Dr. Francis Collins
New Technology Opens Evolutionary Window into Brain Development
Posted on by Dr. Francis Collins
One of the great mysteries in biology is how we humans ended up with such large, complex brains. In search of clues, researchers have spent years studying the protein-coding genes activated during neurodevelopment. But some answers may also be hiding in non-coding regions of the human genome, where sequences called regulatory elements increase or decrease the activity of genes.
A fascinating example involves a type of regulatory element called a human accelerated region (HAR). Although “human” is part of this element’s name, it turns out that the genomes of all vertebrates—not just humans—contain the DNA segments now designated as HARs.
In most organisms, HARs show a relatively low rate of mutation, which means these regulatory elements have been highly conserved across species throughout evolutionary time [1]. The big exception is Homo sapiens, in which HARs have exhibited a much higher rate of mutations.
The accelerated rate of HARs mutations observed in humans suggest that, over the course of very long periods of time, these genomic changes might have provided our species with some sort of evolutionary advantage. What might that be? Many have speculated the advantage might involve the brain because HARs are often associated with genes involved in neurodevelopment. Now, in a paper published in the journal Neuron, an NIH-supported team confirms that’s indeed the case [2].
In the new work, researchers found that about half of the HARs in the human genome influence the activity, or expression, of protein-coding genes in neural cells and tissues during the brain’s development [3]. The researchers say their study—the most comprehensive to date of the 3,171 HARs in the human genome—firmly establishes that this type of regulatory element helps to drive patterns of neurodevelopmental gene activity specific to humans.
Yet to be determined is precisely how HARs affect the development of the human brain. The quest to uncover these details will no doubt shed new light on fundamental questions about the brain, its billions of neurons, and their trillions of interconnections. For example, why does human neural development span decades, longer than the life spans of most primates and other mammals? Answering such questions could also reveal new clues into a range of cognitive and behavioral disorders. In fact, early research has already made tentative links between HARs and neurodevelopmental conditions such as autism spectrum disorder and schizophrenia [3].
The latest work was led by Kelly Girskis, Andrew Stergachis, and Ellen DeGennaro, all of whom were in the lab of Christopher Walsh while working on the project. An NIH grantee, Walsh is director of the Allen Discovery Center for Brain Evolution at Boston Children’s Hospital and Harvard Medical School, which is supported by the Paul G. Allen Foundation Frontiers Group, and is an Investigator of the Howard Hughes Medical Institute.
Though HARs have been studied since 2006, one of the big challenges in systematically assessing them has been technological. The average length of a HAR is about 269 bases of DNA, but current technologies for assessing function can only easily analyze DNA molecules that span 150 bases or less.
Ryan Doan, who was then in the Walsh Lab, and his colleagues solved the problem by creating a new machine called CaptureMPRA. (MPRA is short for “massively parallel reporter assays.”) This technological advance cleverly barcodes HARs and, more importantly, makes it possible to analyze HARs up to about 500 bases in length.
Using CaptureMPRA technology in tandem with cell culture studies, researchers rolled up their sleeves and conducted comprehensive, full-sequence analyses of more than 3,000 HARs. In their initial studies, primarily in neural cells, they found nearly half of human HARs are active to drive gene expression in cell culture. Of those, 42 percent proved to have increased ability to enhance gene expression compared to their orthologues, or counterparts, in chimpanzees.
Next, the team integrated these data with an existing epigenetic dataset derived from developing human brain cells, as well as additional datasets generated from sorted brain cell types. They found that many HARs appeared to have the ability to increase the activity of protein-coding genes, while a smaller—but very significant—subset of the HARs appeared to be enhancing gene expression specifically in neural progenitor cells, which are responsible for making various neural cell types.
The data suggest that as the human HAR sequences mutated and diverged from other mammals, they increased their ability to enhance or sometimes suppress the activity of certain genes in neural cells. To illustrate this point, the researchers focused on two HARs that appear to interact specifically with a gene referred to as R17. This gene can have highly variable gene expression patterns not only in different human cell types, but also in cells from other vertebrates and non-vertebrates.
In the human cerebral cortex, the outermost part of the brain that’s responsible for complex behaviors, R17 is expressed only in neural progenitor cells and only at specific time points. The researchers found that R17 slows the progression of neural progenitor cells through the cell cycle. That might seem strange, given the billions of neurons that need to be made in the cortex. But it’s consistent with the biology. In the human, it takes more than 130 days for the cortex to complete development, compared to about seven days in the mouse.
Clearly, to learn more about how the human brain evolved, researchers will need to look for clues in many parts of the genome at once, including its non-coding regions. To help researchers navigate this challenging terrain, the Walsh team has created an online resource displaying their comprehensive HAR data. It will appear soon, under the name HAR Hub, on the University of California Santa Cruz Genome Browser.
References:
[1] An RNA gene expressed during cortical development evolved rapidly in humans. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M Jr, Vanderhaeghen P, Haussler D. Nature. 2006 Sep 14;443(7108):167-72.
[2] Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions. Girskis KM, Stergachis AB, DeGennaro EM, Doan RN, Qian X, Johnson MB, Wang PP, Sejourne GM, Nagy MA, Pollina EA, Sousa AMM, Shin T, Kenny CJ, Scotellaro JL, Debo BM, Gonzalez DM, Rento LM, Yeh RC, Song JHT, Beaudin M, Fan J, Kharchenko PV, Sestan N, Greenberg ME, Walsh CA. Neuron. 2021 Aug 25:S0896-6273(21)00580-8.
[3] Mutations in human accelerated regions disrupt cognition and social behavior. Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG; Homozygosity Mapping Consortium for Autism, Nieto M, Walsh CA. Cell. 2016 Oct 6;167(2):341-354.
Links:
Christopher Walsh Laboratory (Boston Children’s Hospital and Harvard Medical School)
The Paul G. Allen Foundation Frontiers Group (Seattle)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute
Breakthrough Infections Occur in Those with Lower Antibody Levels, Israeli Study Shows
Posted on by Dr. Francis Collins
To see how COVID-19 vaccines are working in the real world, Israel has provided particularly compelling data. The fact that Israel is relatively small, keeps comprehensive medical records, and has a high vaccination rate with a single vaccine (Pfizer) has contributed to its robust data collection. Now, a new Israeli study offers some insight into those relatively uncommon breakthrough infections. It confirms that breakthrough cases, as might be expected, arise most often in individuals with lower levels of neutralizing antibodies.
The findings reported in The New England Journal of Medicine focused on nearly 1,500 of about 11,500 fully vaccinated health care workers at Sheba Medical Center, Ramat Gan, Israel [1]. All had received two doses of the Pfizer mRNA vaccine. But, from December 19, 2020 to April 28, 2021, they were tested for a breakthrough infection due to a known exposure to someone with COVID-19 or possible symptoms of the disease.
Just 39 confirmed breakthrough cases were found, indicating a breakthrough infection rate of just 0.4 percent. That’s consistent with rates reported in previous studies. Most in the Israeli study who tested positive for COVID-19 had mild or no symptoms and none required hospitalization.
In the new study, researchers led by Gili Regev-Yochay at Sheba Medical Center’s Infection Control and Prevention Unit, characterized as many breakthrough infections as possible among the health care workers. Almost half of the infections involved members of the hospital nursing staff. But breakthrough cases also were found in hospital administration, maintenance workers, doctors, and other health professionals.
The average age of someone with a breakthrough infection was 42, and it’s notable that only one person was known to have a weakened immune system. The most common symptoms were respiratory congestion, muscle aches (myalgia), and loss of smell or taste. Most didn’t develop a fever. At six weeks after diagnosis, 19 percent reported having symptoms of Long COVID syndrome, including prolonged loss of smell, persistent cough, weakness, and fatigue. About a quarter stayed home from work for longer than the required 10 days, and one had yet to return to work at six weeks.
For 22 of the 39 people with a breakthrough infection, the researchers had results of neutralizing antibody tests from the week leading up to their positive COVID-19 test result. To look for patterns in the antibody data, they matched those individuals to 104 uninfected people for whom they also had antibody test results. These data showed that those with a breakthrough infection had consistently lower levels of neutralizing antibodies circulating in their bloodstream to SARS-CoV-2, the coronavirus that causes COVID-19. In general, higher levels of neutralizing antibodies are associated with greater protection and lower infectivity—though other aspects of the immune system (memory B cells and cell-mediated immunity) also contribute.
Importantly, in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person. In fact, more than half of those who developed a breakthrough infection appeared to have become infected from an unvaccinated member of their own household.
Other cases were suspected to arise from exposure to an unvaccinated coworker or patient. Contact tracing found no evidence that any of the 39 health care workers with a breakthrough infection passed it on to anyone else.
The findings add to evidence that full vaccination and associated immunity offer good protection against SARS-CoV-2 infection and severe illness. Understanding how SARS-CoV-2 immunity changes over time is key for charting the course of this pandemic and making important decisions about COVID-19 vaccine boosters.
Many questions remain. For instance, it’s not clear from the study whether lower neutralizing antibodies in those with breakthrough cases reflect waning immunity or, for reasons we don’t yet understand, those individuals may have had a more limited immune response to the vaccine. Also, this study was conducted before the Delta variant became dominant in Israel (and now in the whole world).
Overall, these findings provide more reassurance that these vaccines are extremely effective. Breakthrough infections, while they can and do occur, are a relatively uncommon event. Here in the U.S., the Centers for Disease Control and Prevention (CDC) has recently estimated that infection is six times less likely for vaccinated than unvaccinated persons [2]. That those with immunity tend to have mild or no symptoms if they do develop a breakthrough case, however, is a reminder that these cases could easily be missed, and they could put vulnerable populations at greater risk. It’s yet another reason for all those who can to get themselves vaccinated as soon as possible or consider a booster shot when they become eligible.
References:
[1] Covid-19 breakthrough infections in vaccinated health care workers. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M, Levin EG, Rubin C, Indenbaum V, Tal I, Zavitan M, Zuckerman N, Bar-Chaim A, Kreiss Y, Regev-Yochay G. N Engl J Med. 2021 Oct 14;385(16):1474-1484.
[2] Rates of COVID-19 cases and deaths by vaccination status, COVID Data Tracker, Centers for Disease and Prevention. Accessed October 25, 2021.
Links:
COVID-19 Research (NIH)
Sheba Medical Center (Ramat Gan, Israel)
A Race-Free Approach to Diagnosing Chronic Kidney Disease
Posted on by Dr. Francis Collins
Race has a long and tortured history in America. Though great strides have been made through the work of leaders like Dr. Martin Luther King, Jr. to build an equal and just society for all, we still have more work to do, as race continues to factor into American life where it shouldn’t. A medical case in point is a common diagnostic tool for chronic kidney disease (CKD), a condition that affects one in seven American adults and causes a gradual weakening of the kidneys that, for some, will lead to renal failure.
The diagnostic tool is a medical algorithm called estimated glomerular filtration rate (eGFR). It involves getting a blood test that measures how well the kidneys filter out a common waste product from the blood and adding in other personal factors to score how well a person’s kidneys are working. Among those factors is whether a person is Black. However, race is a complicated construct that incorporates components that go well beyond biological and genetic factors to social and cultural issues. The concern is that by lumping together Black people, the algorithm lacks diagnostic precision for individuals and could contribute to racial disparities in healthcare delivery—or even runs the risk of reifying race in a way that suggests more biological significance than it deserves.
That’s why I was pleased recently to see the results of two NIH-supported studies published in The New England Journal of Medicine that suggest a way to take race out of the kidney disease equation [1, 2]. The approach involves a new equation that swaps out one blood test for another and doesn’t ask about race.
For a variety of reasons, including socioeconomic issues and access to healthcare, CKD disproportionately affects the Black community. In fact, Blacks with the condition are also almost four times more likely than whites to develop kidney failure. That’s why Blacks with CKD must visit their doctors regularly to monitor their kidney function, and often that visit involves eGFR.
The blood test used in eGFR measures creatinine, a waste product produced from muscle. For about the past 20 years, a few points have been automatically added to the score of African Americans, based on data showing that adults who identify as Black, on average, have a higher baseline level of circulating creatinine. But adjusting the score upward toward normal function runs the risk of making the kidneys seem a bit healthier than they really are and delaying life-preserving dialysis or getting on a transplant list.
A team led by Chi-yuan Hsu, University of California, San Francisco, took a closer look at the current eGFR calculations. The researchers used long-term data from the Chronic Renal Insufficiency Cohort (CRIC) Study, an NIH-supported prospective, observational study of nearly 4,000 racially and ethnically diverse patients with CKD in the U.S. The study design specified that about 40 percent of its participants should identify as Black.
To look for race-free ways to measure kidney function, the researchers randomly selected more than 1,400 of the study’s participants to undergo a procedure that allows kidney function to be measured directly instead of being estimated based on blood tests. The goal was to develop an accurate approach to estimating GFR, the rate of fluid flow through the kidneys, from blood test results that didn’t rely on race.
Their studies showed that simply omitting race from the equation would underestimate GFR in Black study participants. The best solution, they found, was to calculate eGFR based on cystatin C, a small protein that the kidneys filter from the blood, in place of the standard creatinine. Estimation of GFR using cystatin C generated similarly accurate results but without the need to factor in race.
The second NIH-supported study led by Lesley Inker, Tufts Medical Center, Boston, MA, came to similar conclusions. They set out to develop new equations without race using data from several prior studies. They then compared the accuracy of their new eGFR equations to measured GFR in a validation set of 12 other studies, including about 4,000 participants.
Their findings show that currently used equations that include race, sex, and age overestimated measured GFR in Black Americans. However, taking race out of the equation without other adjustments underestimated measured GFR in Black people. Equations including both creatinine and cystatin C, but omitting race, were more accurate. The new equations also led to smaller estimated differences between Black and non-Black study participants.
The hope is that these findings will build momentum toward widespread adoption of cystatin C for estimating GFR. Already, a national task force has recommended immediate implementation of a new diagnostic equation that eliminates race and called for national efforts to increase the routine and timely measurement of cystatin C [3]. This will require a sea change in the standard measurements of blood chemistries in clinical and hospital labs—where creatinine is routinely measured, but cystatin C is not. As these findings are implemented into routine clinical care, let’s hope they’ll reduce health disparities by leading to more accurate and timely diagnosis, supporting the goals of precision health and encouraging treatment of CKD for all people, regardless of their race.
References:
[1] Race, genetic ancestry, and estimating kidney function in CKD. Hsu CY, Yang W, Parikh RV, Anderson AH, Chen TK, Cohen DL, He J, Mohanty MJ, Lash JP, Mills KT, Muiru AN, Parsa A, Saunders MR, Shafi T, Townsend RR, Waikar SS, Wang J, Wolf M, Tan TC, Feldman HI, Go AS; CRIC Study Investigators. N Engl J Med. 2021 Sep 23.
[2] New creatinine- and cystatin C-based equations to estimate GFR without race. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, Crews DC, Doria A, Estrella MM, Froissart M, Grams ME, Greene T, Grubb A, Gudnason V, Gutiérrez OM, Kalil R, Karger AB, Mauer M, Navis G, Nelson RG, Poggio ED, Rodby R, Rossing P, Rule AD, Selvin E, Seegmiller JC, Shlipak MG, Torres VE, Yang W, Ballew SH,Couture SJ, Powe NR, Levey AS; Chronic Kidney Disease Epidemiology Collaboration. N Engl J Med. 2021 Sep 23.
[3] A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. Am J Kidney Dis. 2021 Sep 22:S0272-6386(21)00828-3.
Links:
Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Explaining Your Kidney Test Results: A Tool for Clinical Use (NIDDK)
Chronic Renal Insufficiency Cohort Study
Chi-yuan Hsu (University of California, San Francisco)
Lesley Inker (Tufts Medical Center, Boston)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
In Missouri for Grand Opening of Roy Blunt NextGen Precision Health Building
Posted on by Dr. Francis Collins
COVID-19 Vaccines Protect the Family, Too
Posted on by Dr. Francis Collins
Any of the available COVID-19 vaccines offer remarkable personal protection against the coronavirus SARS-CoV-2. So, it also stands to reason that folks who are vaccinated will reduce the risk of spreading the virus to family members within their households. That protection is particularly important when not all family members can be immunized—as when there are children under age 12 or adults with immunosuppression in the home. But just how much can vaccines help to protect families from COVID-19 when only some, not all, in the household have immunity?
A Swedish study, published recently in the journal JAMA Internal Medicine, offers some of the first hard figures on this topic, and the findings are quite encouraging [1]. The data show that people without any immunity against COVID-19 were at considerably lower risk of infection and hospitalization when other members of their family had immunity, either from a natural infection or vaccination. In fact, the protective effect on family members went up as the number of immune family members increased.
The findings come from a team led by Peter Nordström, Umeå University, Sweden. Like in the United States, vaccinations in Sweden initially were prioritized for high-risk groups and people with certain preexisting conditions. As a result, Swedish families have functioned, often in close contact, as a mix of immune and susceptible individuals over the course of the pandemic.
To explore these family dynamics in greater detail, the researchers relied on nationwide registries to identify all Swedes who had immunity to SARS-COV-2 from either a confirmed infection or vaccination by May 26, 2021. The researchers identified more than 5 million individuals who’d been either diagnosed with COVID-19 or vaccinated and then matched them to a control group without immunity. They also limited the analysis to individuals in families with two to five members of mixed immune status.
This left them with about 1.8 million people from more than 800,000 families. The situation in Sweden is also a little unique from most Western nations. Somewhat controversially, the Swedish government didn’t order a mandatory citizen quarantine to slow the spread of the virus.
The researchers found in the data a rising protective effect for those in the household without immunity as the number of immune family members increased. Families with one immune family member had a 45 to 61 percent lower risk of a COVID-19 infection in the home than those who had none. Those with two immune family members enjoyed more protection, with a 75 to 86 percent reduction in risk of COVID-19. For those with three or four immune family members, the protection went up to more than 90 percent, topping out at 97 percent protection. The results were similar when the researchers limited the analysis to COVID-19 illnesses serious enough to warrant a hospital stay.
The findings confirm that vaccination is incredibly important not only for individual protection, but also for reducing transmission, especially within families and those with whom we’re in close physical contact. It’s also important to note that the findings apply to the original SARS-CoV-2 variant, which was dominant when the study was conducted. But we know that the vaccines offer good protection against Delta and other variants of concern.
These results show quite clearly that vaccines offer protection for individuals who lack immunity, with important implications for finally ending this pandemic. This doesn’t change the fact that all those who can and still need to get fully vaccinated should do so as soon as possible. If you are eligible for a booster shot, that’s something to consider, too. But, if for whatever reason you haven’t gotten vaccinated just yet, perhaps these new findings will encourage you to do it now for the sake of those other people you care about. This is a chance to love your family—and love your neighbor.
Reference:
[1] Association between risk of COVID-19 infection in nonimmune individuals and COVID-19 immunity in their family members. Nordström P, Ballin M, Nordström A. JAMA Intern Med. 2021 Oct 11.
Links:
COVID-19 Research (NIH)
Peter Nordström (Umeå University, Sweden)
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