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A CRISPR-Cas9 experiment being undertaken in Berlin, Germany

GIS Essay: GMO holds promise of a better future

  • Humans have engaged in genetic modification for millennia
  • Recent developments are more precise and predictable
  • New technologies could bring enormous benefit
  • Overregulation is holding back progress

The issue of genetically modified organisms, or GMOs, is a frequent topic in the news and often the subject of ill-informed controversy. Over four decades, regulatory policy in many countries has been misdirected and distorted by fruitless debates over what constitutes a GMO.

Throughout history, humans have continuously genetically modified, or improved, microorganisms, animals and crop plants through selection and breeding, to enhance their desirable characteristics. Sometimes, the modification of traits has been so drastic that the new varieties have been designated new species, as in those derived from the versatile Brassica oleracea, like broccoli, Brussels sprouts, cabbage, cauliflower, kale and kohlrabi.

To accomplish desired changes in phenotype (the traits of an organism resulting from the interaction of the genotype and the environment), scientists have invented increasingly sophisticated techniques, particularly since recognizing that all higher organisms have the same carrier of genetic information, the double-stranded helix of DNA.

In 1973, recombinant DNA technology was invented. Sometimes called gene-splicing, the process enables segments of DNA to be moved readily and precisely from one organism to another. Since that time, molecular genetic engineering techniques have become more sophisticated, precise and predictable than earlier methods. This evolution has now culminated in the most recent technologies, the CRISPR-Cas9 system and base editing.

Molecular genetic engineering techniques have become more sophisticated

CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) is a natural system that some bacteria use to defend themselves against invading viruses. CRISPR can identify specific DNA sequences, while the enzyme Cas9 cuts the DNA at the recognized sequence. 

Precise and predictable

Using CRISPR-Cas9, scientists can target and edit DNA at precise locations, deleting, inserting or modifying genes within the target organism. The method is cheaper, faster, easier, more precise and more predictable than its genetic engineering predecessors. Scientists are constantly improving the technique to reduce any unintended, “off-target” effects. (Off-target effects, some of which are discussed below, are routine and extremely common in older, pre-molecular techniques.)

The Royal Swedish Academy of Sciences recognized CRISPR-Cas9’s extraordinary potential by awarding the 2020 Nobel Prize in Chemistry to the technology’s codiscoverers, Professor Jennifer Doudna of the University of California, Berkeley, and Managing Director of the Max Planck Institute for the Science of Pathogens Emmanuelle Charpentier.

The findings of Dr. Charpentier and Dr. Doudna were only published in 2012, but since then CRISPR has been quickly adopted by research laboratories worldwide and is already being used in clinical trials. Many diseases are caused by defective genes and can be treated by replacing or repairing the faulty ones.

Dr. Jennifer Doudna and Dr. Emmanuelle Charpentier at the Breakthrough Prize Awards Ceremony in 2014
Dr. Jennifer Doudna (L) and Dr. Emmanuelle Charpentier coinvented the CRISPR-Cas9 technique, for which they won the 2020 Nobel Prize in Chemistry. Here they are pictured receiving the 2015 Breakthrough Prize Award in Life Sciences (source: Getty Images)
The company CRISPR Therapeutics (founded by Dr. Charpentier) is targeting beta thalassemia, an inherited blood disease in which the bone marrow does not produce enough healthy red blood cells. Clinical trials are underway. Beta thalassemia and sickle cell anemia, another genetic disorder of hemoglobin synthesis, have both been corrected in a clinical trial. Both diseases deplete oxygen-carrying hemoglobin molecules in the blood, and CRISPR disables a gene that, when active, shuts off the production of another form of hemoglobin.

A competitor, Editas Medicine (founded by Dr. Doudna, among others) is targeting Leber congenital amaurosis, a rare disease that causes severe vision loss at birth. Other diseases targeted by researchers include Duchenne muscular dystrophy, and AIDS.

Transformative treatments

This type of gene therapy, which is limited to treating genetic diseases in individual patients, has not engendered significant controversy. More controversial is germline gene editing – the editing of genes within eggs, sperm, or embryo cells, since those changes would be passed to future generations. Nevertheless, preclinical research using CRISPR to make germline modifications is advancing rapidly.

Correcting defective genes in human embryos has the potential to alleviate severe diseases. If allowed, such therapy would likely be as heavily regulated as new drugs, a field overseen by governmental agencies and ethics committees.

Another potentially revolutionary genetic engineering innovation almost ready for the clinic is xenotransplantation, the transplanting of animal organs into humans. Pig lines that have been gene edited to eliminate the antigens that cause rejection by the human recipient could be transformative. So far, experiments have proven promising, and there will likely be a day when xenotransplantation reduces the vast number of people on waiting lists for organs.

Critics of such applications of cutting-edge genetic techniques sometimes call for precautionary delays, but their objections often fail to assess the costs of not undertaking such therapeutic initiatives.

Unscientific regulation

The same shortsightedness can be seen when it comes to agricultural applications. Yet farmers and plant breeders have been selecting and hybridizing plants to enhance their desirable characteristics for millennia. Modern varieties of many crop plants such as corn, tomatoes and wheat now bear little resemblance to their ancestors.

The older, less precise, techniques have not elicited concerns from regulators

A common technique for creating new plant varieties, which originated about a century ago, is to subject seeds to radiation to scramble their DNA and create mutants, some of which may (and often do) exhibit desirable traits. Thousands of plant varieties that are consumed routinely – including lettuce, wheat, rice, oats and popular grapefruit types – were obtained this way.

Since the advent of molecular techniques – first, recombinant DNA technology and, more recently, CRISPR-Cas9, gene editing and so on – we can transfer or alter a single gene in a controlled manner. Yet, the older, less precise, less predictable techniques have not elicited concerns from regulators and activists, and are minimally regulated. On the other hand, those modified with the more precise and predictable molecular techniques are heavily regulated, sometimes to the point of extinction. A basic tenet of regulation – that the degree of oversight should be commensurate with the perceived risk – has been turned on its head.

The European Union’s regulation of new crop varieties is a case in point. The rules governing variations made with molecular techniques are onerous, unscientific and unpredictable. As a result, in 2020, only one such crop trait was planted in the EU, an insect-resistant maize grown in small amounts only in Spain and Portugal. It escaped the regulators’ guillotine only because it is essentially a legacy of the early days of crop approvals of genetically engineered varieties.

Corn being harvested in Illinois, in the U.S.
Most of the maize grown in the U.S. is genetically modified (source: Getty Images)
Worldwide, hundreds of varieties of dozens of species of crops modified with molecular genetic engineering techniques are being grown on more than 200 million hectares annually. In the U.S., most of the maize, cotton, canola and soy are varieties modified using such methods.

An EU Directive (2015/412) allows member states to restrict or ban the cultivation of GMOs in their territories for nonscientific reasons. Eighteen member states and Wallonia, in Belgium, invoked this opt-out to ban crops modified with molecular techniques. Before Brexit, Northern Ireland, Scotland and Wales did as well.

The coup de grace to the gene editing of crop plants was administered by a 2018 ruling of the Court of Justice of the European Union (CJEU), which found that innovations derived from the use of gene editing techniques are “to be considered the same as a GMO” and determined that only mutagenesis techniques that have “conventionally been used in a number of applications and have a long safety record are exempt” from the EU’s onerous GMO regulations. However, organisms made using mutagenesis or gene editing techniques developed after 2001 are not exempt from the GMO-regulation directive.

There is no reason to fear or overregulate innovations that are a clear improvement over their predecessors
There is a certain perverse consistency in that decision. In effect, it recognizes the seamless continuum among techniques for performing genetic modification, but then errs in subjecting only the most precise, predictable, and promising ones to an unscientific, dysfunctional, and costly regulatory regime. In November 2019, the Council of the EU requested that the European Commission submit a study, and a proposal if it were deemed appropriate, to address the legal status of novel genomic techniques under EU law. That should provide more clarity, if not more rationality, for the regulation of products of new techniques for genetic modification.

Moral imperative

The genetic engineering of plants can enhance crop yields and nutritional quality, increase resistance to pests, improve tolerance to drought and reduce insecticide use. The use of biofortified crops can have a significant impact, especially on people in the developing world who obtain most of their calories from a small number of subsistence crops that may be deficient in essential vitamins or minerals.

One example is “golden rice,” fortified with beta-carotene, the precursor of vitamin A. Consumption of these rice varieties can prevent vitamin A deficiency, which is common where people obtain most of their calories from traditional rice. Vitamin A deficiency is the leading cause of preventable blindness among children in developing countries. As many as 500,000 vitamin A-deficient children become blind each year, with half of them dying within 12 months of losing their sight.

A report from the Pontifical Academy of Sciences in 2010 concluded that it is a “moral imperative to make the benefits of [genetic engineering] technology available on a larger scale to poor and vulnerable populations … to raise their standards of living, improve their health and protect their environments.”

Molecular techniques such as CRISPR are the most advanced methods currently available to alter organisms for commercial and humanitarian purposes. They could improve the lives of millions of patients with currently untreatable diseases, combat hunger and malnourishment, protect the environment through decreased use of chemical insecticides and better land utilization, promote food security, and much more.

There is no reason to fear or overregulate innovations in medicine and agriculture that are a clear improvement over their predecessors. Policymakers and end users must include in their risk-analyses the risks and costs of not using new products, processes, and technologies. Science can help to show the way.

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