Porcine gene edits may allow such transplants without rejection.
- A company called Revivicor has received clearance from the FDA to use their genetically modified pigs for medical use or as food.
- The pigs lack genes for alpha-gal sugar, which human bodies reject.
- Revivicor anticipates the first human transplant trials as early as this year.
Science can run along separate, even contradictory, paths simultaneously. At the same time as some research is revealing more and more about animal intelligence and self-awareness, other research seems to be pursuing novel ways in which humans can expand the exploitation of animals on the assumption that they lack these attributes. Growing appreciation for the intellectual and emotional lives of pigs, for example, is counterbalanced by news that the FDA has just certified that pigs bred by a company looking to harvest their organs for transplantation in humans are safe for food and medical use. The contrast can be head-snapping.
Revivicor, a subsidiary of Maryland-based biotech company United Therapeutics, received the FDA clearance in December 2020. To the FDA, this "represents a tremendous milestone for scientific innovation." Revivicor's chief scientific officer, David Ayares, tells Future Human that the company's "ultimate goal is to essentially have an unlimited supply of organs," and clearance for their "GalSafe pigs" brings that goal one step closer.
Credit: Talaj/Adobe Stock/Big Think
The U.S. Health Resources and Services Administration says that 109,000 Americans are currently waiting for organ transplants. Seventeen people die each day while waiting, and every nine minutes a new name goes on the waiting list.
Companies such as Revivicor are hoping to meet this need with xenotransplants, in which organs from non-human species are transplanted into humans. Scientists have been seeking a way to perform successful xenotransplantation for decades—a newborn referred to publicly as "Baby Fae" rejected a transplanted baboon heart as far back as 1984.
Ayares says his company is "right on the cusp" of overcoming such rejection issues, anticipating their first transplants may occur in 2021 or 2022.
Animal tissue may also find use in the formulation of medications.
Credit: ustas /Adobe Stock
The rejection problem stems from the human body's immune system expelling cells from other animals as foreign substances. (Rejection can also be an issue with human-to-human transplants.)
In 2003, Revivicor began development of GalSafe pigs by removing a gene that appears on the surface of porcine cells, and that produces a sugar called "alpha-gal." It's believed that alpha-gal sugar is the agent that causes the most acute rejections experienced with heart and kidney transplants.
Alpha-gal is also implicated in a meat food-allergy that occurs after a person is bitten by a Lone Star tick that leaves alpha-gal sugar behind in its victims' skin. Over time, the individual develops an allergy to pork, red meat, and lamb. Revivicor's Gal Pigs may one day be available to such people as non-allergenic pork.
Revivicor's manipulation of pig genes to support xenotransplantation compatibility doesn't end with eliminating alpha-gal sugar. Today's GalPig carries a total of 10 different genomic modifications—four pig genes have been turned off and six human genes have been introduced.
Tests so far
The company, working with the National Institutes of Health, says that they managed to avoid rejection of pig hearts transplanted into baboons for six years, though these didn't replace the animals' own, original hearts. Rather, the pig hearts were transplanted into the abdomens of the baboons simply to assess rejection. Ayares also says GalPig kidneys survived in monkeys for over six months, though it's unclear if they were functioning as kidneys or simply implanted.
For human trials, Revivicor plans to begin with kidney transplants before attempting heart replacements. They expect to perform these early trials with people awaiting human transplants. XenoTherapeutics of Boston is already testing GalPig skin transplants as a temporary measure for burn victims as their own skin regenerates.
Other companies are also exploring porcine genetic modifications for xenotransplants, including eGenesis in Boston and its partner Qihan Biotech in Zhejiang, China, who are using CRISPR to perform gene edits.
How important is it to consider a romantic partner's genetic profile before getting married?
How important is it to consider a romantic partner's genetic profile before getting married?
It is logical to think that genetic factors may underlie many traits already used by matching sites - like personality and empathy - which many assume could promote initial chemistry and long-term potential in specific couples. So it is perhaps not surprising that there are now websites that combine genetic testing and matchmaking.
But does matching intimate partners on the basis of specific genes have any scientific foundation? Studies have shown that genetically identical twins, raised separately, rate the overall quality of their marriages similarly, suggesting some enduring genetic contribution to marital life. However, the specific genes that are relevant to marriage, and why, remain a mystery.
As such, predicting marital compatibility on the basis of specific combinations of genetic profiles rests on tenuous scientific footing. Currently, researchers are just beginning to identify the genes that may be associated with marital bliss and through what processes.
Why study the effects of genes on marriage?
As a scientist and clinical psychologist, I have a longstanding interest in identifying the factors that contribute to a happy marriage, such as how couples manage conflict. My interest in exploring genetic determinants, however, developed more recently.
Genes are segments of DNA that encode a particular trait. A gene can take on various forms called alleles, and the combination of the two alleles inherited from both parents represent one's genotype. Differences in genotype correspond to observable differences within that trait across individuals.
Though genes underlie individual differences in a broad range of characteristics believed to be relevant to marriage, I am specifically interested in the oxytocin receptor (OXTR) gene. Oxytocin, sometimes referred to as the “love" hormone, appears to play a significant role in emotional attachment. For example, oxytocin floods a new mother at the birth of a child and it spikes during sex. Therefore, I reasoned that the gene that regulates oxytocin, OXTR, might be a good one to study in the context of marriage, as it is frequently implicated in how we become attached to other humans. Moreover, OXTR has been associated with a range of phenomena linked to human social behavior, including trust and sociability.
Of greatest interest to me is that the OXTR gene has been linked with physiological responses to social support and traits believed to be critical to support processes, like empathy. Considered alongside findings that the quality of social support is a major determinant of overall marital quality, the evidence implied that variations on the OXTR gene could be tethered to later marital quality by influencing how partners support each other. To test this hypothesis, I pulled together a multidisciplinary team of scientists including psychologists with additional expertise in marital research, a geneticist and a neuroendocrinologist specializing in oxytocin.
Together our team recruited 79 different-sex married couples to participate in our study. We then asked each partner to identify an important personal problem – unrelated to the marriage – to discuss with their spouse for 10 minutes.
These discussions were recorded and later coded according to how each partner solicited and provided “positive" support by scoring elements like problem-solving and active listening. Couples responded separately to several questionnaires including a measure of perceived quality of the support they received during the interaction. Each person also provided saliva samples that our team analyzed to determine which two alleles of the OXTR gene each person carried.
Genetic variation and marital quality
Based on prior evidence, we focused our attention on two specific locations on the OXTR gene: rs1042778 and rs4686302. As expected, higher quality social support was associated with marital quality. Also, genetic variation at each OXTR site for both husbands and wives was linked with how partners behaved during the support discussions.
However, individuals did not appear more or less satisfied with the support they received based on differences in the positive skills their partners used during the interaction.
Rather, we found that husbands with two copies of the T allele at a specific location on OXTR (rs1042778) perceived that their partners provided lower quality support. This was regardless of whether his partner's support skills were strong or weak.
To us, this implied that husbands with the TT genotype had greater difficulty interpreting their respective wife's behavior as supportive. This is consistent with other findings implicating this same genotype in social-cognitive deficits, as well as autism.
Notably, the husband and wife in couples also reported being less satisfied with their marriage overall, when compared to those with different combinations of alleles. This suggests that couples in which the husband carries two copies of the T allele were worse off, in part, because these men had trouble perceiving their wife's behavior as supportive – a notion that our statistical analysis ultimately supported.
Do we have the evidence necessary to start screening potential husbands for specific combinations of genes that seem harmful to marriage?
I would not recommend doing so for a few reasons. Foremost is that genes can influence a broad range of characteristics, which may be detrimental to a marriage in some respects but beneficial in others. Although we found that having two copies of the T allele seems to be a liability in the context of social support, exploratory analyses revealed that this combination appeared to also confer some positive influence on the marriage. The exact mechanism remains unclear, but we speculate that being less sensitive to social nuance may be protective in other areas of marriage by, for example, blunting hostile exchanges during disagreements.
More to the point, assuming that a single gene can make or break a marriage underestimates the complexity of genetics and marriage. It is possible that certain genes may be more or less detrimental depending on the rest of a partner's genetic profile. However, there is currently no published data on which to rest any type of proposed match. So, ruling out prospective husbands on the basis of variations within or across genes doesn't make much sense.
Nevertheless, there are still practical implications to our current findings. Researchers have shown that social support from intimate partners can buffer the deleterious effects of stress on mental and physical health. To the extent that particular genotypes impair an individual's ability to feel supported, that person may be more susceptible to the effects of stress. Thus, screening men for the TT genotype on OXTR could assist in identifying those at risk for stress-related problems. In addition, future research may highlight how to tailor the delivery of social support in ways that can benefit these individuals.
There are also several other potentially relevant locations on OXTR, as well as other genes that may be relevant to relationships. Our study provides a template for approaching the study of marital genetics.
Richard Mattson, Associate Professor & Director of Graduate Studies in Psychology, Binghamton University, State University of New York
The relationship between our genotypes and our psychological traits, while substantial, is highly indirect and emergent.
Many of our psychological traits are innate in origin. There is overwhelming evidence from twin, family and general population studies that all manner of personality traits, as well as things such as intelligence, sexuality and risk of psychiatric disorders, are highly heritable. Put concretely, this means that a sizeable fraction of the population spread of values such as IQ scores or personality measures is attributable to genetic differences between people. The story of our lives most definitively does not start with a blank page.
But exactly how does our genetic heritage influence our psychological traits? Are there direct links from molecules to minds? Are there dedicated genetic and neural modules underlying various cognitive functions? What does it mean to say we have found 'genes for intelligence', or extraversion, or schizophrenia? This commonly used 'gene for X' construction is unfortunate in suggesting that such genes have a dedicated function: that it is their purpose to cause X. This is not the case at all. Interestingly, the confusion arises from a conflation of two very different meanings of the word 'gene'.
From the perspective of molecular biology, a gene is a stretch of DNA that codes for a specific protein. So there is a gene for the protein haemoglobin, which carries oxygen around in the blood, and a gene for insulin, which regulates our blood sugar, and genes for metabolic enzymes and neurotransmitter receptors and antibodies, and so on; we have a total of about 20,000 genes defined in this way. It is right to think of the purpose of these genes as encoding those proteins with those cellular or physiological functions.
But from the point of view of heredity, a gene is some physical unit that can be passed from parent to offspring that is associated with some trait or condition. There is a gene for sickle-cell anaemia, for example, that explains how the disease runs in families. The key idea linking these two different concepts of the gene is variation: the 'gene' for sickle-cell anaemia is really just a mutation or change in sequence in the stretch of DNA that codes for haemoglobin. That mutation does not have a purpose – it only has an effect.
So, when we talk about genes for intelligence, say, what we really mean is genetic variants that cause differences in intelligence. These might be having their effects in highly indirect ways. Though we all share a human genome, with a common plan for making a human body and a human brain, wired so as to confer our general human nature, genetic variation in that plan arises inevitably, as errors creep in each time DNA is copied to make new sperm and egg cells. The accumulated genetic variation leads to variation in how our brains develop and function, and ultimately to variation in our individual natures.
This is not metaphorical. We can directly see the effects of genetic variation on our brains. Neuroimaging technologies reveal extensive individual differences in the size of various parts of the brain, including functionally defined areas of the cerebral cortex. They reveal how these areas are laid out and interconnected, and the pathways by which they are activated and communicate with each other under different conditions. All these parameters are at least partly heritable – some highly so.
That said, the relationship between these kinds of neural properties and psychological traits is far from simple. There is a long history of searching for correlations between isolated parameters of brain structure – or function – and specific behavioural traits, and certainly no shortage of apparently positive associations in the published literature. But for the most part, these have not held up to further scrutiny.
It turns out that the brain is simply not so modular: even quite specific cognitive functions rely not on isolated areas but on interconnected brain subsystems. And the high-level properties that we recognise as stable psychological traits cannot even be linked to the functioning of specific subsystems, but emerge instead from the interplay between them.
Intelligence, for example, is not linked to any localised brain parameter. It correlates instead with overall brain size and with global parameters of white matter connectivity and the efficiency of brain networks. There is no one bit of the brain that you do your thinking with. Rather than being tied to the function of one component, intelligence seems to reflect instead the interactions between many different components – more like the way we think of the overall performance of a car than, say, horsepower or braking efficiency.
This lack of discrete modularity is also true at the genetic level. A large number of genetic variants that are common in the population have now been associated with intelligence. Each of these by itself has only a tiny effect, but collectively they account for about 10 per cent of the variance in intelligence across the studied population. Remarkably, many of the genes affected by these genetic variants encode proteins with functions in brain development. This didn't have to be the case – it might have turned out that intelligence was linked to some specific neurotransmitter pathway, or to the metabolic efficiency of neurons or some other direct molecular parameter. Instead, it appears to reflect much more generally how well the brain is put together.
The effects of genetic variation on other cognitive and behavioural traits are similarly indirect and emergent. They are also, typically, not very specific. The vast majority of the genes that direct the processes of neural development are multitaskers: they are involved in diverse cellular processes in many different brain regions. In addition, because cellular systems are all highly interdependent, any given cellular process will also be affected indirectly by genetic variation affecting many other proteins with diverse functions. The effects of any individual genetic variant are thus rarely restricted to just one part of the brain or one cognitive function or one psychological trait.
What all this means is that we should not expect the discovery of genetic variants affecting a given psychological trait to directly highlight the hypothetical molecular underpinnings of the affected cognitive functions. In fact, it is an error to think of cognitive functions or mental states as having molecular underpinnings – they have neural underpinnings.
The relationship between our genotypes and our psychological traits, while substantial, is highly indirect and emergent. It involves the interplay of the effects of thousands of genetic variants, realised through the complex processes of development, ultimately giving rise to variation in many parameters of brain structure and function, which, collectively, impinge on the high-level cognitive and behavioural functions that underpin individual differences in our psychology.
And that's just the way things are. Nature is under no obligation to make things simple for us. When we open the lid of the black box, we should not expect to see lots of neatly separated smaller black boxes inside – it's a mess in there.
Innate: How the Wiring of our Brains Shapes Who We Are by Kevin Mitchell is published via Princeton University Press.
This article was originally published at Aeon and has been republished under Creative Commons.
A new study shows how interbreeding of modern humans and Neanderthals boosted our genomes.
- Homo Sapiens mated with Neanderthals when they left Africa for Eurasia.
- Neanderthals developed key genetic adaptations to fighting diseases.
- Modern humans have 152 genes inherited from the Neanderthals that interact with viruses.
We tend to think of the human-like people before us, like the Neanderthals, as part of our biological history that's so far removed that it has little bearing on our current lives. After all, you don't get to meet Neanderthals in the street. Or do you? For one, from 1.8% to 2.6% of the DNA in most modern people comes from the Neanderthals. A new study provides another important link - Neanderthals passed on a key genetic adaptation that kept us protected from killer viruses.
Sex between Neanderthals and homo sapiens is the reason for our genetic connection. The humans were on their way out of Africa into Eurasia, when they met the Neanderthals. Thanks to sharing a common ancestor about 500,000 to a million years prior, the sex between the species produced viable offspring.
What the new study found is that before they hooked up with modern humans, Neanderthals were in Eurasia for hundreds of thousands of years fighting off pathogens. As a result, their genomes developed an ability to survive viruses, which they gifted to us.
The study's co-author David Enard, Ph.D. from the University of Arizona explained to Inverse that interbreeding was like a quick "antidote" for the homo sapiens to protect themselves. They suddenly faced an onslaught of new viruses.
Incorporating the genetic material that was already pre-adapted from the Neanderthals gave the homo sapiens a "fast-track route for adaptation", shares Enard, adding "instead of 'reinventing the genetic wheel,' we just borrowed it from the Neanderthals."
"Neanderthal genetic material was like a protective antidote because Neanderthals had likely been infected for a long time by the same viruses that were now harmful to modern humans," says David Enard. "This long exposure means that Neanderthals had plenty of time to adapt against these viruses before modern humans showed up."
Of course, not everything went smoothly when these two species met in the distant past. The scientists think they likely infected each other with the pathogens from their environments – in what's called "the poison-antidote" model of exchanging genes. The sexual unions produced the antidote.
Poison-antidote model.Credit: Cell magazine.
The research involved creating a list of over 4,500 genes of modern humans that are involved in defending against viruses and contrasting that with the database of sequenced Neanderthal genes. The scientists found 152 genes in modern humans that were also in the Neanderthal genome. The researchers believe that these genes we got from the Neanderthals are those that interact with RNA viruses of today like hepatitis C, HIV, and influenza A.
Notably, while these genes were instrumental in human survival over time, they are not really protecting us any longer from modern viruses. This points to the fact that evolution is "an arms race," as Dr. Enard called it. It's a process where even if we manage to overcome some of them, scores of new viruses constantly spring up to attack us. It was very sobering realization for Dr. Petrov and I that our work likely implies that humans had to adapt to hundreds, if not thousands of different harmful viruses over million years of evolution," related Dr. Enard.
It also bears pointing out that modern humans get depression and cigarette addiction from the Neanderthals.
Scientists have grown a model human esophagus using pluripotent stem cells for the first time.
- By precisely timing the application of different chemicals, scientists have grown a small, model esophagus from stem cells.
- They used the model esophagus to clarify why a certain congenital condition occurs.
- Using this technique, future researchers will be able to understand the nature of diseases better, develop new treatments, and even repair damaged esophagi.
It should come as no surprise that microbiology is a difficult discipline. The sheer amount of work that it takes to be knowledgeable about the current state of the field is staggering, and advancing the field as a whole is even more challenging. A recent study out of Cincinnati Children's Hospital has made a significant advancement, with researchers growing a human esophagus using stem cells for the first time.
The esophagus in question wasn't very large — just 800 micrometers long, which works out to be about 0.03 inches. (We're still a far way off from growing whole human organs in a laboratory.) However, this research represents an important step in that direction, and the ability to grow small models of organs (called organoids) makes us better at developing treatments for common diseases affecting those organs. What's more, the new research also means that it will be possible to regenerate damaged tissue in existing esophagi.
Growing an esophagus
Developing this small esophagus organoid took a lot of precision. The 800-micrometer organoid was grown over the period of two months, but it started out as a slurry of pluripotent stem cells (PSCs). Unlike adult stem cells, which can only grow into specific, specialized types of tissues, PSCs can develop into any type of cell in the body. Essentially, they are our original components — every human started off as a similar slurry of PSCs.
The researchers exposed these cells to precise amounts of different chemicals that recreated the kind of events a PSC would undergo in order to develop into an esophagus in a normal developing fetus. These chemicals manipulated cellular signaling pathways — essentially, a chain of reactions that occur when a cell is exposed to a certain molecule. In the cell, a cascading series of reactions occurs that triggers some kind of event in a cell, such as cell death, replication, or, in this case, differentiation into esophagus cells.
Previous studies had tried to develop human esophagus organoids, but these usually ended up as a mixture of different tissues, including those found in the pharynx, the esophagus, and the respiratory tract. To develop esophageal tissues, the researchers needed to precisely time similarly precise quantities of chemicals to trigger the right signaling pathways for the right amount of time.
As an example, exposing the cells to retinoic acid for four days caused them to develop into tissues found lower down in the foregut, below the esophagus. Treating the cells in retinoic acid for just one day, however, seemed to be the right amount of exposure to encourage esophageal tissues to develop. In addition, treating the cells with Noggin — a curiously named protein — encouraged the tissues to develop into esophageal tissues rather than respiratory tissues.
A diagram depicting the various possible tissues the stem cells could have developed into. Exposing the cells to different molecules, such as retinoic acid (RA) and Noggin (NOG) encourages the stem cells to develop into different tissues.
Trisno et al., 2018
What's useful about this?
Growing a model of the human esophagus is an interesting project, but science like this isn't done out of sheer curiosity. Regarding its utility, Jim Wells, a researcher working on the project, said, "In addition to being a new model to study birth defects like esophageal atresia, the organoids can be used to study diseases like eosinophilic esophagitis and Barrett's metaplasia, or to bioengineer genetically matched esophageal tissue for individual patients." There are other potential applications of this research on esophageal cancer, gastroesophageal reflux disease (GERD), and achalasia, which affects the esophagus's lower muscles, preventing food from passing through. The researchers noted that all of these conditions need better treatments.
To demonstrate the usefulness of this model organ, the researchers examined the impact of the SOX2 gene on the development of the esophagus. In both humans and mice, when SOX2 is repressed or inactivated, the esophagus peters out and fails to connect to the stomach. For babies born with esophageal atresia, this condition can be life-threatening and requires surgery to correct.
Researchers have known that SOX2 was associated with this condition, but the exact mechanism was unknown. By studying the growth of the esophageal organoid and comparing it with the esophagi of mice whose Sox2 genes had been inactivated, the researchers discovered that a molecule called Wnt was the likely reason behind esophageal atresia. Remember how growing this organoid require precisely timed applications of various chemicals? Wnt works like that to — only in a developing body, the SOX2 gene inhibits the amount of Wnt the cells are exposed to. When SOX2 doesn't work correctly, Wnt encourages developing cells to become part of the respiratory tract rather than the esophagus, resulting in esophageal atresia.
This kind of work is very much in the early stages. Before 1998, scientists had no idea how to harvest human stem cells, and now we're building model organs with them. While growing an entire organ is still very much a thing of the future, it's important to remember that every step along the way to that goal will make use better at fighting disease, saving lives, and understanding how the human body functions.