Genetic Test Scores Predicting Intelligence Are Not the New Eugenics
A thinking person.
"A world where people are slotted according to their inborn ability – well, that is Gattaca. That is eugenics."
This was the assessment of Dr. Catherine Bliss, a sociologist who wrote a new book on social science genetics, when asked by MIT Technology Review about polygenic scores that can predict a person's intelligence or performance in school. Like a credit score, a polygenic score is statistical tool that combines a lot of information about a person's genome into a single number. Fears about using polygenic scores for genetic discrimination are understandable, given this country's ugly history of using the science of heredity to justify atrocities like forcible sterilization. But polygenic scores are not the new eugenics. And, rushing to discuss polygenic scores in dystopian terms only contributes to widespread public misunderstanding about genetics.
Can we start genotyping toddlers to identify the budding geniuses among them? The short answer is no.
Let's begin with some background on how polygenic scores are developed. In a genome wide-association study, researchers conduct millions of statistical tests to identify small differences in people's DNA sequence that are correlated with differences in a target outcome (beyond what can attributed to chance or ancestry differences). Successful studies of this sort require enormous sample sizes, but companies like 23andMe are now contributing genetic data from their consumers to research studies, and national biorepositories like U.K. Biobank have put genetic information from hundreds of thousands of people online. When applied to studying blood lipids or myopia, this kind of study strikes people as a straightforward and uncontroversial scientific tool. But it can also be conducted for cognitive and behavioral outcomes, like how many years of school a person has completed. When researchers have finished a genome-wide association study, they are left with a dataset with millions of rows (one for each genetic variant analyzed) and one column with the correlations between each variant and the outcome being studied.
The trick to polygenic scoring is to use these results and apply them to people who weren't participants in the original study. Measure the genes of a new person, weight each one of her millions of genetic variants by its correlation with educational attainment from a genome-wide association study, and then simply add everything up into a single number. Voila! -- you've created a polygenic score for educational attainment. On its face, the idea of "scoring" a person's genotype does immediately suggest Gattaca-type applications. Can we now start screening embryos for their "inborn ability," as Bliss called it? Can we start genotyping toddlers to identify the budding geniuses among them?
The short answer is no. Here are four reasons why dystopian projections about polygenic scores are out of touch with the current science:
The phrase "DNA tests for IQ" makes for an attention-grabbing headline, but it's scientifically meaningless.
First, a polygenic score currently predicts the life outcomes of an individual child with a great deal of uncertainty. The amount of uncertainty around polygenic predictions will decrease in the future, as genetic discovery samples get bigger and genetic studies include more of the variation in the genome, including rare variants that are particular to a few families. But for now, knowing a child's polygenic score predicts his ultimate educational attainment about as well as knowing his family's income, and slightly worse than knowing how far his mother went in school. These pieces of information are also readily available about children before they are born, but no one is writing breathless think-pieces about the dystopian outcomes that will result from knowing whether a pregnant woman graduated from college.
Second, using polygenic scoring for embryo selection requires parents to create embryos using reproductive technology, rather than conceiving them by having sex. The prediction that many women will endure medically-unnecessary IVF, in order to select the embryo with the highest polygenic score, glosses over the invasiveness, indignity, pain, and heartbreak that these hormonal and surgical procedures can entail.
Third, and counterintuitively, a polygenic score might be using DNA to measure aspects of the child's environment. Remember, a child inherits her DNA from her parents, who typically also shape the environment she grows up in. And, children's environments respond to their unique personalities and temperaments. One Icelandic study found that parents' polygenic scores predicted their children's educational attainment, even if the score was constructed using only the half of the parental genome that the child didn't inherit. For example, imagine mom has genetic variant X that makes her more likely to smoke during her pregnancy. Prenatal exposure to nicotine, in turn, affects the child's neurodevelopment, leading to behavior problems in school. The school responds to his behavioral problems with suspension, causing him to miss out on instructional content. A genome-wide association study will collapse this long and winding causal path into a simple correlation -- "genetic variant X is correlated with academic achievement." But, a child's polygenic score, which includes variant X, will partly reflect his likelihood of being exposed to adverse prenatal and school environments.
Finally, the phrase "DNA tests for IQ" makes for an attention-grabbing headline, but it's scientifically meaningless. As I've written previously, it makes sense to talk about a bacterial test for strep throat, because strep throat is a medical condition defined as having streptococcal bacteria growing in the back of your throat. If your strep test is positive, you have strep throat, no matter how serious your symptoms are. But a polygenic score is not a test "for" IQ, because intelligence is not defined at the level of someone's DNA. It doesn't matter how high your polygenic score is, if you can't reason abstractly or learn from experience. Equating your intelligence, a cognitive capacity that is tested behaviorally, with your polygenic score, a number that is a weighted sum of genetic variants discovered to be statistically associated with educational attainment in a hypothesis-free data mining exercise, is misleading about what intelligence is and is not.
The task for many scientists like me, who are interested in understanding why some children do better in school than other children, is to disentangle correlations from causation.
So, if we're not going to build a Gattaca-style genetic hierarchy, what are polygenic scores good for? They are not useless. In fact, they give scientists a valuable new tool for studying how to improve children's lives. The task for many scientists like me, who are interested in understanding why some children do better in school than other children, is to disentangle correlations from causation. The best way to do that is to run an experiment where children are randomized to environments, but often a true experiment is unethical or impractical. You can't randomize children to be born to a teenage mother or to go to school with inexperienced teachers. By statistically controlling for some of the relevant genetic differences between people using a polygenic score, scientists are better able to identify potential environmental causes of differences in children's life outcomes. As we have seen with other methods from genetics, like twin studies, understanding genes illuminates the environment.
Research that examines genetics in relation to social inequality, such as differences in higher education outcomes, will obviously remind people of the horrors of the eugenics movement. Wariness regarding how genetic science will be applied is certainly warranted. But, polygenic scores are not pure measures of "inborn ability," and genome-wide association studies of human intelligence and educational attainment are not inevitably ushering in a new eugenics age.
In this week's Friday Five, an old diabetes drug finds an exciting new purpose. Plus, how to make the cities of the future less toxic, making old mice younger with EVs, a new reason for mysterious stillbirths - and much more.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here is the promising research covered in this week's Friday Five:
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- How to make cities of the future less noisy
- An old diabetes drug could have a new purpose: treating an irregular heartbeat
- A new reason for mysterious stillbirths
- Making old mice younger with EVs
- No pain - or mucus - no gain
And an honorable mention this week: How treatments for depression can change the structure of the brain
Researchers at Stanford have found that the virus that causes Covid-19 can infect fat cells, which could help explain why obesity is linked to worse outcomes for those who catch Covid-19.
Obesity is a risk factor for worse outcomes for a variety of medical conditions ranging from cancer to Covid-19. Most experts attribute it simply to underlying low-grade inflammation and added weight that make breathing more difficult.
Now researchers have found a more direct reason: SARS-CoV-2, the virus that causes Covid-19, can infect adipocytes, more commonly known as fat cells, and macrophages, immune cells that are part of the broader matrix of cells that support fat tissue. Stanford University researchers Catherine Blish and Tracey McLaughlin are senior authors of the study.
Most of us think of fat as the spare tire that can accumulate around the middle as we age, but fat also is present closer to most internal organs. McLaughlin's research has focused on epicardial fat, “which sits right on top of the heart with no physical barrier at all,” she says. So if that fat got infected and inflamed, it might directly affect the heart.” That could help explain cardiovascular problems associated with Covid-19 infections.
Looking at tissue taken from autopsy, there was evidence of SARS-CoV-2 virus inside the fat cells as well as surrounding inflammation. In fat cells and immune cells harvested from health humans, infection in the laboratory drove "an inflammatory response, particularly in the macrophages…They secreted proteins that are typically seen in a cytokine storm” where the immune response runs amok with potential life-threatening consequences. This suggests to McLaughlin “that there could be a regional and even a systemic inflammatory response following infection in fat.”
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
The macrophages studied by McLaughlin and Blish were spewing out inflammatory proteins, While the the virus within them was replicating, the new viral particles were not able to replicate within those cells. It was a different story in the fat cells. “When [the virus] gets into the fat cells, it not only replicates, it's a productive infection, which means the resulting viral particles can infect another cell,” including microphages, McLaughlin explains. It seems to be a symbiotic tango of the virus between the two cell types that keeps the cycle going.
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
Macrophages are mobile; they engulf and carry invading pathogens to lymphoid tissue in the lymph nodes, tonsils and elsewhere in the body to alert T cells of the immune system to the pathogen. Perhaps some of them also carry the virus through the bloodstream to more distant tissue.
ACE2 receptors are the means by which SARS-CoV-2 latches on to and enters most cells. They are not thought to be common on fat cells, so initially most researchers thought it unlikely they would become infected.
However, while some cell receptors always sit on the surface of the cell, other receptors are expressed on the surface only under certain conditions. Philipp Scherer, a professor of internal medicine and director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center, suggests that, in people who have obesity, “There might be higher levels of dysfunctional [fat cells] that facilitate entry of the virus,” either through transiently expressed ACE2 or other receptors. Inflammatory proteins generated by macrophages might contribute to this process.
Another hypothesis is that viral RNA might be smuggled into fat cells as cargo in small bits of material called extracellular vesicles, or EVs, that can travel between cells. Other researchers have shown that when EVs express ACE2 receptors, they can act as decoys for SARS-CoV-2, where the virus binds to them rather than a cell. These scientists are working to create drugs that mimic this decoy effect as an approach to therapy.
Do fat cells play a role in Long Covid? “Fat cells are a great place to hide. You have all the energy you need and fat cells turn over very slowly; they have a half-life of ten years,” says Scherer. Observational studies suggest that acute Covid-19 can trigger the onset of diabetes especially in people who are overweight, and that patients taking medicines to regulate their diabetes “were actually quite protective” against acute Covid-19. Scherer has funding to study the risks and benefits of those drugs in animal models of Long Covid.
McLaughlin says there are two areas of potential concern with fat tissue and Long Covid. One is that this tissue might serve as a “big reservoir where the virus continues to replicate and is sent out” to other parts of the body. The second is that inflammation due to infected fat cells and macrophages can result in fibrosis or scar tissue forming around organs, inhibiting their function. Once scar tissue forms, the tissue damage becomes more difficult to repair.
Current Covid-19 treatments work by stopping the virus from entering cells through the ACE2 receptor, so they likely would have no effect on virus that uses a different mechanism. That means another approach will have to be developed to complement the treatments we already have. So the best advice McLaughlin can offer today is to keep current on vaccinations and boosters and lose weight to reduce the risk associated with obesity.