

Though this scientific insight doesn’t answer all the difficult questions associated with spontaneous abortions, it can offer some source of comfort knowing that a rationale exists for pregnancy loss. As science journalist Alice Klein writes:

As traumatic as my own miscarriage was, it is comforting to learn that it probably wasn’t because of anything I did or anything that was wrong with me. On the contrary, it was most likely due to a random genetic error that I had no control over. Instead of my body failing me, it may have protected me from investing further in a pregnancy that probably wasn’t going to produce a healthy baby.⁸

All these years later, I find comfort, too, in knowing that there is a reason why my wife suffered a miscarriage. Still, Amy and I are left with many questions—questions for which we may never receive answers. Though it may sound odd to nonreligious people, in the midst of this uncertainty, we choose to rely on the fact that God is just and merciful and sovereign over all things.

Resources

The Fixed Laws of Nature

“Q and A: Why Would a Limitless Creator Face Trade-Offs in Biochemical Designs?” by Fazale Rana (article)

The Elegant Design of Human Reproduction

“The Remarkable Scientific Accuracy of Psalm 139” by Fazale Rana (article)
“Placenta Optimization Shows Creator’s Handiwork” by Fazale Rana (article)
“Recent Insights into Morning Sickness Bring up New Evidence for Design” by Fazale Rana (article)
“The Female Brain: Pregnant with Design” by Fazale Rana
“Curvaceous Anatomy of the Female Spine Reveals Ingenious Obstetric Design” by Virgil Robertson (article)

Disabilities and the Image of God

“Deformed in God’s Image? ” by Nick Tavani (article)
“Fearfully and Wonderfully Made: The Image of God and Human Disabilities” by Fazale Rana and Gavin Ortlund (video)

Pro-Life Argument

“The Argument for the Silent: A Biblical Case Against Abortion” by Robert Bowman, Jr.

Endnotes

Gavin E. Jarvis, “Early Embryo Mortality in Natural Human Reproduction: What the Data Say,” F1000Research 5 (June 12, 2017): 2765, doi:10.12688/f1000research.8937.2.
University of Cambridge, “Human Reproduction Likely to Be More Efficient Than Previously Thought,” ScienceDaily (June 13, 2017), sciencedaily.com/releases/2017/06/170613101932.htm.
University of Cambridge, “Human Reproduction.”
Lucia Carbone and Shawn L. Chavez, “Mammalian Pre-Implantation Chromosomal Instability: Species Comparison, Evolutionary Considerations, and Pathological Correlations,” Systems Biology in Reproductive Medicine 61, no. 6 (2015): 321–35, doi:10.3109/1939638.2015.1073406.
Gijs Teklenburg et al., “Natural Selection of Human Embryos: Decidualizing Endometrial Stromal Cells Serve as Sensors of Embryo Quality upon Implantation,” PLoS One 5 (April 21, 2010): e10258, doi:10.1371/journal.pone.0010258; Jan J. Brosens et al., “Uterine Selection of Human Embryos at Implantation,” Scientific Reports 4 (February 6, 2014): 3894, doi:10.1038/srep03894.
Alice Klein, “The Real Reasons Miscarriage Exists—And Why It’s So Misunderstood,” New Scientist (August 5, 2020), https://www.newscientist.com/article/mg24732940-900-the-real-reasons-miscarriage-exists-and-why-its-so-misunderstood/.
Klein, “The Real Reasons Miscarriage Exists.”
Klein, “The Real Reasons Miscarriage Exists.”

Reprinted with permission by the author

Original article at:
https://reasons.org/explore/blogs/the-cells-design

The Female Brain: Pregnant with Design

BY FAZALE RANA – JANUARY 25, 2017

When Jesus saw his mother there, and the disciple whom he loved standing nearby, he said to her, “Woman, here is your son.”

–John 19:26

I’ve learned the hard way: It is best to be circumspect when offering commentary about pregnancy, especially when women are around.

So, it’s with some hesitation I bring up the latest scientific insight developed by a team of researchers from Spain. These investigators discovered that pregnancy alters a woman’s brain. In fact, pregnancy reduces her grey matter.¹ (Okay Fuz. Hold your tongue. Don’t say what you’re thinking.)

But, as it turns out, the loss of grey matter is a good thing. In fact, it reveals the elegant design of the human brain and adds to the growing evidence of human exceptionalism. This scientific advance also has implications for the pro-life movement.

The Spanish research team was motivated to study brain changes in pregnant women because of the effects that sex hormones have on adolescent brains. During this time, sex hormones cause extensive reorganization of the brain. This process is a necessary part of the neural maturation process. The researchers posited that changes to the female brain should take place, because of the surge of sex hormones during pregnancy. While pregnant, women are exposed to 10 to 15 times the “normal” progesterone levels. During nine months of pregnancy, women are also subjected to more estrogen than the rest of their life when not pregnant.

To characterize the effect of pregnancy on brain structure, the research team employed a prospective study design. They imaged the brains of women who wanted to become pregnant for the first time. Then, they imaged the brains of the subjects once the women had given birth. Finally, they imaged the brains of the subjects two years after birth, if they didn’t become pregnant again. As controls, they imaged the brains of women who had never been pregnant and the brains of the fathers.

The Effects of Pregnancy on Women’s Brains

While the brain’s white matter is unaffected, the researchers found that pregnancy leads to a loss of grey matter that, minimally, lasts up to two years. They also discovered that the grey matter loss was not random or arbitrary. Instead, it occurred in highly specific areas of the brain. In fact, the grey matter loss was so consistent from subject to subject that the researchers could tell if a woman was pregnant or not from brain images alone.

As it turns out, the area of the brain that loses grey matter is the region involved in social cognition that harbors the theory-of-mind neural network. This network allows human beings to display a quality anthropologists call theory of mind. Along with symbolism, our theory-of-mind capacity makes us unique compared to other animals, providing scientific justification for the idea of human exceptionalism. As human beings, we recognize that other humans possess a mind like ours. Because of that recognition, we can anticipate what others are thinking and feeling. Our theory-of-mind capability makes possible complex social interactions characteristic of our species.

Even though the pregnant women lost grey matter, they showed no loss of memory or cognitive ability. The researchers believe that the loss of grey matter stems from synaptic pruning. This process occurs in adolescents and is a vital part of brain development and maturation. Through the loss of grey matter, neural networks form. The research team posits that synaptic pruning in pregnant women establishes a neural network that plays a role in the deep attachment mothers have with their children. This attachment helps mothers anticipate their babies’ needs. The deep social connection between mother and child is critical for human survival, because human infants are so vulnerable at birth and have a prolonged childhood.

In support of this proposal, the researchers found that when they showed the pregnant women pictures of their babies, the brain areas that lost grey matter became active. On the other hand, they saw no corresponding brain activity when the mothers were shown pictures of other babies.

The Case for Human Exceptionalism Mounts

This work highlights the elegant design of human pregnancy and child rearing—features that I take as evidence for a Creator’s handiwork. It is nothing short of brilliant to have the surge of sex hormones during pregnancy, priming the brain to ensure a close attachment between mother and child, at the time of birth and throughout the first few years of childhood.

More importantly, this work adds to the mounting scientific evidence for human exceptionalism. Not only do humans uniquely possess theory of mind, but our theory-of-mind neural network is more complex and sophisticated than previously thought. It is remarkable that this neural network can be adapted and fine-tuned to ensure an intimate mother-infant attachment while maintaining relationships in the midst of complex social surroundings, typical of human interactions.

As an interesting side note: Recent research indicates that for Neanderthals, the area of their brain devoted to maintaining social interactions was much smaller than the corresponding area in modern humans, highlighting our unique and exceptional nature even when compared to the hominids found in the fossil record.²

Pro-Life Implications

In my view, this work also has pro-life implications. I frequently hear pro-choice advocates argue that the fetus is a mass of tissue, just like a tumor. But, this study undermines this view. It is hard to think of a fetus as being just a lump of tissue, when such a sophisticated system is in place during pregnancy to form a neural network (that is, a subset of the theory-of-mind network) in the mother’s brain that generates the special capacity of the mother to bond with the fetus at birth.

It also raises concerns for the health of women who receive abortions. Though speculative, one has to wonder what effect prematurely terminating a pregnancy has on women whose brains have become fine-tuned to bond to the very infants that are destroyed by the abortion.

Resources

“Placenta Optimization Shows Creator’s Handiwork” by Fazale Rana (article)
“Curvaceous Anatomy of the Female Spine Reveals Ingenious Obstetric Design” by Virgil Robertson (article)
“Does the Childbirth Process Represent Clumsy Evolution or Good Engineering?” by Fazale Rana (article)
“Neanderthal Brains Make Them Unlikely Social Networkers” by Fazale Rana (article)

Endnotes

Elseline Hoekzema et al., “Pregnancy Leads to Long-Lasting Changes in Human Brain Structure,” Nature Neuroscience, published electronically December 19, 2016, doi:10.1038/nn.4458.
Eiluned Pearce, Chris Stringer, and R. I. M. Dunbar, “New Insights into Differences in Brain Organization between Neanderthals and Anatomically Modern Humans,” Proceedings of the Royal Society B 280 (May 2013): doi:10.1098/rspb.2013.0168.

Reprinted with permission by the author

Original article at:
https://www.reasons.org/explore/blogs/the-cells-design/read/the-cells-design/2017/01/25/the-female-brain-pregnant-with-design

Placenta Optimization Shows Creator’s Handiwork

BY FAZALE RANA – OCTOBER 19, 2016

The Creator of the universe desires an intimate relationship with each of us.

It is one of the more outrageous claims of the Christian faith. And no passage of Scripture expresses the intimacy between Creator and creature more than Psalm 139:13.

A fresh perspective on this passage of Scripture comes from recent work by researchers from Cambridge University in the UK. This study reveals the central role the placenta plays in properly allocating nutritional resources between mother and child, illustrating the intimate care God provided for us through the elegant design of embryological development.¹

This research also has important pro-life implications, providing a response to the claim that the fetus is nothing more than a harmful mass of tissue.

Nutritional Demands of the Fetus and the Mother

For a pregnancy to be successful, nutrients must be carefully distributed between the fetus and the mother. Yet sharing nutrients runs contrary to the biological tendencies of the mother and the unborn baby. The fetus has a genetic drive for growth and craves all the nutrients it can get. So does the mother. But for the fetus to grow and develop, the mother must provide it with the nutrients it needs, setting up a potential tug of war between the mother and the developing baby in her womb.

Ironically, if the fetus hoards nutrients excessively, the hoarding can backfire. If the mother doesn’t have access to sufficient nutrients during the pregnancy, it can negatively impact lactation and the mother’s long-term health, which, in turn, compromises her ability to care for the child after birth.

As it turns out, the placenta plays a critical role in managing this trade-off. Instead of being passive tissue that absorbs available nutrients from the mother, the placenta dynamically distributes nutrients between mother and fetus, optimally ensuring the health of both mother and developing baby. To do this, the placenta receives metabolic signals from both the mother and fetus and responds to this input by regulating the nutrient amounts made available to the fetus.

One of the key genes involved in nutrient regulation is called p110α. This gene codes for a protein that integrates the metabolic signals from mother and fetus. The Cambridge University researchers wanted to understand the role that the maternal and fetal versions of this gene play in parsing the nutrient supply between mother and developing baby.

What Happens When p110α Is Defective in Mother and Child?

What happens when p110α is defective in mother and child? To answer this question, the research team used mice as a model system, preparing genetic mutants, so that either the mother or fetus had a defective version of the p110α gene. If the mother had a healthy p110αgene, but the fetus a defective version, the placenta developed abnormally. But in spite of its defective appearance, the placenta compensated so that it would still take up the nutrients the fetus needed to develop. However, if the mother had a defective version of the p110αgene, the placenta (which formed abnormally even though the fetus had a healthy version of the p110α gene) transported fewer nutrients to the fetus.

In adult tissue, the p110α gene plays a role in regulating growth in relationship to nutrient supply and mediates the metabolic effects of insulin and insulin-like growth factors. That means that a defective version of this gene models conditions in which the mother’s health is compromised due to disease, poor nutrition, stress, or other factors.

On the basis of this study, it appears that when the mother is healthy, the placenta readily transports nutrients to the fetus and dynamically adjusts, even if it forms abnormally. On the other hand, if the mother’s health is compromised, the placenta restricts nutrient flow to the fetus to ensure the mother’s long-term health, with the prospects that the fetus can still grow and develop.

This insight has important biomedical implications. In the developing world, one in five pregnancy complications involve the placenta. In the developed world, this number is one in eight. The researchers hope that this insight will help them understand the etiologies behind problem pregnancies and also help them identify biomarkers that will alert physicians to problems earlier in the pregnancy.

This work also has important apologetics implications, as well.

Indeed, We Are Fearfully and Wonderfully Made

This work highlights the elegance of embryological development. It seems an exquisite rationale—a biological logic, if you will—undergirds every aspect of development. The optimal way the placenta partitions resources between mother and fetus, carefully managing trade-offs, evinces the handiwork of the Creator, and reveals the Creator’s intimate care for the fetus.

The devastating effects caused by mutations to the p110α gene raises questions about the capacity of evolutionary mechanisms to explain the origin of the reproductive system in placental mammals. Because the placenta is not a passive conduit for nutrients between mother and fetus, the challenges of explaining its genesis via unguided evolutionary process become insurmountable. If the placenta lacks the capability to effectively allocate resources between the mother and fetus—or even if this process operates in a suboptimal manner—the fetus may not survive, or the mother may not be healthy enough to nurse and rear the child once it’s born. In other words, it becomes difficult to imagine how the placenta’s role in embryological development could evolve from an imperfect system to an optimal system under the influence of natural selection because of the critical, dynamic role the placenta plays in embryological development. If this role isn’t properly executed, the child isn’t likely to make it to reproductive age.

Is the Fetus Like a Tumor?

This work also has implications for the pro-life debate. I have often heard pro-choice advocates argue that abortion is not murder, because the fetus is like a tumor. But the work by the scientists from Cambridge University makes this view impossible. Because the placenta dynamically allocates resources between the mother and the fetus in a way that preserves the mother’s health, the fetus cannot be viewed as a tumor robbing the mother of nutrients. Instead, it looks as if the placenta’s function has been designed in such a way to ensure optimal health for both the mother and the fetus. This study also shows that if the mother’s health is in jeopardy, the placenta actually compromises the health of the fetus so that the mother’s health is not unduly harmed by the pregnancy.

Resources
“Curvaceous Anatomy of the Female Spine Reveals Ingenious Obstetric Design” by Virgil Robertson (article)
“What Are the Odds of You Being You?” by Matthew McClure (article)
“Morning Sickness May Protect Embryos from Toxins” with Fazale Rana (podcast)

Endnotes

Amanda Sferruzzi-Perri et al., “Maternal and Fetal Genomes Interplay through Phosphoinositol 3-Kinase (PI3K)-p110α Signaling to Modify Placental Resource Allocation,” Proceedings of the National Academy of Sciences, USA 113 (October 2016): 11255–60, doi:10.1073/pnas.1602012113.