She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (76 page)

In the process, we would be raising the concentration of carbon dioxide in the atmosphere to levels not seen in the last 200 million years, raising the temperature of the planet to levels far beyond what we humans—a species of ape that evolved in the modest swings of Ice Ages—could handle. And the day that the final gas tank ran dry, the last lightbulb winked out, the planet would not immediately set itself back to the way it was before cultural heredity became such a titanic force. It would take thousands of years for the planet to naturally draw down the carbon dioxide to levels close to what they were before the Agricultural Revolution.

To solve a problem like global warming, we cannot come up with a clever technological fix. We are not being threatened by a giant volcano belching out carbon dioxide from the depths of the Earth, which we can simply cover with a titantic plug. Global warming is a problem of cultural inheritance. To fix it, we need a social form of CRISPR—a means to alter the practices and the values that make their way from one generation to the next.

A cynic may say that there are no systems that can possibly put the brakes on the problems we have made for ourselves. But the environmental scientist
Erle Ellis has observed that history records many examples of cultures that transmitted customs through the generations that allowed them to thrive while not destroying their environment in the process. The Maasai of East Africa, for example, have herded cattle for centuries on a landscape that also supported elephants, zebra, lions, and many other wild animals. The long-term health of their ecosystem was the direct result of the culture that the Maasai inherited from their ancestors. Much of their cultural identity is wrapped up in herding cattle—which means they have no need to hunt wild game. To lose a herd of cows and have to hunt marks a huge fall in status. The result was that East Africa could support the great diversity of large mammals on Earth.

“This is a gift to every one of us on Earth now and in the future,” Ellis wrote in a 2017 essay. “The megafauna and landscapes they helped to sustain might yet outlast the Great Pyramids or New York City.”

When the rest of us look at a culture like the Maasai, we should ask what sort of world we want to leave as a legacy, and then figure out how to do so. It may be that CRISPR can be one tool that we can use toward that end. But we must be confident it reworks the world as we truly need it to.

By the time I paid a visit to Anthony James's insectarium in 2017, gene drive was already becoming something of a Manhattan Project. James and other researchers were getting massive grants from the United States Department of Defense, as well as from major foundations around the world. Yet neither James nor any other gene drive researcher had yet released a CRISPR-bearing creature into the wild. And they were in no rush to do so. They were all too aware of past attempts to fix environmental problems that had turned into ecological disasters. And since those introduced species could keep reproducing, every new generation inherited a warped ecosystem.

Starting in the late 1800s, for example, Australian farmers established sugarcane farms, but they fell into a constant fight with cane beetles. In the early 1930s, an Australian entomologist named Reginald Mungomery got an idea for how to win the battle. He heard stories of the giant marine toad. Native to South and Central America, it had a tremendous appetite for insects, and some people had brought the toads to Hawaii to control sugarcane pests there. He got hold of the toads and raised 2,400 of them. And then, in 1935, he set them loose.

Mungomery didn't understand that the toads were catholic in their tastes. Soon the enormous amphibians—known in Australia as cane toads—were hopping out of the plantations and feeding on small mammals. Australian snakes and other predators sometimes tried to eat the cane toads, but a poisonous secretion in their skin made that impossible. At best, the predators spat out the toads and never tried eating them again. At worst, they died. The cane toad spread relentlessly across Australia, pushing a number of native species toward extinction. Australian researchers have tried all sorts of ways to stop them—poisoning the frogs, training native species not to try to eat them—but so far, nothing has worked.

No one wants to be the Reginald Mungomery of the CRISPR age. It's possible that gene drives could go wrong by hopping from a species we want to eradicate to a related one we want to save. It's possible that changing how mosquitoes and other animals respond to one disease could lead them to carry others. Perhaps getting rid of mosquitoes might disrupt ecosystems in ways we can't yet imagine.

Jennifer Kuzma and Lindsey Rawls, two legal scholars at North Carolina State University, have started to examine the ethics of gene drive as a kind of inheritance. Altering the heredity of disease-carrying insects in the short-term could be tremendously valuable in the number of lives it saves and in the suffering it eliminates. But we also owe future generations a careful, forward-looking consideration of the world they will inherit.

Kuzma and Rawls suggest that, by this standard, some gene drives will prove to be justified and others not. They suggest that saving endangered birds should get ranked over altering weeds. The birds deserve a higher priority because they may very well go extinct if we do nothing. Their disappearance will itself be a permanent legacy we leave to future generations.

When I visited James and his colleagues, I asked them about these ethical issues. They didn't have a lot to say. It's not that they didn't care. They just had more pressing problems at hand. They weren't sure if CRISPR gene drives would work at all.

After all, the natural world was littered with the remains of dead gene drives. They had evolved, raced through populations, and then stopped. In some cases, mutations destroyed them. In other cases, animals evolved defenses that kept them in check. Some biologists have argued that it would be easy for mosquitoes to evolve resistance to a CRISPR gene drive. Some of the insects might gain mutations that changed the sequence of DNA that the CRISPR guide molecules searched for. Their descendants would inherit those mutations and
might outbreed the ones carrying the gene drive.

“It's probably easier to break because it isn't an evolved system,” Bier told me. “The system we're making is all completely synthetic. It's frail.”

Meanwhile, James was toiling away in his insectarium, trying to figure out how to make CRISPR work better. When he put Gantz's malaria-
fighting gene drive into a mosquito, all of its offspring inherited it. In the second generation, though, it faltered. Almost all the males inherited it but only some of the females did.

James could still carry forward the gene drive to a new generation by mating the male mosquitoes with normal females. The hairy larvae that I inspected in James's insectarium were all males from his twenty-ninth generation, ready to produce the thirtieth. But James still puzzled over why the female mosquitoes were proving a weak link in the hereditary chain.

The answer may have to do with how mosquitoes develop from a single egg. As a female mosquito develops, it requires many divisions before some of its cells develop into a new batch of eggs. Along the way, a chromosome inside a cell may break. Cells repair this sort of damage by copying DNA from the undamaged copy of the chromosome. James suspected that, during these bouts of repair, the female mosquitoes were editing out their own CRISPR genes. Male mosquitoes, on the other hand, may not lose their gene drives because they set aside sperm cells earlier in their development. If James and his colleagues were right in this hunch, it was hard to see how to overcome it. The inner heredity of mosquitoes isn't easily altered.

After James had shown me all his mosquitoes and answered all my questions, it was time for us to leave the insectarium. We stepped back out into the vestibule, and he closed the inner door loudly behind us. On the other side were thousands of mosquitoes drinking blood, and thousands of larvae writhing in tubs. Here, in the quiet of the vestibule, it was just us two humans, as far as I could tell.

James turned to the pale door to the insectarium and stared at its blankness. The blue smock still hung from his arms.

“The protocol is for us to stand here for a little while,” he said. “See if anybody followed us out.”

The mosquitoes that James raises come from India. They're adapted to the wet, tropical climate there. If a CRISPR-infused mosquito managed to escape James's insectarium, buzz down the hallways, slip up an elevator shaft, and dart through the doorways into the dry hills around Irvine, it would almost certainly die. And yet, even with such safeguards in place, James
still stared at the door, to be sure all his mosquitoes were still penned in his insectarium. As time passed, we both grew quiet. On the other side, a potential new chapter of heredity was crawling, swimming, flying.

Once James felt satisfied that no mosquitoes had escaped, he turned away from the pale inner door. He opened the outer door and we stepped out into the basement hallway. We cast off our smocks into a bin and took the elevator up to the mosquito-killing California sun. We left the next chapter penned in its underground cell, at least for now.

Allele:
A variant form of a gene. In some cases, different alleles will produce variations in an inherited trait.

Amino acids:
The building blocks of proteins.

Bases:
The four building blocks of DNA (A, C, G, and T).

Cell lineage:
The cells that share common descent with a common ancestral cell in the body.

Chromosome:
A threadlike structure of DNA and proteins. Humans have twenty-three pairs of chromosomes.

CRISPR (clustered regularly interspaced short palindromic repeats):
A naturally occurring mechanism that gives bacteria immunity to viruses, allowing them to identify and destroy specific sequences of foreign DNA. Adapted to edit DNA.

DNA:
The double-stranded molecule that encodes genes.

Dominant:
A kind of allele that has an effect when either one or two copies are inherited.

Endosymbiont:
A microbe that can exist only within a host and has to be transmitted from mother to offspring.

Enzyme:
A protein that catalyzes a chemical reaction in the cell, such as breaking down nutrients.

Epigenetic:
Related to molecules such as transcription factors and methylation that affect the expression of genes by altering their DNA sequence.

Epigenome:
The physical factors that affect the expression of genes without affecting the actual DNA sequences of the genome.

Eukaryotes:
A lineage of species that evolved about 1.8 billion years ago, characterized by features such as the nucleus. Includes animals, plants, fungi, and protozoans.

Gametes:
Sperm or eggs.

Gemmule:
A hypothetical hereditary particle that Charles Darwin proposed streamed from somatic cells to the gametes.

Gene:
A segment of DNA that encodes a protein or a functional RNA molecule.

Gene drive:
A system of biased inheritance that allows a genetic element to pass from parents to offspring more than Mendel's Law would allow.

Gene expression:
The production of proteins or functional RNA molecules from a gene.

Gene flow:
The transfer of DNA from one population into another population.

Gene therapy:
A method to treat genetic disorders by delivering correct versions of genes to somatic cells.

Genetic engineering:
Introduction of DNA, RNA, or proteins that are manipulated by humans to effect a change in an organism's genome or epigenome.

Genome:
The complete sequence of DNA in an organism.

Genome-wide
association study:
An analysis of a group of genomes that can reveal unusually common genetic variants in people who have the same condition.

Germ cell:
A cell in a lineage that produces gametes. Distinguished from cells in the rest of the body (somatic cells).

Germ line:
A cellular lineage in sexually reproducing organisms that produces gametes, which transmit genetic material to the next generation.

Germ line engineering:
Altering DNA in the germ line (in gametes or embryos) to create changes that can be inherited by descendants.

Haplogroup:
A group of people who can trace their ancestry to a single person, sharing a set of genetic variants.

Heritability:
The proportion of variance in a trait in a population due to genetic variance, measured from 0 to 100 percent.

Hybrid:
The offspring of two plants or animals of different species or varieties.

Meiosis:
A type of cell division leading to the development of gametes. Meiosis reduces the number of chromosomes in the mother cell by half and produces four gamete cells. During meiosis, chromosomes can undergo recombination.

Mendelian:
A trait that follows Mendel's Law, with a three-to-one ratio of dominant and recessive alleles.

Methylation:
An epigenetic mechanism to silence a gene through the addition of a methyl group (-CH
3
) to a site on a DNA molecule.

Microbiome:
The set of microbes that resides in a host.

Mitochondria:
Fuel-generating organelles inside the cell containing a small amount of DNA. Mitochondria are inherited only through the maternal line.

Mitochondrial replacement therapy:
A treatment for mitochondrial disorders in which the nucleus of a healthy egg or zygote is inserted into a donor egg whose nucleus has been removed.

Mosaicism:
Genetic variation among somatic and germ cells in a single multicellular organism.

Mutation:
A new genetic variation that arises in a cell and can be inherited by its offspring.

Nucleus:
A sac containing chromosomes found in cells of humans and other eukaryotes.

PKU:
Phenylketonuria, a recessive hereditary disorder caused by a faulty enzyme.

Pluripotent:
An embryonic cell that can develop into a wide range of (but not all) types of cells.

Protein:
A long chain of amino acids encoded in a gene.

Recessive:
A kind of allele that has an effect only when two copies are inherited.

Recombination:
An exchange of DNA between pairs of chromosomes during meiosis.

RNA:
A single strand of bases. The production of RNA is a step in the production of proteins, but RNA molecules can also act on their own to catalyze chemical reactions in the cell.

Single-nucleotide polymorphism:
A site in DNA where a single base varies in a population.

Somatic cell:
A cell that is not in the germ line, typically unable to carry genes to the next generation.

Stem cell:
A cell that can generate other types of cells, either in an embryo or in an adult.

STRUCTURE:
A computer program first developed by Jonathan Pritchard and his colleagues to trace the ancestry of individuals to unknown populations.

Totipotent:
The earliest cells in an embryo, which can develop into any type of cell in the embryo or placenta.

Transcription
factors:
Proteins that bind to DNA to alter the expression of genes.

X and Y chromosomes:
The sex chromosomes in mammals. Females have two X chromosomes; males have an X and a Y.

Zygote:
A fertilized egg.