For the first time in the United States, researchers have used gene editing to repair a mutation in human embryos.

Molecular scissors known as CRISPR/Cas9 corrected a gene defect that can lead to heart failure. The gene editor fixed the mutation in about 72 percent of tested embryos, researchers report August 2 in Nature. That repair rate is much higher than expected. Work with skin cells reprogrammed to mimic embryos had suggested the mutation would be repaired in fewer than 30 percent of cells.
In addition, the researchers discovered a technical advance that may limit the production of patchwork embryos that aren’t fully edited. That’s important if CRISPR/Cas9 will ever be used to prevent genetic diseases, says study coauthor Shoukhrat Mitalipov, a reproductive and developmental biologist at Oregon Health & Science University in Portland. If even one cell in an early embryo is unedited, “that’s going to screw up the whole process,” says Mitalipov. He worked with colleagues in Oregon, California, Korea and China to develop the embryo-editing methods.

Researchers in other countries have edited human embryos to learn more about early human development or to answer other basic research questions (SN: 4/15/17, p. 16). But Mitalipov and colleagues explicitly conducted the experiments to improve the safety and efficiency of gene editing for eventual clinical trials, which would involve implanting edited embryos into women’s uteruses to establish pregnancy.
In the United States, such clinical trials are effectively banned by a rule that prevents the Food and Drug Administration from reviewing applications for any procedure that would introduce heritable changes in human embryos. Such tinkering with embryo DNA, called germline editing, is controversial because of fears that the technology will be used to create so-called designer babies.

“This paper is not announcing the dawn of the designer baby era,” says R. Alta Charo, a lawyer and bioethicist at the University of Wisconsin Law School in Madison. The researchers have not attempted to add any new genes or change traits, only to correct a disease-causing version of a gene.

In the study, sperm from a man who carries a mutation in the MYBPC3 gene was injected into eggs from women with healthy copies of that gene. Carrying just one mutant copy of the gene causes an inherited heart problem called hypertrophic cardiomyopathy (SN: 9/17/16, p. 8). That condition, which strikes about one in every 500 people worldwide, can cause sudden heart failure. Mutations in the MYBPC3 gene are responsible for about 40 percent of cases. Doctors can treat symptoms of the condition, but there is no cure.

Along with the man’s sperm, researchers injected into the egg the DNA-cutting enzyme Cas9 and a piece of RNA to direct the enzyme to snip the mutant copy of the gene. Another piece of DNA was also injected into the egg. That hunk of DNA was supposed to be a template that the fertilized egg could use to repair the breach made by Cas9. Instead, embryos used the mother’s healthy copy of the gene to repair the cut.

Embryos’ self-healing DNA came as a surprise, because gene editing in other types of cells usually requires an external template, Mitalipov says. The discovery could mean that it will be difficult for researchers to fix mutations in embryos if neither parent has a healthy copy of the gene. But the finding could be good news for those concerned about designer babies, because embryos may reject attempts to add new traits.

Timing the addition of CRISPR/Cas9 is important, the researchers also discovered. In their first experiments, the team added the gene editor a day after fertilizing the eggs. Of 54 injected embryos, 13 were patchwork, or mosaic, embryos with some repaired and some unrepaired cells. Such mosaic embryos probably arise when the fertilized egg copies its DNA before researchers add Cas9, Mitalipov says.

Injecting Cas9 along with the sperm — before an egg had a chance to replicate its DNA — produced only one patchwork embryo. That embryo had repaired the mutation in all its cells, but some cells used the mother’s DNA for repair while others used the template supplied by the researchers.

None of the tested embryos showed any signs that Cas9 was cutting where it shouldn’t be. “Off-target” cutting has been a safety concern with the gene editor because of the possibility of creating new DNA errors.

The study makes progress toward using gene editing to prevent genetic diseases, but there’s still has a long way to go before clinical testing can begin, says Janet Rossant, a developmental biologist at the Hospital for Sick Children and the University of Toronto. “We need to be sure this can be done reproducibly and effectively.”

A growing band of digital characters that converse, read faces and track body language is helping humans to communicate better with one another. While virtual helpers that perform practical tasks, such as dealing with customer service issues, are becoming ubiquitous, computer scientist M. Ehsan Hoque is at the forefront of a more emotionally savvy movement. He and his team at the University of Rochester in New York create software for digital agents that recognize when a person is succeeding or failing in specific types of social interactions. Data from face-to-face conversations and feedback from professional counselors and interviewers with relevant expertise inform this breed of computer advisers.

One of Hoque’s digital helpers grooms people to be better public speakers. With words on a screen, this attentive app notes, for example, how many times in a practice talk a person says “um,” gestures inappropriately or awkwardly shifts vocal tone. With the help of Google Glass, the app even offers useful reminders during actual speeches. Another computerized helper, this one in the form of an avatar, helps people hone their job interviewing skills, flagging long-winded responses or inconsistent eye contact in practice interviews. In the works are computerized conversation coaches that can improve speech and communication skills among people with developmental conditions such as autism and mediate business meetings in ways that encourage everyone to participate in decision making.

“There has been some progress in artificial intelligence, but not much in developing emotional aspects of AI,” Hoque says. “We’re just cracking through the surface at this point.”
The U.S. Department of Defense and the U.S. Army have taken notice. With their financial support, Hoque is developing avatars that collaborate with humans to solve complex problems, and digital observers that monitor body language to detect when people are lying.
This is heady stuff for a 35-year-old who earned a doctoral degree just four years ago. Hoque, who was born in Bangladesh and immigrated to the United States as a teenager, did his graduate work with the MIT Media Lab’s Affective Computing research group. The group’s director, Rosalind Picard, helped launch the field of “affective computing” in the 1990s, which focuses on the study and development of computers and robots that recognize, interpret and simulate human emotions.

Hoque’s approach puts a service spin on affective computing. As a grad student, he developed software he dubbed MACH, short for My Automated Conversation coacH. This system simulates face-to-face conversations with a computer-generated, 3-D man or woman that sees, hears and makes decisions while conversing with a real-life partner. Digital analyses of a human partner’s speech and nonverbal behavior inform the avatar’s responses during a session. A simulated coach may, for instance, let a user know if smiles during an interview look forced or are mistimed. After a session, users see a video of the interaction accompanied by displays of how well or poorly they did on various interaction skills, such as keeping eye contact and nodding at appropriate times.

MACH got its start in trials that trained MIT undergraduates how to conduct themselves during interviews with career counselors. First, Hoque analyzed smiles and other behaviors that either helped or hurt the impressions job candidates left on experienced counselors in mock interviews. In a series of follow-up studies, his team developed an automated system that recognized impression-enhancing behaviors during simulated interviews. That pilot version of MACH was then put to the test. Women, but not men, who received MACH training and got feedback from their digital coach while watching videos of their initial interviews with a counselor displayed substantial improvement in follow-up interviews. MACH trainees who watched interview videos but got no feedback showed minimal improvement. Testing with larger groups of men and women is under way.
As he developed MACH, Hoque consulted MIT sociologist and clinical psychologist Sherry Turkle. That was a bold move, since Turkle has warned for 30 years that, despite its pluses, digital culture discourages person-to-person connections. Social robots, in particular, represent a way for people to escape the challenges of forging authentic relationships, Turkle contends.

But she came away impressed with Hoque, whose goals she calls refreshingly modest and transparent. “His avatars will be helpers and facilitators,” she says, “not companions, friends, therapists and pretend people.”

Hoque’s approach grew out of personal experience. He is the primary caregiver for his 16-year-old brother, Eshteher, who has Down syndrome and does not speak. Eshteher can make sounds to refer to certain things, such as food, and has limited use of sign language. “I’ve spent a lot of time with him and can read what he’s experiencing, like when he’s frustrated or repentant,” Hoque says.
So it’s not surprising that Hoque’s next-generation MACH, dubbed LISSA for Live Interactive Social Skill Assistance, is an avatar that conducts flexible, “getting acquainted” conversations while providing feedback on users’ eye contact, speaking volume, smiling and body movements via flashing icons.

LISSA has shown promise in preliminary tests aimed at improving the conversational chops of college students attending speed-dating sessions and individuals with autism spectrum disorders. Hoque plans to expand this technology for use with people suffering from social phobia and post-traumatic stress disorder. He’s also working on an avatar that trains doctors to communicate clearly and compassionately with patients being treated for life-threatening cancers.

Hoque’s work on emotionally perceptive avatars may eventually transform the young industry of digital assistants, currently limited to voices-in-a-box such as Apple’s Siri and Microsoft’s Cortana, says cognitive scientist Mary Czerwinski, a principal researcher at Microsoft Research Lab in Redmond, Wash. Avatar research “could lead to more natural, personable digital assistants,” Czerwinski predicts. Hoque agrees.

“In the future, we’ll all have digital, personalized assistants,” he says. If he gets his way, emotionally attuned helpers will make us more social and less isolated. That’s something to applaud — if we can manage to put down our smartphones.