Cellular Alchemy
Roger Highfield
Director of external affairs, Science Museum Group, U.K.; co-author (with Martin Nowak), Supercooperators
A remarkable convergence of technologies is sending shockwaves through genetics and medicine. The widespread adoption of easy-to-use, inexpensive, and effective genome-editing techniques has made recent headlines. But it’s just as significant that their power has been amplified because we live in the era of cheap genome sequencing. There are ways to regulate how genes are used without making permanent changes to DNA, and we can now reprogram adult cells to return them to an embryonic state and then convert them into any desired cell type.
This is the era of cellular alchemy.
To underline why today’s gene-editing methods are so important, look back to 1990, when John Clark’s team at the Roslin Institute, near Edinburgh, unveiled Tracy the sheep. Tracy, the first transgenic farm mammal, was a pharming pioneer that made 30 grams of a human protein in every liter of her milk. Tracy was considered so significant that after her death in 1997, she was stuffed and placed in the Science Museum’s collections.
She had been genetically altered to make alpha 1-antitrypsin (AAT), then regarded as a potential drug for the treatments of cystic fibrosis and emphysema. But the Roslin team could use only crude methods that offered no control over where the DNA would end up. They could add calcium salts to make DNA precipitate out of a solution onto the embryo, hoping that some would migrate inside; use electrical pulses to punch holes in the embryo membranes to drive DNA inside; package DNA in fat particles (liposomes), which dissolve in cell membranes; or, best of all, inject a few hundred copies of the DNA directly into the nucleus of a zygote. The Roslin team attached the AAT gene to the promoter region of a gene responsible for a sheep’s-milk protein and injected 1,000 embryos with this “construct” to end up with one sheep—Tracy—that could make alpha-1-antitrypsin in her mammary gland.
The use of such crude genetic-engineering methods on people is inconceivable. But today we have a way to change DNA at a precise spot. Gene editing permits specific stretches of DNA to be deleted from genomes and new stretches to be inserted into the gap in a much more precise, reliable way. Gene-editing methods can also insert or remove a number of genes at a time, offering huge opportunities when it comes to altering crops, animals, and even people.
The reason this subtle knife is so powerful is that we wield it at a time when we can cheaply and easily sequence DNA to check edits. We know how to manipulate genes without altering them, by inducing epigenetic changes that regulate how they’re used, and we know how to manipulate cells, too—notably by the use of “Yamanaka factors” to turn adult cells into embryonic cells.
When it comes to people, this will pave the way for model systems to test drugs, the creation of T-cells designed to fight cancer, creation of a patient’s own disease-free cells for therapies, humanized pig organs, and so on. Work by Mitinori Saitou of Kyoto University and Azim Surani in the Gurdon Institute at Cambridge University has shown that these reprogrammed embryonic cells can even be turned into immortal germline cells.
By combining these technologies, one might take a skin biopsy from someone with a serious disease, correct the underlying genetic defect in these cells, convert them to primordial germ cells and thence into healthy, corrected sperm or eggs. Given the limitations of embryo screening, and assuming that the wider ethical concerns will be tempered by reasonable pragmatism, it is inevitable that one day children will be born with a skin cell as a parent. When that day dawns, the convergence of gene editing, sequencing, and reprogramming into cellular alchemy will have led to the permanent alteration of the human genome. With significant numbers of people born this way, human evolution will be heading on a new course.
A Terrible Beauty Has Been Born
Randolph Nesse
Foundation Professor of Life Sciences, director, Center for Evolution and Medicine, Arizona State University; co-author (with George C. Williams), Why We Get Sick
The biggest news of 2015 was recognition that new abilities to edit specific genes will transform life itself, transform it utterly. Simple enough to be implemented in labs everywhere, the CRISPR/Cas9 technique replaces a specified DNA sequence with a chosen alternative. The system has revolutionized genetic research and offers hope to those with genetic diseases. It also, however, enables us to change future generations. It even lends itself to creating “gene drives” that can, in just a few generations, replace a given sequence in all members of a sexually reproducing species. A terrible beauty has been born.
The possibilities are beyond our imagining, but some are already real. Trials with caged mosquitoes demonstrate fast transmission of a new gene providing resistance to malaria. If released into the wild, the gene could spread and eliminate that scourge. Would it? What else would it do? No one knows. Other gene drives could eliminate a species. Good riddance to smallpox, but what would happen to ecosystems without mice and mosquitoes? Again, no one knows.
Specters from Disney’s The Sorcerer’s Apprentice come to mind. How will a species with limited ability to control itself use such vast new power? The answer will determine the future of humankind and, indeed, life on this planet. In a remarkable demonstration of transparency and foresight, the National Academy of Sciences organized a meeting last December with sibling organizations from the U.K. and China to discuss the opportunities and threats. The risks were taken seriously, but there was little consensus on where this technology will take us and how (or if) we can control it. It will probably transform life itself, fast. In what way, no one knows.
DNA Programming
Paul Dolan
Behavioral scientist, London School of Economics; author, Happiness by Design
At a time when groundbreaking discoveries seem almost commonplace, it is difficult to predict which scientific news is important enough to stay news for longer than a few days. To stick around, it would have to potentially redefine “who and what we are.” One of the recent advances that fulfills these prerequisites is the decoding and reprogramming of DNA via bioinformatics.
Although mapping the human genome was a great achievement, it was bioinformatics that allowed a practical application of the acquired knowledge. Uploading a genome onto a computer has enabled researchers to use genetic markers and DNA amplification technologies in ways that shed light on the intricate, otherwise unfathomable gene/environment interactions causing disease. Researchers also hope to use bioinformatics to solve real-life problems; imagine microbes programmed to generate inexpensive energy, clean water, fertilizer, drugs, and food, or tackle global warming by sucking carbon dioxide from the air.
But like most things in life, there are also possible negative side effects. With DNA being written like software, cloning and designing complex living creatures, including humans, no longer seems a sci-fi fantasy. All possible advantages aside, it is likely to stir a wide range of ethical debates, requiring us to ponder what it means to be human: a naturally conceived, unique, and largely imperfect creature or a designed, aimed-to-be-perfect being?
Asked about the future of DNA coding and bioinformatics, genomics pioneer Craig Venter replied, “We’re only limited by our imagination.” I’m somewhat more skeptical, but one thing is for sure: Digital DNA is here to stay in scientific news about evolutionary biology, forensic science, and medicine, and also in debates about the way we humans define ourselves.
Human Chimeras
David Haig
George Putnam Professor of Biology; Harvard University; author, Genomic Imprinting and Kinship
A man conceived a child whose genotype did not match his own but was consistent with the child’s being the grandson of the man’s parents. The proposed explanation is that the man had a twin brother who was never born but whose cells colonized the man’s testes when the man was a fetus. Those cells produced the sperm that conceived the child.
In the modern era of sensitive genetic te
sting, multiple examples of chimerism are being detected—where chimerism refers to a body containing cells derived from more than one fertilized egg. All of us probably contain replicating cells from more than one member of our genetic family. A distinction should be made between bodily individuals (who are chimeric) and genetic individuals who may be distributed across multiple bodies.
The Race Between Genetic Meltdown and Germline Engineering
John Tooby
Founder of evolutionary psychology; professor of anthropology, UC Santa Barbara; codirector, UCSB Center for Evolutionary Psychology
The most remarkable breaking news in science is that I exist. Well, not just me. People like me who, without technology, would have died early. Of the roughly 5.5 billion people who have survived past puberty, perhaps only 1 billion would be here were it not for modern sanitation, medicine, technology, and market-driven abundance. Ancestrally, the overwhelming majority of humans died before they had a full complement of children, often not making it past childhood. For those who live in developed nations, our remodeled lifetables are among the greatest of the humane triumphs of the Enlightenment—delivering parents from the grief of holding most of their children dead in their arms, or of children losing their parents (and then themselves dying from want).
But there is hidden and unwelcome news at the core of this triumph. This arises out of the brutal way natural selection links childbearing to the elimination of genetic disease.
The first thing to recall is that even our barest functioning depends on advanced organic technology at all scales—technology engineered by selection. For example, our eyes—macroscopic objects—have 2 million moving parts, and yet individual rods are so finely crafted they can respond to single photons. Successful parents in every species live near summits on adaptive landscapes.
The second thing to remember is that physics is perpetually hurling us off these summits, assaulting the organization necessary to our existence. Entropy not only ages and kills us as individuals but also successfully attacks each parent’s germline. Indeed, the real news is that a number of methods have converged on the estimate that every human child contains roughly 100 new mutations—genetic changes not present in their parents. To be sure, many of these occur in inert regions or are otherwise “silent” and so do no harm. But a few are harmful, and although the rest are individually small in effect, collectively they plague each individual with debilitating infirmities.
These recent estimates are striking when one considers how, in an entropy-filled world, we maintained our high levels of biological organization. Natural selection is the only physical process that pushes species’ designs uphill—against entropy, toward greater order (positive selection)—or maintains our favorable genes against the downward pull exerted by mutation pressure (purifying selection). If a species is not to melt down under the hard rain of accumulating mutations, the rate at which harmful mutations are introduced must equal the rate at which selection removes them (mutation-selection balance). This removal is self-executing: Harmful genes cause impairments to the healthy design of the individuals they’re situated in. These impairments (by definition) reduce the probability that the carrier will reproduce, and thereby they reduce the number of harmful genes passed on. For a balance to exist between mutation and selection, a critical number of offspring must die before reproduction—die because they carry an excess load of mutations.
Over the long run, successful parents average a little more than two offspring that survive into parenthood. (The species would go extinct or fill the planet if the average were smaller or greater.) This is as true for humans with our handful of children as it is for an ocean sunfish with a nest full of 300 million. To understand how endlessly cruel the anti-entropic process of selection is, consider a sunfish mother with one nest. On average, 299,999,997 of her progeny die, and two or three become comparable parents. Since the genotypes of offspring are generated randomly, the number of coin flips (in 300 million series) guarantees a lower end of the bionomial distribution of mutations that are many standard deviations out. That is, there are two or three who become parents because they received a set of genes improbably free of negative mutations. These parents therefore restart the lineage’s next generation, having shed enough of the mutational load to have rolled back mutational entropy to the parental level. Ancestral humans, with far smaller offspring sets, maintained our functional organization more precariously, having survived over evolutionary time on the edge of a far smaller selective gradient, between those children with somewhat smaller sets of impairments and those with somewhat larger sets. Most ancestral humans were fated by physics to be childless vessels whose deaths served to carry harmful mutations out of the species.
Now along comes the demographic transition—the recent shift to lower death rates and then lower birth rates. Malthusian catastrophe was averted, but the price of relaxing selection has been moving the mutation-selection balance toward an unsustainable increase in genetic diseases. Various naturalistic experiments suggest this meltdown can proceed rapidly. (Salmon raised in captivity for only a few generations were strongly outcompeted by wild salmon subject to selection.) Indeed, it is possible that the drop in death rates over the demographic transition caused, by increasing the genetic load, the subsequent drop in birth rates below replacement: If humans are equipped with physiological assessment systems to detect when they are in good enough condition to conceive and raise a child, and if each successive generation bears a greater number of micro-impairments that aggregate into, say, stressed exhaustion, then the paradoxical outcome of improving public health for several generations would be ever lower birth rates. One or two children are far too few to shed incoming mutations.
No one could regret the victory over infectious disease and starvation now spreading across the planet. But we as a species need an intensified research program into germline engineering, so that the Enlightenment science that allowed us to conquer infectious disease will allow us to conquer genetic disease (through genetic repair in the zygote, morula, or blastocyst). With genetic counseling, we have already focused on the small set of catastrophic genes, but we need to sharpen our focus on the extremely high number of subtle, minor impairments that statistically aggregate into major problems.
I am not talking about the ethical complexities of engineering new human genes. Imagine instead that at every locus, the infant received healthy genes from her parents. These would not be genetic experiments with unknown outcomes: Healthy genes are healthy precisely because they interacted well with each other over evolutionary time. Parents could choose to have children created from their healthiest genes, rather than leaving children to be shotgunned with a random and increasing fraction of damaged genes. Genetic repair would replace the ancient cruelty of natural selection, which fights entropy only by tormenting organisms because of their genes.
The Ongoing Battles with Pathogens
Robert Kurzban
Psychologist, University of Pennsylvania; founder and codirector, Pennsylvania Laboratory for Experimental Evolutionary Psychology (PLEEP); author, Why Everyone (Else) Is a Hypocrite
The end of the year saw two stories about pathogens, one hopeful and the other less so. The hopeful one is the advancing ability to insert genes that are desirable (from humans’ point of view) into organisms and facilitate that gene’s spread through the population.
Consider the case of malaria, a focus of current efforts. Malaria still infects tens of millions of people and causes hundreds of thousands of deaths. Inserting a gene that blocks malaria into a mosquito genome is helpful, but only to a limited degree: If the gene doesn’t spread in wild populations, then its effects will be fleeting. If, however, mosquitoes are released that have the gene in question as well as genes that facilitate its spread, then the effects can be long-lasting.
The less hopeful case involves so-called “super-gonorrhea” strains of the pathogen, resistant to the antibiotics currently in use. As is well known, the
use of antibiotics gives an advantage to resistant strains of pathogens. The tools we use to treat disease become the means by which we make the diseases harder to treat. Cases of super-gonorrhea have appeared in England, leading to a certain amount of concern.
Historically, as illustrated by the super-gonorrhea case, fighting pathogens has been something of an arms race: Humans build better weapons, pathogens evolve counter-strategies. But the present age is seeing a confluence of advances that promise to turn the arms race into something more like a winnable war. First is progress in genetics, including techniques for inserting genes into genomes. Second is a sophisticated understanding of evolution and a burgeoning of ideas about how to harness it. In the past, evolution worked against us—as in the case of resistant strains of pathogens; we are becoming better at harnessing it. And third is a growing sophistication in thinking about systems. It is unlikely that the same sorts of mistakes will be made as were made in the past, when simplistic ecological interventions led to disastrous outcomes, as in the case of cane toads in Australia. Our view of ecosystems is both humbler and more sophisticated than ever before.
It seems likely that pathogens of one sort or another will be important for a long time: They are moving targets with tremendous capacity for harm. On the other hand, recent advances may well be able to tame them in ways we have not previously seen.
Antibiotics Are Dead; Long Live Antibiotics!
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