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When the Smithsonian National Museum of Natural History opened its genomics exhibit in 2013, the field was just celebrating the 10th anniversary of the completed Human Genome Project. Sequencing that first genome cost over $500 million. The genomes since cost $10,000.

In 2022, as the museum prepares to wrap up the landmark exhibit, much has changed. Gene names such as BRCA1 and HER2 have entered the public consciousness. Sequencing DNA has become faster, cheaper, and smaller-scale. Portable sequencers that were not even being sold commercially in 2013 have since been used to trace the evolution of the Ebola virus as it wreaked havoc in West Africa. The development of CRISPR-Cas9 landed a Nobel Prize. The cost of genome sequencing is rapidly approaching $100.

What seemed cutting edge maybe in 2013, now in 2022, were just things that were somewhat more routine, said Carla Easter, who helped organize the exhibit while at the National Human Genome Research Institute, which partnered with the Smithonian to launch the project.

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Nobody knew what CRISPR was ten years ago, added Easter, now at the Smithsonian. But now, people will mention it and theyll know what that is. They may not know understand the science behind it, but at least theyve heard the word.

Before the exhibit closes its doors later this year, STAT spoke with curators, educators, and leading scientists involved in its creation about how genomics has changed in the past decade.

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The field of genomics has gone way beyond genomics experts, people who would call themselves genomicists, and its applied everywhere, said Lawrence Brody, who leads the NHGRI Division of Genomics and Society. Weve done these analyses of the NIH budget, and theres way more genomics being done outside of our institute than there is inside our institute, because its such a powerful tool. And thats a great thing.

Most of those improvements have been with sequencing, he said. Were now talking about what genetic variation might be. If you study people who have a disease, [and] find a genetic variant that seems to be common in those people, you dont really know anything until you ask yourself, How common is that variant in people who dont have the disease? And you need to look at large numbers of people to understand that. This also means involving people who are not normally represented in research, a task the NIH-funded All of Us program has taken up.

Another change he sees is the newfound ability to broadly study the entire genome, rather than only specific genes, and to analyze how various parts of the genome are being turned on or off in individual cells.

Even though all cells but sperm and egg share the same genome, they do not all make the same proteins. A decade or two ago, studying these differences involved an arduous process, and scientists could only study a few specific genes at a time. But Brody said that has changed thanks to advances in RNA sequencing, which allow you to ask questions about all the genes completely, objectively, and agnostically. And to me, thats really the power and has always been the power of genetics is to ask the question and have the organism tell you whats important, as opposed to guess and saying It must be this gene or it must be that gene.

Now, he said, the field needs to understand how diseases are caused by a combination of genes and environmental exposures, manipulate the genome to treat diseases, and survey life on the planet because, as a geneticist, its really important for me to know the variations out there.

We often say Oh, in ten years, well be doing this, and if you look back at those predictions, were wrong a lot, said Brody. But we will get there.

To Stephen Palumbi, a professor of marine sciences at Stanford who studies corals, the biggest change in genomics is the speed and cost of sequencing.

The same questions are there, the same approaches are there, said Palumbi. But its like you took a garden hose that you were plenty of water flow and everything and you turned it into a firehose of information. That deluge of data that you can get right now is incredible. So the whole field, not just natural history or oceans, but the whole field of genomics, has become more and more and more tuned to being a high-flow data-rich, incredible science of whats now called bioinformatics. Bioinformatics at the time, a decade ago, was really important. Its probably increased in importance 50-fold because the data sets have increased 100-fold, and being able to actually pull information out of these data sets has become one of the most interesting, challenging, and rewarding parts of how genomes are used.

The human genome is the most traveled, well-mapped genome in the known universe, no big surprise. But I study organisms that are not humans and have genomes anyway. And so were always sort of scrambling a little bit behind that technology, but adopting it and adapting it, he said.

He pointed to work he is doing to study corals living on reefs in an archipelago in Palau that look strikingly similar, but have turned out to be genetically different. Being able to deeply mine the genomes of those corals offers valuable clues about their genetic capacity to adapt to environmental change.

So genomics gives me a map to their current patterns of adaptation that I would not get in any other way, he said. When this exhibit opened, I couldnt have done what I just told you because it would have been prohibitively expensive. And the people who can do the bioinformatics really werent there. And the genetic, genomic resources that I need to do this work werent there. But theyre there now. So thats where the whole field has changed so much. In that period of time, 2011 till now, the entire landscape, seascape, forestscape changed.

He said the fields advances like enabling handheld sequencing will make it even easier to reveal DNA in the environment, whether that is samples pulled from a kelp forest or fungus living in the soil of wetlands. Those insights are more critical than ever, as they can offer insights on monitoring pathogens and endangered species.

What I dont want to see in 50 years in a genome exhibit, is a whole lot of genomes of extinct species that weve lost because of climate change.

Harvard professor and genetics pioneer George Church was involved in the Human Genome Project from its earliest days, having joined the effort in 1984, years before the National Institutes of Health got involved. He saw the project pique the interest first of lawmakers, and then the public at large. Some projects that are highly technical, whether theyre expensive or not, are unpopular or ignored, said Church. But this one actually captured Congresss interest, around 1987 was really when they started paying attention. They liked this and they committed to $3 billion, which was quite a lot in 1987. And then they proceeded to get excited in all kinds of science and they ended up doubling the NIH budget, which is almost unprecedented and hasnt happened since then.

And despite the celebration of the sequencing of the human genome, Church said, the work is far from over.

[It] had been sort of declared done in 2001, and then was re-declared done in 2004. And its actually still not done in my opinion. This year marks the first year that weve finished one genome, one human genome, but in a way that really isnt generally applicable we did it to a haploid cell. Haploid cells have only a single set of chromosomes, in contrast to the typical human cell which is diploid and has two. So if you want to diagnose a patient, you have to be able to do a diploid genome. And no ones ever completed a diploid genome yet, although we are on our way, Church said.

Church said genomics has already made an impact in medical care. It played a role in the development of the Covid-19 vaccines, and can give prospective parents insight about when they carry a recessive gene for certain diseases. It also enabled the development of the first gene therapy to be approved by the Food and Drug Administration. Even when the exhibit was being developed a decade ago, he said, the idea of gene therapy wasnt that popular. In fact, it just barely was recovering from its 2001 setback, or 1999 to 2001 setbacks, plural.

In the future, Church would like to see a bioweather map that uses genomics to keep tabs on and track the evolution of viruses and bacteria, akin to a weather forecast. What flu just flew in the town? And what is happening at the daycare? Should you take your kid? he asked.

But for all his big ideas about genomics, Church also has his sticking points. Among them: One of my pet peeves is when people say, Oh, you know that humans share fill in your favorite number with fill in your favorite organism. So itd be like 46% related to plants or bananas, he said. I mean, its a completely meaningless statistic.

(It is a battle he did not win with the Smithsonian exhibit, which tells viewers that the human genome is 41% similar to a bananas.)

For Joann Boughman, a senior vice chancellor at the University System of Maryland, advances in genomics have changed how people perceive genetic diseases. From the historical perspective, if you will, in human genetics, we have understood and have always looked at variability as an essential theme, said Boughman. It wasnt until the human genome started and people started understanding about the variations at the DNA level that they made the connection between genes and ultimate phenotype, what we look like. And it has been really fascinating to see how these two worlds, as you will, collide and hopefully come together.

During the pandemic, Boughman served as the point person for the Maryland university systems Covid response, which included a community of over 200,000 students, staff, and faculty. And I realize Im working with an educated population, but all kinds of people really understood when we started talking about viral variants, they understood what had changed was the DNA in the virus, that there had been a mutation. These were not absolutely foreign concepts to people, and they, with very little explanation, would understand why one vaccine might fight this virus, but not a mutated form of that virus, Boughman said.

This is part of a growing awareness she had seen unfolding long before the pandemic hit. The fact that the double strand of DNA is not a foreign concept, even to relatively small children, really makes our conversation different. And thats been an incredible thing to watch over the last 40 years. Today, if people see an image of DNA, theyll recognize it.

Boughman said that shift struck her recently when she saw a commercial for a treatment for a rare genetic disease. It hit me right between the eyes that they actually have an ad on TV and named a genetic syndrome and talked about that drug that was helping these children. But 20 years ago, the idea of putting on television a picture of a child who has physical abnormalities and labeling them as having a genetic disease or a genetic syndrome just would have been devastating. But now that we are getting to the point where we understand enough about the genetics that we can start to intervene and treat, it becomes a very different perspective than somebody who is simply doomed. They labeled it genetic and they labeled it as a syndrome, and then they talked about hope that they had. And that simply was not the case 20 or 30 years ago, at all.

As a geneticist and professor at the University of Pennsylvania, Sarah Tishkoff originally got involved in the exhibit to share her expertise on what genetics and genomics can tell us about the evolutionary history of humans. Given her research, she is keenly aware of how much the field has changed in the past few decades.

She is also aware of how far the field still needs to go specifically when it comes to securing better representation in genomics research, which is overwhelmingly centered on white and European populations. What we dont really have are good reference genomes, she said. So there are populations or people in different parts of the world that might have insertions or deletions in their genome or things that arent even in that reference.

But if the Smithsonian were to open the exhibit again in 50 years, she said, we will have unraveled far more mysteries and the public will be far more familiar with the science.

I think at that point, most people are going to have their genome sequenced, she said. That would give scientists a far deeper trove of data to understand structural variation large-scale differences across the DNA of individuals, including duplications of certain genes and, in turn, knowledge of how humans have adapted to different environments and develop different levels of risk for disease. She added that by that time, were going to know more about what the genome variation actually does, similar to her findings that multiple different gene mutations can cause lactose tolerance.

She is also hopeful that we will have wide-ranging insights into ancient DNA and the origins of human history, including a far more complete picture. Right now, she noted, we are limited by the fact that ancient DNA is often poorly preserved. Someday, somebody is going to get ancient DNA from a fossil in Africa thats 50,000 years old or 100,000 or 200,000. Thats going to really help shed light on human history in that region, which is where we all evolved, Tishkoff said. Im hoping that were going to know a lot more examples of how people adapted to different environments.

In addition to his day job at the E.O. Wilson Biodiversity Foundation, Dennis Liu serves on the board of the American Chestnut Foundation, which has funded efforts to introduce a gene into American chestnut trees that can help them resist a group of diseases known as blight. To Liu, there are clear benefits that advances in genomics can bring to conservation efforts like this one.

But as the field ages, he also sees a downside to the growing distance from the Human Genome Project.

When the initiative launched, Liu said, there was a sense of a moonshot at the time. And I think that kind of new excitement isnt necessarily here. I havent done a survey or a poll, but I imagine that these things are now kind of all lumped together with big pharma and the pharmaceutical industry and sort of high-tech medicine. And I would imagine that a lot of people still would wonder, Oh, I dont know, what does this do for me? I do think theyd hope, of course, that this kind of information is going to help cancer treatments, for example, and those sorts of things.

For example: To the field, the increase in sequencing speeds is a huge advance. But I dont think that means much of anything to the general public, Liu said. Instead of feeling that genomics completed with the sequencing of the genome, he hopes we will continue to wonder about genomics. It is not like Oh, the genome, we did that, its over. Its like, No, its both that this work has continued and it continues to matter, said Liu, who was then with the Howard Hughes Medical Institute, And you should know something about it even if youre not a professional scientist.

Eric Green has served as the director of the NHGRI since 2009. The biggest difference he sees in genomics then, and genomics now? At the time I started as director, when this exhibition was being created, there was a lot of clarity around what had been accomplished and a lot of growing knowledge about how the human genome works. But the idea of actually using genomic information for the practice of medicine was pretty hypothetical.

When he stepped into his role, he wanted to close that gap and figure out how to use genomic information to improve the practice of medicine. And the biggest difference between then and now is then it was hypothetical and, while it is certainly not pervasive in medicine, there are a number of just very clear areas where now genomics is mainstream. Green highlighted the use of genomics to diagnose rare diseases. They were like the very first home runs in those areas, he said. But now its just routine practice. Another notable change, he added, is the proliferation of DNA genealogy tests from companies such as 23andMe and Ancestry.

Looking ahead, Green said he is a realist about the role of genomics in medicine.

The implementation of some aspects of genomic medicine are no longer scientifically difficult. Theyre sociological, because of the societal challenges associated with health care, said Green, who trained as a physician-scientist. What I would say going forward is that, Im actually quite optimistic were going to figure out a lot of these really valuable uses of genomics. But I cant claim to be as optimistic about the effective use of those tools in health care, because we all appreciate that health care is really complicated.

It is a hurdle he had not considered early on in research, he said. Science drives some things, but its not the only thing.

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As the Smithsonian wraps a genome exhibit, leaders in the field reflect - STAT

UW-Madison scientists studying the genetics of orangutans in zoos were stumped. The lineages they found didnt match those made public when the orangutan genome was sequenced in 2011.

When they pulled a photo for one animal from the 2011 research, supposedly a female, it had cheek pads, a distinctly male trait. In further digging, they learned a label for one orangutan was really for a pig. Another orangutan, marked as Doris from Dallas Zoo, was actually Sibu from Zoo Atlanta.

Things just didnt add up, said Graham Banes, who now directs the Madison-based Orangutan Conservation Genetics Project. Our data just could not reconcile with what had already been published.

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At the same time, the related journal Nature Scientific Data included a paper by Banes and his colleagues detailing their finding that nine of 10 samples in the 2011 research were inadvertently switched.

I was aghast, said Michael Sweet, who researches coral genomes at the University of Derby in England and worries that recent examples of scientific fraud have already increased public skepticism about topics such as climate change. The general public is going to start mistrusting science.

Marc Tollis, whose research at Northern Arizona University involves bioinformatics and genomics, called the orangutan genome mishap a nightmare scenario for almost all scientists.

The revelation about the orangutan research doesnt only raise questions about scientific error, public trust and the validity of subsequent studies based on the genome work. Banes said it has implications for the management of orangutans in zoos, as there is now proof that at least several orangutans in American zoos are from a new third species announced only in 2017. Should they be prevented from breeding with other species, which he argues can increase the risk of disease and birth defects?

This is a really massive problem for zoos, Banes said. If zoos allow different species of the animals to mate freely, at that point, its not a conservation breeding program, he said. Its an experiment.

Rob Vernon, spokesperson for the American Association of Zoos and Aquariums, said the group would review the research and consult with experts for advice. Ronda Schwetz, leader of the associations Orangutan Saving Animals from Extinction program and director of Vilas Zoo in Madison where orangutan Chelsea had a baby in June did not respond to requests for comment.

Devin Locke, lead author of the 2011 genome paper and of the recent correction, could not be reached for comment. Formerly with Washington University Genome Center in St. Louis, which headed up the genome-sequencing project, Locke is now with the Massachusetts-based cancer research company Foundation Medicine, according to his LinkedIn profile.

Sweet, one of numerous scientists who have raised concerns about the new report on social media, is part of a group that published standards on sequencing coral genomes to help prevent such mistakes. He said misconduct recently identified in investigations of a University of Delaware coral scientist and a spider behavior ecologist at McMaster University in Canada have already damaged scientific credibility.

The whole mess (about the orangutan genome) underlines the need for careful curation of genomic data, including checking apparently solid identification in the genomic databases, said Michael Cobb, a zoologist at the University of Manchester in England.

Different species

It wasnt until the 1980s, decades after orangutans were first captured from the islands of Borneo and Sumatra in Southeast Asia for placement in zoos, that two distinct species were identified: Bornean orangutans and Sumatran orangutans.

Interbreeding was discouraged and zoos separated the populations, Banes said.

Graham Banes heads up theOrangutan Conservation Genetics Project, based in Madison, and was part of a research team that discovered orangutan genome mix-ups.

The genome published in 2011 was based on a Sumatran female. Ten other orangutans five identified as Sumatran and five as Bornean were also sequenced in less detail, serving as reference samples of the diversity of orangutan genetics.

The orangutan was the third nonhuman primate genome to be sequenced, after the chimp and the rhesus macaque. The analysis showed humans and orangutans share about 97% of their DNA, compared with 99% between humans and chimps.

Banes, who left UW-Madisons Wisconsin National Primate Research Center in May but still conducts primatology research in Madison, focuses on the effects of inbreeding, or mating between closely related groups, and outbreeding, or mating between divergent groups.

In 2016, his research showed a non-native subspecies of Bornean orangutan, released into Tanjung Puting National Park on Borneo in Indonesia, bred with apes in the park, creating a cocktail hybrid species. One of two non-native females rescued from the pet trade, Siswoyo, had fewer surviving offspring than any other female in the park.

Banes said preliminary data suggest outbreeding may be connected to birth defects he saw among intermixed orangutans at zoos in China and chronic respiratory disease found in some captive orangutans.

It appears theyre ill-adapted to each others novel pathogens, he said.

Science sleuths

In 2018, Banes UW-Madison research team was testing orangutans in U.S. zoos to determine the extent of interbreeding. Graduate student Alyssa Karklus, now a veterinarian with the Wisconsin Humane Society, noticed that the genetics of some animals didnt line up with the reference genomes from 2011.

A female orangutan reintroduced to the wild is pictured carrying her wild-born offspring. UW-Madison researchers found a mix-up in a genome-sequencing research project that could have implications for orangutan-breeding programs at zoos.

Banes and Karklus, along with post-graduate researcher Emily Fountain, became sleuths, sifting through volumes of data and eventually finding that even the sex reported for five animals in the 2011 paper was wrong. Three researchers from Washington University, who participated in the initial genome work, assisted the UW-Madison group and are co-authors of the paper about the mix-ups.

Its not clear who made the mistakes or how, Banes said. The errors likely occurred at several stages, from when samples were collected from animals and labeled in vials to when sequencing data was linked to individuals, he said.

It was probably multiple people, he said. It was a series of unfortunate events.

Banes said hes not out to vilify the genome researchers and is glad they agreed to do the correction. He said his goal is to improve the integrity of science.

Theres no shame in making mistakes. What is critically important is that we correct them, he said. I personally mixed up three samples on Wednesday last week, but I caught it.

Tapanuli orangutans

Banes said one of the switches in the genome samples has implications for managing Tapanuli orangutans the newly discovered third species, from part of Sumatra.

One of the five animals identified as Sumatran in the 2011 paper turned out to be Tapanuli, which scientists wouldnt have been expected to know at the time. But it wasnt Baldy, a long-deceased male animal from the Sacramento Zoo that had only two offspring and no second-generation offspring, as identified by the genome researchers, Banes said. The Tapanuli was Bubbles, from the San Diego Zoo, a female that had eight descendants, some of which are still alive and in zoos, he said.

That led Banes and his colleagues to discover additional Tapanulis in zoos in the U.S. and elsewhere, with studies underway in Europe. He plans to publish a report soon on the extent of Tapanulis found, which he said raises questions for the future of orangutans in zoos.

What are the zoos going to do if 50% of their population now has to be taken out of the breeding program? he asked.

Visitors enter Henry Vilas Zoo on the first day of the reopening since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Deynah Thao, 7, gets a close look at a grizzly bear during a trip to Henry Vilas Zoo on the first day of the reopening of the zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Visitors to Henry Vilas Zoo follow one way walking paths on the first day of the reopening of the zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Visitors stop to see the grizzly bears on the first day of the reopening of Henry Vilas Zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Visitors follow the paw prints as they check out animal exhibits on the first day of the reopening of Henry Vilas Zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Visitors enter Henry Vilas Zoo on the first day of the reopening since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

The first day of the reopening of Henry Vilas Zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Employee Ryan Brockner, right, shows off an umbrella cockatoo named Reggie to visitors Samia Sanders, 4, front, Nazilah Lites, 4, and Miyauna Sanders, 10, on the first day of the reopening of Henry Vilas Zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Nicole Josi Lema, with her daughters Arianna, 7, and Akemi, 5, right, are greeted by Courtney Cordova, educational specialist, as she explains the rules before entering Henry Vilas Zoo on the first day of the reopening since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Employee Debbie Scheffel cleans picnic tables after they are used by guests on the first day of the reopening of Henry Vilas Zoo since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Dan Tortorice, center, sits with his grandchildren, Aria Oettiker, 9, left, and her brother, Anthony, 6, as they eat ice cream during a visit to Henry Vilas Zoo on the first day of the reopening since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

Signs reminding visitors to social distance are seen at Henry Vilas Zoo on the first day of the reopening since it closed due to COVID-19 in Madison, Wis., Thursday, June 18, 2020. AMBER ARNOLD, STATE JOURNAL

The whole (genome) mess underlines the need for careful curation of genomic data, including checking apparently solid identification in the genomic databases.

Michael Cobb, University of Manchester zoologist

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UW researchers discover orangutan genome mix-ups that could affect zoo animals - Madison.com