The association technique hasn’t always paid off—but starting in 2007 the gene searches hit pay dirt for sickle-cell. In one study, for instance, a team in Italy studied DNA from thousands of Sardinians (some of whom had beta-thalassemia, another hemoglobin disorder, which is shockingly common on the island) as well from Americans with sickle-cell. When they compared each person’s DNA with the amount of fetal hemoglobin each had, variations kept popping up in one gene: BCL11A.
This gene was far from the hemoglobin sequences—in fact, on an entirely different chromosome. And until then, it had been mostly known for its connection to some cancers. It was a complete surprise. “No amount of sequence-gazing would have told you what to look for,” Orkin says now. But the blaring signal told them this could be the control mechanism. Orkin likes to illustrate the impact this clue had with a quote from Marcel Proust: “The only real voyage of discovery consists not in seeking new landscapes but having new eyes.”
All eyes were now on BCL11A. And very quickly, Orkin’s students and trainees showed that it could control fetal hemoglobin. In fact, it was a transcription factor—a type of gene that controls other genes. By shutting off BCL11A they were able to rekindle production of fetal hemoglobin in cells growing in their lab—and later, in 2011, they showed that mice could be cured of sickle-cell in the same fashion. “What this meant is if you could do this to a patient, you could cure them,” says Orkin.
However, in humans it wasn’t going to be as simple as turning the gene off altogether. BCL11A turns out to be an important gene, and losing it wasn’t ultimately good for mice. One study found mice lacking it were mostly dead within six months. But then came another lucky break. Those hits from the Sardinia study? They turned out to cluster in a special region of the BCL11A gene, called an “erythroid enhancer,” that was active only during the production of red blood cells.
Think of it as a gas pedal for BCL11A, but one that is exclusively employed when a stem cell is making red blood cells—a big job, by the way, since your body makes a few billion each day. “It’s absolutely cell specific,” says Orkin. And that meant the gas pedal could be messed with: “We’d gone from the whole genome to one [site] that we could exploit therapeutically.”
The switch had mostly been a matter of scientific curiosity. But now researchers at Harvard, and at a company they’d teamed with, Sangamo Biosciences, began to define a treatment. They peppered the enhancer with every possible damaging edit they could—“like a bunch of BBs,” says Bauer, who did the work at Harvard. Eventually, they found the perfect one: a single disruptive edit that would lower BCL11A by about 70%, and consequently allow fetal hemoglobin to increase.
The editing target, a short run of a few DNA letters, never appears elsewhere in most people’s genomes. That’s important, because once programmed, CRISPR will cut the matching target sequence every time it encounters it, whether or not you want it to. Creating unintentional extra edits is considered hazardous, but Bauer says he’s found only one such “off target” site, which he estimates will appear in the genomes of about 10% of African-Americans. But its location isn’t in a gene, so accidental edits there aren’t expected to matter. Bauer thinks the risk, whatever it is, is probably a lot lower than the danger posed by having sickle-cell disease.
There are signs Orkin’s lab may have found a perfect edit—one that can’t be easily improved on. His institution, Boston Children’s Hospital, patented the discoveries, and later CRISPR Therapeutics and Vertex agreed to pay it for rights to use the edit. They’ll likely contribute royalties, too, once the treatment goes on sale. Orkin told me he thinks the companies tried to develop an alternative—a different, nearby edit—but hadn’t been successful. “They tried to find a better [one] but they couldn’t,” says Orkin. “We have the whole thing.”
The hunter-gatherer groups at the heart of a microbiome gold rush
The first step to finding out is to catalogue what microbes we might have lost. To get as close to ancient microbiomes as possible, microbiologists have begun studying multiple Indigenous groups. Two have received the most attention: the Yanomami of the Amazon rainforest and the Hadza, in northern Tanzania.
Researchers have made some startling discoveries already. A study by Sonnenburg and his colleagues, published in July, found that the gut microbiomes of the Hadza appear to include bugs that aren’t seen elsewhere—around 20% of the microbe genomes identified had not been recorded in a global catalogue of over 200,000 such genomes. The researchers found 8.4 million protein families in the guts of the 167 Hadza people they studied. Over half of them had not previously been identified in the human gut.
Plenty of other studies published in the last decade or so have helped build a picture of how the diets and lifestyles of hunter-gatherer societies influence the microbiome, and scientists have speculated on what this means for those living in more industrialized societies. But these revelations have come at a price.
A changing way of life
The Hadza people hunt wild animals and forage for fruit and honey. “We still live the ancient way of life, with arrows and old knives,” says Mangola, who works with the Olanakwe Community Fund to support education and economic projects for the Hadza. Hunters seek out food in the bush, which might include baboons, vervet monkeys, guinea fowl, kudu, porcupines, or dik-dik. Gatherers collect fruits, vegetables, and honey.
Mangola, who has met with multiple scientists over the years and participated in many research projects, has witnessed firsthand the impact of such research on his community. Much of it has been positive. But not all researchers act thoughtfully and ethically, he says, and some have exploited or harmed the community.
One enduring problem, says Mangola, is that scientists have tended to come and study the Hadza without properly explaining their research or their results. They arrive from Europe or the US, accompanied by guides, and collect feces, blood, hair, and other biological samples. Often, the people giving up these samples don’t know what they will be used for, says Mangola. Scientists get their results and publish them without returning to share them. “You tell the world [what you’ve discovered]—why can’t you come back to Tanzania to tell the Hadza?” asks Mangola. “It would bring meaning and excitement to the community,” he says.
Some scientists have talked about the Hadza as if they were living fossils, says Alyssa Crittenden, a nutritional anthropologist and biologist at the University of Nevada in Las Vegas, who has been studying and working with the Hadza for the last two decades.
The Hadza have been described as being “locked in time,” she adds, but characterizations like that don’t reflect reality. She has made many trips to Tanzania and seen for herself how life has changed. Tourists flock to the region. Roads have been built. Charities have helped the Hadza secure land rights. Mangola went abroad for his education: he has a law degree and a master’s from the Indigenous Peoples Law and Policy program at the University of Arizona.
The Download: a microbiome gold rush, and Eric Schmidt’s election misinformation plan
Over the last couple of decades, scientists have come to realize just how important the microbes that crawl all over us are to our health. But some believe our microbiomes are in crisis—casualties of an increasingly sanitized way of life. Disturbances in the collections of microbes we host have been associated with a whole host of diseases, ranging from arthritis to Alzheimer’s.
Some might not be completely gone, though. Scientists believe many might still be hiding inside the intestines of people who don’t live in the polluted, processed environment that most of the rest of us share. They’ve been studying the feces of people like the Yanomami, an Indigenous group in the Amazon, who appear to still have some of the microbes that other people have lost.
But there is a major catch: we don’t know whether those in hunter-gatherer societies really do have “healthier” microbiomes—and if they do, whether the benefits could be shared with others. At the same time, members of the communities being studied are concerned about the risk of what’s called biopiracy—taking natural resources from poorer countries for the benefit of wealthier ones. Read the full story.
Eric Schmidt has a 6-point plan for fighting election misinformation
—by Eric Schmidt, formerly the CEO of Google, and current cofounder of philanthropic initiative Schmidt Futures
The coming year will be one of seismic political shifts. Over 4 billion people will head to the polls in countries including the United States, Taiwan, India, and Indonesia, making 2024 the biggest election year in history.
Navigating a shifting customer-engagement landscape with generative AI
A strategic imperative
Generative AI’s ability to harness customer data in a highly sophisticated manner means enterprises are accelerating plans to invest in and leverage the technology’s capabilities. In a study titled “The Future of Enterprise Data & AI,” Corinium Intelligence and WNS Triange surveyed 100 global C-suite leaders and decision-makers specializing in AI, analytics, and data. Seventy-six percent of the respondents said that their organizations are already using or planning to use generative AI.
According to McKinsey, while generative AI will affect most business functions, “four of them will likely account for 75% of the total annual value it can deliver.” Among these are marketing and sales and customer operations. Yet, despite the technology’s benefits, many leaders are unsure about the right approach to take and mindful of the risks associated with large investments.
Mapping out a generative AI pathway
One of the first challenges organizations need to overcome is senior leadership alignment. “You need the necessary strategy; you need the ability to have the necessary buy-in of people,” says Ayer. “You need to make sure that you’ve got the right use case and business case for each one of them.” In other words, a clearly defined roadmap and precise business objectives are as crucial as understanding whether a process is amenable to the use of generative AI.
The implementation of a generative AI strategy can take time. According to Ayer, business leaders should maintain a realistic perspective on the duration required for formulating a strategy, conduct necessary training across various teams and functions, and identify the areas of value addition. And for any generative AI deployment to work seamlessly, the right data ecosystems must be in place.
Ayer cites WNS Triange’s collaboration with an insurer to create a claims process by leveraging generative AI. Thanks to the new technology, the insurer can immediately assess the severity of a vehicle’s damage from an accident and make a claims recommendation based on the unstructured data provided by the client. “Because this can be immediately assessed by a surveyor and they can reach a recommendation quickly, this instantly improves the insurer’s ability to satisfy their policyholders and reduce the claims processing time,” Ayer explains.
All that, however, would not be possible without data on past claims history, repair costs, transaction data, and other necessary data sets to extract clear value from generative AI analysis. “Be very clear about data sufficiency. Don’t jump into a program where eventually you realize you don’t have the necessary data,” Ayer says.
The benefits of third-party experience
Enterprises are increasingly aware that they must embrace generative AI, but knowing where to begin is another thing. “You start off wanting to make sure you don’t repeat mistakes other people have made,” says Ayer. An external provider can help organizations avoid those mistakes and leverage best practices and frameworks for testing and defining explainability and benchmarks for return on investment (ROI).
Using pre-built solutions by external partners can expedite time to market and increase a generative AI program’s value. These solutions can harness pre-built industry-specific generative AI platforms to accelerate deployment. “Generative AI programs can be extremely complicated,” Ayer points out. “There are a lot of infrastructure requirements, touch points with customers, and internal regulations. Organizations will also have to consider using pre-built solutions to accelerate speed to value. Third-party service providers bring the expertise of having an integrated approach to all these elements.”