We are in the midst of a gene-editing revolution.

For four decades, scientists have tinkered with our genes. Since the 1970s, they've experimentally switched them on and off, uncovering their functions; mapped their location within our genome; and even inserted or deleted them in animals, plants and human beings.

And in November 2018, aChinese scientist claimedto have created the world's first genetically modified human beings.

Though scientists have made great inroads into understanding human genetics, editing our genes has remained a complex process requiring imprecise, expensive technology, years of expertise and just a little luck, too.

In 2012, a pair of scientists developed a new tool to modify genes, reshaping the entire field of gene-editing forever: CRISPR. Often described as "a pair of molecular scissors," CRISPR is widely considered the most precise, most cost-effective and quickest way to edit genes. Its potential applications are far-reaching, affecting conservation, agriculture, drug development and how we might fight genetic diseases. It could even alter the entire gene pool of a species.

The field of CRISPR research is still remarkably young, yet we've already seen how it might be used to fight HIV infection, combat invasive species and destroy antibiotic-resistant bacteria. Many unknowns remain, however, including how CRISPR might damage DNA, leading to pathologies such as cancer.

Such a monumental leap in genetic engineering is full of complexities that ask big, often philosophical questions about science, ethics, how we conduct research and the future of humanity itself. With the confirmation that two human embryos were modified using CRISPR and carried to term, those questions have come sharply into focus. The future of gene-editing seemingly arrived overnight.

But what exactly is CRISPR and what are the outstanding concerns about such a powerful tool?

Let's break it all down.

CRISPR has the potential to be used in editing human embryos to create "designer babies."

Few predicted how important CRISPR would become for gene editing upon its discovery 30 years ago.

As early as 1987, researchers at Osaka University studying the function of Escherichia coli genes first noticed a set of short, repeated DNA sequences, but they didn't understand the significance.

Six years later, another microbiologist, Francisco Mojica, noted the sequences in a different single-celled organism, Haloferax mediterranei. The sequences kept appearing in other microbes and in 2002, the unusual DNA structures were given a name: Clustered regularly interspaced short palindromic repeats.

CRISPR.

Studying the sequences more intensely revealed that CRISPR forms an integral part of the "immune system" in bacteria, allowing them to fight off invading viruses. When a virus enters the bacteria, it fights back by cutting up the virus' DNA. This kills the virus and the bacteria stores some of the leftover DNA.

The leftover DNA is like a fingerprint, stored in the CRISPR database. If invaded again, the bacteria produce an enzyme called Cas9 that acts like a fingerprint scanner. Cas9 uses the CRISPR database to match the stored fingerprints with those of the new invader. If it can find a match, Cas9 is able to chop up the invading DNA.

Nature often provides great templates for technological advances. For instance, the nose of a Japanese bullet train is modeled on the kingfisher's beak because the latter is expertly "designed" by evolution to minimize noise as the bird dives into a stream to catch fish.

In a similar way, CRISPR/Cas9's ability to efficiently locate specific genetic sequences, and cut them, inspired a team of scientists to ask whether that ability could be mimicked for other purposes.

The answer would change gene editing forever.

In 2012, pioneering scientists Jennifer Doudna, from UC Berkeley, and Emmanuelle Charpentier, at Umea University Sweden, showed CRISPR could be hijacked and modified. Essentially, they'd turned CRISPR from a bacterial defense mechanism into a DNA-seeking missile strapped to a pair of molecular scissors. Their modified CRISPR system worked marvelously well, finding and cutting any gene they chose.

An illustration of the CRISPR-Cas9 gene editing complex. The Cas9 nuclease protein (white and green) uses a guide RNA (red) sequence to cut DNA (blue) at a complementary site.

Several research groups followed up on the original work, showing that the process was possible in yeast and cultured mouse and human cells.

The floodgates opened, and CRISPR research, which had long been the domain of molecular microbiologists, skyrocketed. The number of articles referencing CRISPR in preeminent research journal Nature has increased by over 6,000 percent between 2012 and 2018.

While other gene-editing tools are still in use, CRISPR provides a gigantic leap because of its precision and reliability. It's really good at finding genes and making accurate cuts. That allows genes to be cut out with ease, but it also provides an opportunity to paste new genes into the gap. Previous gene-editing tools could do this, too, but not with the ease that CRISPR can.

Another huge advantage CRISPR has over alternative gene-editing techniques is its expense. While previous techniques might cost a laboratory upward of $500 to edit a single gene, a CRISPR kit can do the same thing for under $100.

The CRISPR/Cas9 system has been adapted to enable gene editing in organisms including yeast, fungi, rice, tobacco, zebrafish, mice, dogs, rabbits, frogs, monkeys, mosquitoes and, of course, humans -- so its potential applications are enormous.

For research scientists, CRISPR is a tool that provides better, faster tinkering with genes, allowing them to create models of disease in human cell lines and mouse models with much higher proficiency. With better models of say, cancer, researchers are able to fully understand the pathology and how it develops, and that could lead to improved treatment options.

One particular leap in cancer therapy options is the genetic modification of T cells, a type of white blood cell that's critical for the human immune system. A Chinese clinical trial extracted T cells from patients, used CRISPR to delete a gene that usually acts as an immune system brake, and then reintroduced them into the patients in an effort to combat lung cancer. And that's just one of the many trials underway using CRISPR edited cells to fight particular types of cancer.

Beyond cancer, CRISPR has the potential to treat diseases caused by a mutation in a single gene, such as sickle cell anemia or Duchenne muscular dystrophy. Correcting a defective gene is known as gene therapy, and CRISPR is potentially the most powerful way to perform it. Using mouse models, researchers have demonstrated the efficacy of such treatments but human gene therapies using CRISPR remain untested.

Mosquitoes will be targeted using CRISPR gene drives, which could potentially drive malaria-carrying species to extinction.

Then there are CRISPR gene drives, which use CRISPR to guarantee a genetic trait will be passed from parent to offspring -- essentially rewriting the rules of inheritance. Guaranteeing certain genes will spread through a population provides an unprecedented opportunity to tackle mosquito-borne diseases such as malaria, enabling scientists to create infertile mosquitoes in the lab and release them in the wild to crash the population -- or even render a species extinct.

And CRISPR's potential benefits don't end there. The tool opens up new ways of creating antimicrobials to combat rising levels of antibiotic resistance, targeted manipulation of agricultural crops such as wheat to make them hardier or more nutritious, and, potentially, the ability to design human beings, gene by gene.

CRISPR may be the most precise way to cut DNA we've yet discovered, but it's not always perfect.

One of the chief barriers to getting CRISPR effectively working in humans is the risk of "off-target effects." When CRISPR is tasked with hunting down a gene, it sometimes finds genes that look very similar to its target and cuts them, too.

An unintended cut may cause mutations in other genes, leading to pathologies such as cancer, or it may have no effect at all -- but with safety a major concern, scientists will need to ensure CRISPR acts only on the gene it's intended to impact. This work has already begun, and several teams of researchers have tinkered with CRISPR/Cas9 to increase its specificity.

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To date, CRISPR work in humans has been confined to cells that don't pass on their genome to the next generation. But gene editing can also be used to edit embryos and thus, change the human gene pool. In 2015, an expert panel of CRISPR scientists suggested that such editing -- known as germline editing -- would be irresponsible until consensus can be reached on safety, efficacy, regulation and social concerns.

Still, research into germline editing has been occurring for several years. In 2017, scientists in the UK edited human embryos for the first time, and researchers in the US used CRISPR to correct a defective gene that causes heart disease. The ability to edit embryos begins to raise ethical concerns about so-called designer babies, wherein scientists may select beneficial genes to increase physical fitness, intelligence or muscle strength, creeping into the controversial waters of eugenics.

That particular future is likely a long way off -- but the era of editing the human genome has already begun.

On Nov. 25, 2018, Chinese scientist Jiankui He said he had created the world's first CRISPR babies. By using CRISPR, He was able to delete a gene known as CCR5. The modified embryos resulted in the birth of twin girls, known by the pseudonyms Lulu and Nana.

The scientific community widely condemned the research, criticizing He's lack of transparency and asking whether there was an unmet medical need for the two girls to receive such a modification. In the wake of the research, several high-profile researchers involved with CRISPR's creation even suggested a global moratorium on using the tool for germline editing.

Few would argue that He's work highlights a need for stricter regulatory controls and effective oversight of clinical trials in which embryos are edited. While He maintains his own experiment was concerned with improving the health of the twin girls by making them HIV-resistant, the experiment was deemed reckless and ethically wrong and the potential consequences overlooked. In January 2019, the Chinese government said that He acted both unlawfully and unethicallyand would face charges. He was later dismissed by his university.

Jiankui He claimed to have created the world's first gene-edited babies.

The most recent International Summit for Human Genome Editing, in November 2018, concluded, as it did in 2015, "the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at the time."

He's work, which remains unpublished, heralds the first clinical trial and birth of genetically modified human beings -- which means, whether it was the intention or not, a new era for CRISPR has begun.

We've already seen CRISPR transform the entire field of molecular biology -- and that effect has rippled across the biological and medical fields at lightning speed. In only six years, CRISPR went from an evolutionary adaptation in bacteria to a gene-editing tool that, potentially, created the very first genetically modified human beings.

As the revolution surges forward, the greatest challenges will lie in oversight and regulation of the technology, the technical hurdles that science must overcome to ensure it is precise and safe, and the larger societal concerns of tinkering with the stuff that makes us us.

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