Gene Editing 101

Gene editing is one of those phrases that polarizes groups of people quickly. Part of the reason for the strong feelings around this phrase is that gene editing is a broad term that brings to mind many different controversial topics.

The reality is that few people are comfortable with selective breeding, GMOs, CRISPR CAS9, and designer babies. but many of us are used to at least a few of these topics.

Before we start, let’s take a look at the science and history of genetics.

We’ve Started Modifying Genes Before We Discovered Genes

A gene is basically a unit of heritability. To be a bit more technical, a gene is a sequence of nucleotides (Adenine, Cytosine, Guanine, and Thymine) that comes together to code for a given trait.

Basically, a gene is the bit of our DNA that tells our cells what to be.

But long before humans knew that we were already tinkering with genes. If you had a sheep that produced exceptionally soft wool, you’d make sure that you kept her lambs. If your horse had sturdy feet and a steady temperament, you were more likely to breed him.

The Mid-1800s: Mendel Discovered Dominant and Recessive “Factors”

Gregor Mendel started experimenting with heredity in the 1800s in his famous pea experiments. He found that some traits were “dominant” over others when he carefully crossbred peas. He didn’t know that genes existed but attributed these patterns to invisible “factors.”

The 1900s: Genome Sequencing and Cloning Takes Off

People largely ignored Mendel’s work in his lifetime. Skipping ahead through a lot of important but relatively technical work, Rosalind Franklin, James Watson, and Francis Crick discovered that DNA is a double helix shape in 1953.

In 1972, Walter Fiers and his team mapped out a gene sequence for the first time. a gene for the protein coat of a bacteria. In four years, the team had mapped out the whole genome of the bacteria. Knowing which genes go what and how the genome is put together is the first step towards making more precise edits.

1980 saw the first patent for gene cloning after Stanley Norman Cohen and Herbert Boyer cloned a plasmid with the ability to express a foreign to the organism. And thus, gene editing really took off.

In 1982, the US FDA approved genetically engineered insulin. In 1987, Yoshizumi Ishino accidentally discovered the part of a DNA sequence that will come to be known as CRISPR. More on that later.

in 1997, Scientists cloned Dolly the sheep . Dolly was famous thanks to being the first animal cloned from an adult cell. The next year saw the first multicellular eukaryote (an organism with cells with nuclei) genome sequenced.

Of course, a lot more happened in the 1900s — especially later on in the timeline. But it’s important to note that we already were genetically engineering insulin in the ‘80s.

The 2000s: Age of CRISPR

Almost every biologist alive currently uses CRISPR in their work somehow. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats — that’s why we shorten it! Scientists discovered an odd series of repeating genes in many bacteria. But they didn’t know why it was there.

Eventually, scientists discovered that these short palindromic repeats match up with patterns seen in some viruses. This system allows bacteria to find and delete specific strains of viral DNA if the infected bacteria.

But scientists realized that we can use CRISPR and the corresponding proteins (such a CAS9 proteins) to edit the genomes of other animals. Using the repeats, we can target sequences of genes to “snip” out of an organism and replace.

Gene editing isn’t new – but the precision and ease of CRISPR sets it apart. That said, scientists are already finding the limitations of CRISPR and are looking for other ways to edit genes.

This is especially important after reports found that CRISPR can sometimes delete large chunks of non-target DNA, which could cause more problems than it solves.

Beyond CRISPR: Other Ways to Edit Genes

Humans have been altering genomes since we first domesticated animals — and probably before then. Selective breeding is a rudimentary way to edit genes, but it still gave us Pugs, Irish Wolfhounds, hairless cats, and Micro-Pigs. So it’s not that bad!

Scientists have also worked to edit genes by inducing mutations. by using ultraviolet or ionizing radiation, or several different mutagenic chemicals. OF course, this is far less precise than using CRISPR.

As some of the issues with CRISPR have come up, scientists are looking for other ways to potentially edit human genes. For example, it’s possible to use CRISPR to just active or deactivate genes, rather than deleting them. This is a bit less risky.

Some other scientists are looking at modifying CRISPR to make smaller, more precise swaps (an A to a T or a C to a G), which also are less risky than wholesale insertions or deletions.

The world of gene editing is moving so quickly that it’s hard to keep up right now. So, how worried should we be? What’s actually going on with gene editing right now?

GMO Crops: Genetically Modified Foods

The World Health Organization defines a GM food as food in which the genetic material has been altered in such a way that does not occur naturally. They use the term “GM food” because most foods don’t contain an entire organism (the “O” in GMO).

Most genetically modified foods are plants that have been modified to improve yield, increase drought tolerance, build resistance to a plant disease, or otherwise make the plant more efficient to grow.

Skepticism surrounding GM foods dates back to when the first herbicide-resistant soybeans reached the markets in the early 1990s. Given that GMs don’t offer better taste, better shelflife, lower costs, or other obvious benefits to the consumer, consumers remained skeptical and focused on the risk side of the risk-reward equation.

The World Health Organization urges organizations and governments to make safety decisions surrounding GM foods to be made on a case-by-case basis because different technologies and different organisms may yield different results.

Much of the corn and soy in what you eat is likely produced from GM crops. In 2017, there were roughly 182 million hectares (449 million acres) of GM soybeans on earth. Many of these soybeans are part of Monsanto’s Roundup Ready soybeans, which are genetically resistant to Monsanto’s hallmark herbicide. This means that farmers who use Roundup Ready crops can spray their fields with herbicides to kill weeds without harming their crops.

Part of the pushback against GMs is due to the public perception that GMs allow for (and even encourage) the use or over-use of chemicals in food production. Many other types of GMs exist, but it’s hard to extricate the implications of Roundup Ready crops from something like Golden Rice, which supplies people with Vitamin A.

While Golden Rice also falls under the umbrella category of GM crops, its support from the FDA, Bill and Melinda Gates Foundation, 107 Nobel Laureates, and others support the idea that GM crops should be assessed on a case-by-case basis rather than being unilaterally approved or denied.

The Legal and Patent Battles of GM Crops

One of the biggest concerns surrounding GM crops is that of intellectual property rights. If a technology company can patent a gene (or a whole organism), that company can sue farmers for growing crops without the proper rights. However, it’s possible for a GM crop to cross-polinate with another farmer’s crop, spreading the GM crops without a human’s hand in the process. The big companies, Monsanto in particular, are known for being legally aggressive in going after farmers for patent infringement.

It’s also easy for farmers to become reliant on GM seeds if the GM crops do perform better than traditional crops. This locks the farmers into a cycle of purchasing expensive seeds from monopoly-like biotech and chemical companies, rather than saving their own seeds for future use. The utility patents that many tech companies hold on their GM crops prohibit seed-saving.

Are GM Crops Safe to Eat?

The legal and patent rights discussions surrounding GM crops are complex and vary from country to country. But what about the health issues surrounding GM crops? Are they safe to eat?

The WHO outlines three main safety issues surrounding GMs that should be addressed in each case:

1. Allergenicity. The WHO urges against using genes from a commonly allergenic plant (like peanuts) in other plants without demonstrating that the transferred gene is not allergenic. Otherwise, it would possible to create a soybean that harms someone with a peanut allergy
2. Gene Transfer. It’s possible, but unlikely, for genes to transfer from the food to the gastrointestinal tract during digestion. The WHO encourages avoiding antibiotic resistant markers for this reason. Antibiotic resistant markers in GMs could be harmful to humans if they transferred to bacteria in our guts.
3. Outcrossing. Some GMs are only approved for consumption by animals, but have been detected in fields intended for human consumption. The ability of plants to reproduce at a distance is a concern, especially if the spreading GM is not approved for a given use or location. The WHO suggests keeping fields clearly separated as a preliminary step to combat this concern.

There’s a scientific consensus (see more info here) that currently available GM food poses no greater risk to human health than conventional food – but that case-by-case assessments of safety need to continue.

That doesn’t mean that GMOs are without risk, though. Aside from the legal implications outlined above, there’s a viable concern around GMOs surrounding crop diversity. If given GM crops are far superior to other strains, it’s likely that those other strains will die out. This may not pose a problem, but it also could mean that some crop breeds with other advantages could die out. Losing genetic crop diversity is always a concern!

Gene Drives

Gene editing can be used (and has been used) to engineer mosquitos that can’t carry Zika or Malaria and ticks that can’t carry Lyme disease. This has the potential to dramatically reduce or even eliminate certain dangerous diseases.

However, this requires more than just creating a malaria-resistant mosquito and releasing it to the wild. Scientists have to figure out how to get the malaria-resistant genes into all of the mosquitos in an area. Rather than relying on just releasing enough malaria-resistant mosquitos that the gene took over, scientists have a different approach.

They created a new version of CRISPR technology that passes on not only the gene (the malaria-resistant gene in this example), but also the “scissors and glue,” essentially allowing CRISPR to perpetually copy-and-paste the malaria-resistant gene throughout populations. It’s like a “global search and replace,” in the words of Jennifer Kahn in her TED Talk (above).

A CRISPR-based gene drive will share a trait relentlessly as long as the trait it’s sharing isn’t hugely detrimental for the organism (like a mosquito that can’t fly). With a good gene drive, you could replace 1% of the Anopheles mosquitoes with malaria-resistant mosquitos. Within a single year, malaria would be all but eliminated (saving roughly 1,000 children per day from malaria). The same goes for many other diseases, like Dengue and Yellow Fever. We’re still a few years away from this level of technology.

Scientists can also use Gene drives to eliminate invasive species by introducing a gene that only allows females to produce male offspring. so within few years, they can eliminate Asian carp from the Great Lakes or goats from the Galapagos – because there’d be no females left to reproduce. Luckily, this is far less likely to happen in slow-reproducing animals, like humans or elephants.

There are three main concerns with using gene drives to change the genetic makeup of a population:

1. Over-efficacy. Gene drives are so effective that an accidental release could change an entire species quickly. For example, if a few invasive species with the all-male gene drive made it back to their native habitat, they could wipe out the native population. A labratory escape could be catastrophic.
2. Gene Flow. Genes don’t just affect a single species – neighboring species often interbreed. This isn’t catastrophic if the gene you promote is relatively harmless to the species itself, like malaria resistance in mosquitos spreading to a different species of mosquito. Scientists eliminate invasive species using the all-male gene drive, could be devastating.
3. Malicious Use. Gene drives are shockingly easy to pull off – an undergraduate can handle the science. So far, scientists have been cautious and responsible with the science. But that might not always be true.

Luckily, it’s actually really difficult to create a CRISPR trait that is truly devastating – especially when something is attempting to control the behavior of an organism. It’s also relatively easy to create a “reverso-drive,” which in theory undoes the damage from the first gene drive.

Scientists are already working on regulations and creating gene drives that self-regulate and peter out after a few generations. But scientists and governments still need to discuss the risks and benefits – and who regulates gene drives that can fly or swim or otherwise migrate.

As Kahn points out at the end of her TED Talk on Gene Drives, “Humans have a tendency to assume that the safest option is to preserve the status quo. But that’s not always the case. Gene drives have risks, and those need to be discussed, but malaria exists now and kills 1,000 people a day. To combat it, we spray pesticides that do grave damage to other species, including amphibians and birds…. It can be frightening to act, but sometimes, not acting is worse.”

Gene drives, like GMs, are the sort of technology that can be very scary when poorly handled, unregulated, or misunderstood. Like GMs, they’re best assessed on a case-by-case basis. They have huge potential to help the world, if used properly.

Designer Babies, Eugenics, and More

It’s impossible to have a discussion on genetically modified organisms without bringing up designer babies. As with the rest of the discussions here, there’s a wide variety of technologies and implications for editing the human genome.

For example, it’s one thing to change the single gene that causes Huntington’s in an adult to cure a disease. It’s another to edit the genome of an unborn baby. It’s yet another thing to edit the genome in a way that those changes can pass on. This germline gene editing is probably the most controversial version of human gene editing.

The thing is that “designer babies” are already here. Many parents don’t like this term, as it implies a flippant or self-absorbed goal (like hair color or perfect pitch). But in vitro fertilization already allows parents to only implant embryos of babies that are healthy. If a parent is a carrier for a genetic disease, this is a way to ensure that only healthy babies are born.

But even this version of human gene editing, which is more of selection than editing, is controversial. At upwards of $20,000 for in vitro fertilization, this means that only wealthy couples can avoid expensive genetic diseases. Cost isn’t the only barrier, though. Couples may avoid IVF and embryo selection due to ethical, moral, geographic, or language barriers.

While pre-implantation selection might feel more morally acceptable for many of us, it’s not cut and dry, either. Is it more OK if the disease the parents are preventing is fatal and certain? What if the genetic disorder is painful, inconvenient, and uncertain rather than deadly and certain?

Embryo selection

it is also related to egg donor selection, where families can choose who the egg (or sperm) donor of their baby is based on desired traits. While this isn’t the same as “CRISPR-ing a baby,” it certainly falls into a similar category of wealthy people being able to select certain traits for their babies. In the words of Dr. David King, “Once you start creating a society in which rich people’s children get biological advantages over other children, basic notions of human equality go out the window.”

It doesn’t take much imagination to see potential risks with selecting or editing babies based on genetics.

Human germline editing is the heritable version of genetic engineering. Scientists can’t do this in humans yet for logistical and legal reasons, but it’s got the potential to eliminate a lot of terrible diseases thanks to CRISPR. While this may be something that’s desirable to prevent diseases, it’s also possible to use human germline editing for more superficial traits.

There’s a serious fear that germline editing will dehumanize children, leading parents to think of their children as things to create and control. Given how little we actually know about how genes interact with each other and the environment, even “good” changes could backfire if parents and children don’t have expectations that match up with reality. How would a parent feel if they engineered a child to excel at basketball, but that child loves piano? How would the child feel if they knew that?

That scenario is still far off – but it’s still worth discussing now.

All versions of genome editing are potentially slippery slopes towards eugenics, but the risk levels (and reward levels) are not uniform.

It’s important to separate the different levels of human gene-editing – from selecting which embryos to implant to making non-heritable changes to making fully heritable changes.

Genetics is still a young field. It’s entirely possible to accidentally change a gene other than the original target. It’s impossible to know how the changed genes will interact with the environment. Again, many scientists and ethicists alike urge caution and measured responses with genetic modifications.