Reading an Embryo's Genome Before Birth: Orchid's Case for Whole-Genome Embryo Screening

Siddiqui begins by saying that for 300,000 years every parent handed their child a genetic hand they had never seen, with no way to know what was in it. Parents had no means to prepare for health problems or to choose, so the genetic lottery ran and children received whatever it produced.

She says that era is over and that the way babies are made is changing permanently.

Siddiqui explains that each person begins as two cells, an egg and a sperm, each carrying 23 chromosomes, and that their union fixes the individual's genetic destiny.

She gives the scale of the odds: a mother produces about two million eggs and a father over 500 billion sperm, so the specific combination that makes a given person is about a one-in-a-trillion chance. She compares it to picking one particular grain of sand from all the beaches on Earth.

Siddiqui describes growing up watching her mother go blind. Getting a diagnosis took years, and after extensive testing and office visits the answer was that nothing could be done. Her mother lost night vision first, then peripheral vision, and finally central vision.

She places this within a larger problem: she says about 400 million people worldwide have a genetic disease, more than the population of the United States, and half of those affected are children. Around 95 percent of these conditions have no FDA-approved treatment, and more than 3,000 genetic diseases have been catalogued.

Siddiqui says she started Orchid because of her mother. She says her mother will never see her grandchildren's faces because of a random genetic typo in her DNA, and that she built the company so her own children would not have their lives hijacked by a similar error.

She says Orchid was the first company able to sequence the entire genome of an embryo created through IVF. She notes that an IVF round produces five to 15 embryos and that today the choice among them is made either by appearance under a microscope or by a small slice of available genetic information.

Siddiqui describes current IVF testing as zooming in on specific chromosomes to check whether they are present or missing, which detects cases such as an extra chromosome 21, the cause of trisomy 21 or Down syndrome.

She explains the genome as a book with about three billion bases organized into 23 chapters, the chromosomes. Chromosome testing only tells whether each chapter is present and does not read the letters inside, so a spelling error in chapter seven would not be found. Whole-genome sequencing reads every letter, which she says is why it is far more valuable.

Siddiqui says a few changed letters can be the difference between a child who will never be able to talk and one who will. She says reading such changes is hard because an embryologist sends only five cells, containing about 30 picograms of DNA. A picogram is a trillionth of a gram.

She says her team had to invent a new technology to amplify that DNA hundreds of thousands of times without corrupting it. She says the method is validated because embryo results were matched with the babies born nine months later.

She then describes what parents can screen for: birth defects, heart defects, skeletal defects, neurodevelopmental disorders, genetic forms of autism, and other single-gene diseases that existing testing misses.

Siddiqui says conditions such as schizophrenia, bipolar disorder and heart disease are driven by the combined effect of many millions of variants, so some people carry a high genetic predisposition and others do not. She says the company now has data from hundreds of thousands of individuals, including sequenced genomes and medical records, which it uses to build models that estimate disease risk at the embryo level.

She tells parents that an embryo can be identified as at high or low genetic predisposition. She says someone going through an IVF cycle with only five embryos can expect a risk reduction of 30 to 50 percent. She adds that the models are currently at their weakest because they have the least data they will ever have, and that they will improve as data grows, letting parents reduce more risk with fewer embryos.

Siddiqui says this is not science fiction because such babies already exist, have been photographed by The New York Times, and have drawn international news coverage because their parents did something never before possible.

She states that humans are the first generation able to read their own source code and choose the next generation, and that they can now choose health rather than only hope for it. She predicts that this will soon be the default way people have babies. In a line that drew laughter, she says sex is for fun and embryo screening is for babies, and that the two have quietly separated. She asks why anyone would choose IVF electively and answers by asking why anyone would do it any other way.

Siddiqui introduces Mia, who was born with lissencephaly, a terminal brain disorder caused by a genetic mutation with no cure and no warning. She says most children with the condition do not reach their 10th birthday.

Mia's mother had the standard tests, carrier screening and NIPT. Siddiqui says those tests evaluate less than one percent of the genome and cannot identify most of these diseases, so there was no way to know. The mother used Orchid to screen her next embryos and is now pregnant. Siddiqui says she is going into this pregnancy more confident that her next child will not suffer in the same way.

Siddiqui says it is hard to grasp how powerful one base pair can be and points to the world's tallest woman, over seven feet tall, and its shortest, just over two feet tall. The tallest has Weaver syndrome and the shortest has achondroplasia.

She says both conditions are caused by one letter changed among three billion letters in the genome, which she calls miraculous. Both are spontaneous mutations, so no one else in their families has these typos.

Siddiqui says women often receive blame for eggs that age, but men usually do not know that sperm also accumulates mutations as they get older. She says there is a whole category of genetic diseases caused by mutations in sperm that do not affect the father, and achondroplasia, one of the most common causes of dwarfism, is among them.

Siddiqui says the genetic lottery does not only bring risk but also what she calls superpowers. She describes a Finnish Olympic skier with a single base-pair change in a gene controlling red blood cell production, which she says gives his muscles far more oxygen than competitors' and made him practically unbeatable during his reign.

She also describes a Midwest family with eight times the documented bone density of anyone else, whose bones are virtually unbreakable. She adds that women have been found with four color receptors instead of the usual three, letting them see about 100 million colors where most people see about a million. She says these are already present but handed out only by the genetic lottery.

Siddiqui acknowledges that some people think this is playing God and unnatural. She says she believes the opposite is true, since wanting to protect one's child and wanting them to suffer less is among the most natural and human impulses. She says people simply never had this information before and now they do.

Siddiqui introduces Lydia, the first child of Rohan and Jen, who was born with a serious neurodevelopmental disorder caused by a single-base-pair mutation in the gene KCNQ2. The couple wanted a sister for Lydia and used Orchid for their next pregnancy. The result is Lydia's younger sister Lucy.

Siddiqui says the parents' choice made the difference, and that Lucy will become a child rather than a patient. She closes the family examples with the statement that the future is not hypothetical and is being born now, describing this as the first generation whose genetic odds are stacked in its favor.

In a brief Q&A, Sal Khan asks two questions: whether the technology is not free and so favors those with resources, and where the line should be drawn when considering CRISPR and enhancements such as superhuman sight, bones or endurance.

Siddiqui answers that compared with the cost of the diseases, embryo screening is affordable. She says the first approved gene therapy for retinitis pigmentosa, the condition her mother has, costs about a million dollars per eye, so IVF screening is quite affordable by comparison. On where the technology should go, she says that is up to the audience and that it needs to become a major societal conversation because the technology and its capabilities are moving quickly.