Promise and Peril of Genetic Modification in Humans
Where is the line between can and should?
No lab coats or goggles required. We wore civilian clothes and latex gloves as we huddled over beakers, pipettes in hand. In Dakar, Senegal two dozen young scientists, mostly masters and PhD students from the U.S., France, and several African nations, a few post-doctoral researchers and veteran scientists, and one non-scientist—a communication specialist—crowded into a couple of small lab rooms. Grateful for not having to wear extra layers given the warm temperature and close quarters, I nonetheless marveled at the minimal protective gear. After all, we were manipulating genes using cutting edge CRISPR technology. I half expected a hazmat suit.
Our task that day was to snip out a sequence of DNA in the cells of rice plants. The experiment was part of an advanced crop improvement course conducted by Colorado State University, Cornell University, AfricaRice, and other research institutions. The one non-scientist, me, was there to teach a session on communicating the incalculable value of gene modification in agriculture. Scientists sometimes struggle to convey the significance of their work and I aimed to equip them to winsomely head off confusion and misinformation.
The ability to alter the genes of domesticated plants and animals in the lab is revolutionary on par with the Green Revolution of the last century. By 2050, the world population will be 9 billion and genetic modification will provide the key to ensuring there is enough food to go around. Scientists are using this biotechnology to increase food production, to make plants and animals naturally resistant to disease (thereby decreasing pesticides and antibiotics), and to bolster plant resistance to adverse environmental factors such as hotter temperatures, drought, salty soils, and flooding which are likely to increase due to global warming.
A brief history of genetic modification
Over the past 10,000 years human beings have been manipulating the genes of plants and animals through selective breeding. All domesticated lifeforms, from dogs and cattle to green beans and cherries, descended from wild progenitor species selected and bred for desirable treats.
Genetic modification through selective breeding is time intensive. In the 20th Century, scientists made significant advances that reduced the amount of time needed to alter DNA. They discovered that if they subjected seeds to radiation, for example, some of the seeds that survived would have genetic changes that resulted in desirable traits. Mutagenesis produced Ruby Red grapefruit and many other types of crop plants. Scientists also made advancements in hybridization whereby closely related plants are crossbred to enhance certain features.
Even more remarkably, they discovered ways to modify the genetic code at the molecular level. In 1972, the lab of Stanford scientist Paul Berg successfully combined bacterial and viral DNA. In the years that followed other scientists created transgenic bacteria. The most significant of these experiments was done by Herbert Boyer and Stanley Cohen who pioneered transgenic insulin-producing bacteria.
The foundation for their success was basic scientific work two decades earlier. In the mid-1950s, a few years after James Watson and Francis Crick determined the structure of DNA, Biologist Armin Braun speculated that bacterial DNA was causing plant tumors called galls to develop on trees. By1977, scientists had figured out that Agrobacterium tumefaciens, a soil bacteria, was injecting its own DNA into trees and causing the galls. In addition to regular DNA, bacteria contain plasmids, small rings of DNA that exist and replicate separately from the organism’s main DNA. Agrobacterium tumefaciens’s plasmid DNA can enter into a cell of another organism and its DNA is incorporated into the other organism’s DNA.
Boyer and Cohen modified a bacteria plasmid to include DNA instructions for the making of insulin. The plasmid transferred the DNA into an E. coli bacteria and that bacteria began to make insulin. The insulin production method was approved by the FDA and went on the market in 1983.
In the 1970s, scientists also began to experiment with using a virus as a vector for introducing DNA or RNA into a cell. Today both methods are used to transfer genetic material. In the 1980s, John Sanford invented the gene gun which can shoot genetic material into a cell. This method is used on plant cells. Also in the 1980s, biotechnology for removing genes from a living cell was pioneered. Zinc-finger nucleases (ZFNs) are still used to make cuts in the code but it is no longer the only method. In the 21st Century, scientists would invent two more methods, TALENS transcription-like effector nucleases and Clustered Regularly Interspaced Short Palindromic Repeats CRISPR Cas biotechnology. See footnote for uses of this biotechnology in agriculture.[1]
This is Walter Isaacson’s The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race picks up. The book describes the people who discovered CRISPR in bacteria and harnessed it for gene modification, the process of scientific discovery, and the potential costs and benefits of the biotechnology.
The People
The Code Breaker is principally but not exclusively about Jennifer Doudna, the scientist who, along with Emmanuelle Charpentier won the Nobel prize in chemistry. Her life’s story from childhood through the year 2020 provides a coherent structure for the book. Isaacson profiles other scientists along the way and their interactions as they collaborate and compete with each other.
Throughout Doudna’s career we see the importance of inspiring and mentoring young people in science. Doudna was inspired by James Watson’s The Double Helix. She looked past Watson’s chauvinistic remarks about Rosalind Franklin and admired her. Doudna saw a woman scientist worth emulating. Doudna’s dad encouraged his daughter’s natural curiosity as did her high school biology teacher Marlene Hapai. Family friend Don Hemmes took her on nature walks and later invited her to work at his lab. Later, Doudna was mentored by her biochemistry professor Sharon Panasenko. In Jack Szostak’s lab where she did her post doctorate research, Szostak encouraged her to take risks, explore new ground, and ask big questions. “Never do something that a thousand other people are doing” was his axiom (Isaacson p.46). Doudna would go on to inspire and mentor young scientists in her own lab.
The field of science is both collaborative and competitive. Scientists not only collaborate with each other, they work with funders, businessmen and women, and others. They are united by curiosity, the joy of discovery, and the prospect of improving the world around us. Science is also a competitive sport that drives participants to outcompete each other for prizes, grants, recognition, publishing, and patents. Great rivalries—Darwin and Wallace, Koch and Pasteur, Watson/Crick and Pauling, Ventor and Collins, and Doudna and Zhang—produced great discoveries. Sometimes the competition and the drive for recognition leave a lingering taste of bitterness, however. Isaacson recounts the toll of competition on Charpentier and Doudna’s friendship. Even so, Charpentier recognizes the positive power of competition. “If it were not for competitive people like Jennifer, our world would not be as good. Because what drives people to do good things is recognition,” she said (Isaacson p.160).
The Process
Isaacson quotes engineer and inventor Vannevar Bush who said in 1945, “Basic research leads to new knowledge. It provides scientific capital. It creates the fund from which the practical applications of knowledge must be drawn. New products and new processes do not appear full-grown. They are founded on new principles and new conceptions, which in turn are painstakingly developed by research in the purest realms of science” (Isaacson p.90).
Just as plasmid biotechnology originated with a basic question about tree galls, the origin of CRISPR biotechnology started with a simple inquiry by Francisco Mojica about the clustered repeated segments of DNA he found in the bacteria genome. Yogurt and cheese scientists Barrangou and Horvath noticed that between those repeats are sequences of DNA that match the viruses that attack the bacteria. Turns out these seemingly simple one celled organisms have an immune system of sorts that recognizes and remembers viral attacks. The DNA instructions enable the bacteria to create a kind of ballistic missile defense to the incoming virus attack. The bacteria cell generates two kinds of RNA and an enzyme that bind to and destroy the viral DNA by cutting it up.
RNA is a fantastic molecule that does a lot of work in a cell. Under normal conditions, messenger RNA (mRNA) copies a sequence of DNA and takes it to a ribosome (another type of RNA—rRNA). Transfer RNA (tRNA) carry amino acids to the ribosome to be assembled according to the mRNA sequence. That’s how cells make proteins. To use a kitchen metaphor: mRNA copies a recipe from the recipe book (DNA) and takes it to the kitchen countertop (rRNA). Cooks (tRNA) bring the ingredients to the countertop to put together according to the recipe. RNA has other functions as well. In bacteria (CRISPR Cas) and plants (RNA Interference), RNA plays a role in defending against pathogens.
Having discovered CRISPR, scientists asked the next big question: if bacteria can use this bio-mechanism to alter viral DNA, can we use it to alter DNA? Other biotechnology exist for this purpose (TALENS, ZFN) but CRISPR Cas biotechnology provides another method that is faster and in many cases (but not all) better than existing biotechnology. Scientists have another tool to alter genomes for agricultural, environmental, and medical purposes.
The Potential
Modifying genes in plants, livestock, and wild animals has not been without controversy. There are still people who fear genetically modified organisms (GMOs) despite the fact that scientists have time and again found them to be safe for consumption. Benefits notwithstanding, there are still ethical considerations concerning genetic modification in agriculture. For example, should we worry about unintended edits such as what happened in the Holstein horn case?
Genetic modification of wild animals raises questions as well. Is it ethical to use a gene drive to wipe out an insect species that carries disease? Should we bring back extinct species? Animals hunted to extinction like the passenger pigeon, steller’s sea cow, the dodo, the aurochs, and the thylacine could once again walk, fly, and swim. We could use science to right a wrong. That said, what happens to the species that filled the environmental niche vacated by the extinction? What else could be impacted in the environment? Consider the controversy around wolf reintroduction in Colorado and that species has only been gone from the state 80 years.
What about transgenic modification? The mouse genome has been edited to include human genes so that researchers can study medical therapies for human diseases in mice. Is this narrow transgenic application ethical? It is medically beneficial. What if genetic modification was key to a species’ survival in a warming environment? What about importing animal genes into other animals to create chimeras that have no purpose other than to satisfy curiosity?
Human genetic editing raises even more questions. Scientists have been working on genetic therapies that involve the editing of somatic (non-reproductive cells) to correct genetic flaws that cause certain kinds of blindness, sickle cell anemia, and cystic fibrosis. Cells can be taken from the body, corrected, and returned to the body. Genetic correction can also be injected directly into the body encapsulated in a virus. The latter entails more risk such as a reaction to the viral vector.
Another development in genetic therapy is the use of RNA in vaccines. Traditional vaccines expose the body to a weakened or deactivated virus to stimulate the creation of antibodies. The first three approved COVID-19 vaccines used RNA, specifically messenger RNA, in a unique way. The vaccine contained a bit of viral RNA. Once in the body, human cells respond to the RNA by making the protein it encodes. Once released from the cell, the immune system recognizes the foreign protein and attacks it. If exposed to the COVID-19 virus in the future, the body recognizes the protein and attacks the virus, thus fighting off infection. The vaccine mRNA does not interact with or change human DNA and breaks down within hours of the inoculation.
Gene therapies are less controversial than genetic modification of embryos for several reasons. The modification will be passed along in the next generation and thus impact not just the individual but the broader human genome. There are ethical issues involving both means and ends.
Let’s start with the ends. If we could modify embryos in vitro to eliminate sickle cell anemia, Huntington’s disease, and cystic fibrosis why wouldn’t we? A friend of mine has cystic fibrosis. She’s had more surgeries than anyone I know and is about to have her large intestine and stomach removed because both organs have died due to the disease. Her health battles have also made her deeply empathetic, kind, artistic, and persevering. Would I spare her a life of pain by making a genetic correction at conception knowing that it might take from her some what makes her special? Yes. Am I not making a judgement call that health is of greater value than depth of character? Also yes and perhaps I’m wrong.
Isaacson makes an apt distinction between genetic modification to cure disease and genetic modification for enhancement, that is, modifying embryonic DNA to make a child more athletic, taller, smarter, or more beautiful. He rightly raises the issue of eugenics. The creation of a class of improved humans through genetic modification isn’t much different than similar efforts achieved through selective breeding (and sterilization of the “unfit”) a century ago. Eugenics through private versus government efforts is still eugenics.
Most people would agree that all things being equal, it is better to be healthy than sick. Other choices are not as black and white. Is being tall better than being short? Will 10 IQ points make someone happier or a better person? Which physical characteristics are most beautiful? Can we make these choices for someone else? Genetic homogeneity is bad for any species because it renders the species less adaptable to new conditions. In humans, attainment of homogeneity has a dark history of eugenics, genocide, ethic cleaning, and subjugation. Would genetic modification produce similar ends albeit by gentler means?
The means of genetic modification also raises questions. Presumably only those who afford in vitro fertilization with genetic enhancement treatment would have access. The haves would have more. The gulf between rich and poor would most certainly widen. Could an enhanced elite compete fairly with their non-enhanced peers in the Olympics? What about enhanced soldiers on the battlefield?
Isaacson mentions two prescient works of fiction: the 1932 book Brave New World and the 1997 movie Gattaca. In each case, genetic modification grants privileges not accessible to the non-engineered.
It’s also worth considering what happens to those not chosen. Unwanted human embryos are killed. People have eliminated unwanted children by one means or another throughout human history. Disability (or simply being the wrong sex) can be a death sentence. As Isaacson points out, ever since science enabled genetic testing in utero for Down Syndrome, two thirds of babies with Downs have been killed. Germany’s T4 program vastly reduced the prevalence of disability in the nation by eliminating the disabled. What will the availability of genetic correction for the elite mean for everyone else with a disability? Will they be valued even less? Geneticist Bentley Glass once remarked that, “No parents will have a right to burden society with a malformed or mentally incompetent child” (Isaacson p.266). At what point does choice become compulsion?
Fortunately, most human characteristics involve multiple genes so this brave new world is still in the future. Yet it is important to grapple with these issues now. There have been a number of conferences and consensus papers devoted to these topics over the past few decades. Is consensus really possible given the different values people hold about humanity, the good life, and what is most important?
[1] There have been great scientific gains particularly in agriculture. Here are a few examples: In 1998 ring spot virus was destroying Hawaii’s papaya groves. Once infected, papaya trees do not recover from the virus. Plants do not have an immune system like animals do but they have defense mechanisms of their own such as RNA interference capabilities. The plant’s cells create short strands of RNA that bind to and destroy the virus’s RNA. To trigger this response, scientists injected papaya embryos with a genetic sequence from the ring spot virus which the plants incorporated into their own DNA. When faced with the virus, the presence of the virus sequence enables the plant to make interference RNA. Scientists are currently working to save the Cavendish banana (most common banana), which like the papaya, will be doomed to extinction without gene modification biotechnology.
More recently, scientists used CRISPR to edit the genome of pigs to make them immune to deadly porcine reproductive and respiratory syndrome. The edit removed 450 base pairs of DNA so that the virus cannot attach to the pig cells.
In the 1990s, scientists added genes to the rice from a daffodil and a soil bacteria to enable the plant to make the building blocks for Vitamin A. Millions of people who rely on rice as a prime stable experience Vitamin A deficiency which can lead to blindness. Success in creating a fortified transgenic rice shows the potential for this biotechnology to improve nutrition.
Scientists at Colorado State University and Cornell University are using gene modification to make rice more disease resistant. Researchers have a data set that includes the genomes of 3,000 rice varieties. Half of the world depends on rice as a staple crop including some of the poorest nations and at least 15 percent of rice crops worldwide are lost to disease. Scientists are working with the rice genomes rather than importing transgenic DNA.
Not all gene modification is an unalloyed success. In 2016, scientists used TALENS technology and a plasmid to cut and paste DNA from Angus cattle to dairy cattle. Angus cattle naturally do not grow horns which is a desirable feature in cattle as hornless cattle cannot gore each other or their handlers. Dairy cattle have horns which are removed in a process that is painful for the animal. Rather than cross breed the beef and dairy cattle, which would have diluted desirable features in dairy cattle, scientists decided to implant the hornless DNA directly into a Holstein bull cell. That cell was cloned to produce to two bulls both born without horns. The success was tarnished when it was discovered that some of the plasmid bacteria DNA also transferred to the cattle. Will the extra DNA produce any adverse consequences? Probably not but time will tell.