The field of human genetic engineering is on the brink of changing the world. But how did it get to this point, and what does the future hold? In her new series, Allegra Chatterjee delves into the past, present and future of genetic engineering. Part 2 explores the present capabilities of genetic engineering, and how it can be applied to human beings.
The dawn of the Genetic Revolution is upon us. Since the beginning of the new millennium the complete mapping of the human genome, dramatic reductions in DNA sequencing costs, and the development of powerful gene-editing technologies, have granted us novel abilities to manipulate our DNA, allowing us to make changes that would take millions of years to evolve in nature. In this article, we will explore how this unprecedented level of biological control is currently being wielded.
The promise of the Human Genome Project
The Human Genome Project, launched in 1990 and completed in 2003, promised to radically change the world. The world’s largest collaborative biological project, the HGP was carried out by more than twenty universities and research centres around the world, taking 13 years and costing around $2.7 billion. The complete code was announced by President Bill Clinton on 14 April 2003, who described it as “without a doubt… the most important, most wonderous map ever produced by humankind.”
Through identifying the many thousands of disease genes which litter the human genome, the complete transcribing of the three-billion-letter genetic code was expected to revolutionise the diagnosis, prevention and treatment of these diseases, leading to an era in which humankind would be free from all genetic maladies. Some even predicted the “evolution” of super-humans and the possibility of immortality.
However, in possibly the greatest scientific anti-climax of all time, for the first decade or so little changed. Why?
Among the many false predictions of what reading the genetic code would reveal, one of the most significant was the assumption that the majority of genetic diseases would be controlled by a single (or very few) easily identifiable genes. The hereditary nature of many disorders had been demonstrated for a long time through twin studies, which showed that identical twins (who share 100% of their DNA) are more likely to suffer from the same disorder than non-identical twins (who share only 50% of their DNA) if that disease is due to genetics. Optimists hoped that the HGP would elucidate the genes behind most, if not all, of these disorders, and this enhanced understanding would ultimately lead to the development of cures.
The true picture, however, turned out to be far more complex than even many of the world’s most esteemed scientists had anticipated. Few single-gene disorders were identified, and the genes for many of those that were had already been found in the pre-HGP era. The reality is that most diseases are due to hundreds or thousands of genes, each with tiny effects that are combined with the influence of environmental factors. To deliver the promise of the HGP, the complex web of genetic and environmental contributors to disease would need to be disentangled, and a way to safely and precisely edit disease-causing mutations from the genome would need to be developed.
Another barrier was the astronomical cost of DNA sequencing during the early 2000s, which prohibited the widespread experiments necessary to uncover more of the human genome’s mysteries. In 2003, the estimated cost for generating a second whole genome sequence using the then-available technologies was $50 million, but due to rapid advances in technology, the price soon began to plummet dramatically. Just three years later in 2006, this had halved to $20-25 million, and by 2016 it had dropped to $4,000. Today, sequencing a human genome costs less than $1,000, and a team from the Rady Children’s Institute for Genomic Medicine in San Diego recently set a new Guinness World Record for the fastest ever sequencing, delivering an analysis and interpretation of a genome in just 19.5 hours; a stark contrast to the 13 years and billions of dollars it took to produce the first sequence just 15 years ago.
The massive reductions in sequencing costs and increases in processing speed have led to the initiation of many large-scale sequencing projects, the most ambitious of which is arguably the 100,000 Genomes Project. The largest of its kind in the world, the project aims to sequence the genomes of NHS patients with cancer or rare diseases and their families, hoping to enhance understanding of the genetic basis of these diseases, and ultimately enable the development of better treatments that are tailored to individuals based on their genetic profile.
A promise fulfilled: CRISPR
Just under a decade after the completion of the Human Genome Project, a new discovery has begun to fulfil the promise it was unable to keep. Clustered Regularly Interspaced Palindromic Repeats and the CRISPR-associated protein 9 system (also known as CRISPR/Cas-9 or simply CRISPR), allows us to alter our DNA in ways never before possible outside the realm of science fiction.
Optimists expect CRISPR to lead to the eradication of many of the world’s most devastating and currently incurable diseases, as well as reducing the impacts of climate change and famine, improving the lives of millions across the world. Pessimists are predicting a future of ‘designer babies’, new forms of biological warfare, and the accidental creation of organisms which disrupt ecosystems by altering evolutionary balance that has taken millions of years to evolve.
How does CRISPR work?
‘Extremophiles’ are organisms that can survive in the harshest environments. In 2006 Jennifer Doudna, Professor of Chemistry and Biology at the University of California, Berkeley, became interested in one extremophile bacteria’s ability to survive in the water pools of old mine shafts, which are often very acidic and contain metal contaminants that would be toxic to most life.
Doudna found that the answer was CRISPR; short DNA sequences that the bacterial cells used to protect themselves. Doudna describes CRISPR as being like a “genetic vaccination card… a way that cells store information in the form of DNA from viruses to use in the future to protect cells if that virus should show up again in the cell.” Doudna and Emanuelle Charpentier, a researcher from Umea University in Sweden, later discovered that a protein called Cas9 is programmable by the cell, allowing bacteria to locate and destroy viral DNA by grabbing onto DNA and cutting it in that precise place like a pair of scissors.
When this ancient bacterial immune system is modified and transplanted into cells, the CRISPR-Cas9 complex can be used to introduce very precise changes to DNA. If a disease is caused by a mutation in a specific gene, or genes, a modified CRISPR-Cas9 complex can be modified and used to specifically edit the DNA in the defective gene, correcting the sequence and rendering the individual disease-free.
Gene editing in the pre-CRISPR era was a time-consuming, non-specific, and often unsuccessful process, and ‘treatment’ of genetic disorders was limited to mitigation of the symptoms rather than tackling the root genetic cause.
Over the past few years, there has been an explosion in the use of CRISPR. It has become ubiquitous in labs around the world, allowing never-before-possible experiments to be carried out in many fields including agriculture, microbiology, and human biology.
But what exactly is the most powerful gene-editing tool ever created being used for and what are the implications?
Among the thousands of applications for CRISPR, arguably the most significant is the potential to cure genetic diseases. Since the first CRISPR-edited human cells were created in the lab in 2013, the molecular complex has been used to edit human cells in working towards a cure for thousands of diseases around the world.
For example, a 2017 study carried out by the Oregon Health and Science University, showed that CRISPR was able to successfully eliminate the defective gene in embryos containing mutations responsible for Hypertrophic cardiomyopathy, a heart condition which causes a stiffening of the heart tissue, leading to host of symptoms including sudden cardiac arrest.
Similar studies in labs worldwide have demonstrated that it is not only scientifically feasible, but relatively cheap and easy, to permanently remove many disease causing mutations in human embryonic cells. Although not legal (at the moment), if these embryos were allowed to fully develop, CRISPR could theoretically be used to create adult humans free from disease. These people could then pass on the CRISPR-edited gene to their children, and all of their descendants, potentially creating thousands, or even millions, of genetically modified humans.
As well as editing embryos, CRISPR can be used for somatic-cell editing, which involves making changes to the DNA only in the body cells of a fully developed human, leaving the reproductive cells unedited. Right now, the world’s first human CRISPR trials in real patients are already underway in China to treat several types of cancer, and 2018 could be the first year in which CRISPR-based treatments are used on real patients in Europe and the US, as regulatory approvals have begun to be granted.
The company CRISPR Therapeutics plans to soon begin clinical trials to fix genetic mutations in people with beta thalassemia and sickle-cell anaemia, both of which are caused by inherited mutations in genes which make haemoglobin. Stem cells will be extracted from the bone marrow of patients, CRISPR edited, and then injected back into patients. Researchers at several other labs are also planning to begin CRISPR trials for other disorders including cancers, inherited blindness, and autoimmune, metabolic and neurodegenerative disorders as soon as 2019.
As well as human genetics, CRISPR has been used to create genetically modified extra-muscular beagles, malaria-free mosquitos, human organ-donor pigs, and plants which are nutritionally enhanced, climate-change and disease resistant… the list goes on and on. The USDA recently approved CRISPR-edited foods, and it is even being used to bring back the woolly mammoth through ‘de-extinction’.
But is CRISPR too good to be true?
Although ideal for treating monogenic disorders such as Hypertrophic cardiomyopathy, the polygenic nature of most diseases presents a major limitation in the ability of CRISPR to rid the world of all genetic maladies, as all contributing genes would need to be edited. Furthermore, as some genes are pleiotropic – having many apparently unrelated effects – editing a gene to reduce a negative effect may have unpredictable and dangerous consequences for other characteristics.
More worryingly, concerns have been raised about the specificity of CRISPR, and the potential for unintended changes to be made elsewhere in the genome. A 2017 Nature paper alleged that CRISPR led to 2,000 unexpected off-target mutations, and although this paper was later retracted, there are undeniably inherent risks associated with CRISPR, particularly when editing the germ-line (sperm and egg) cells that are inherited and have the potential to affect large numbers of people without their consent.
Perhaps with the outcomes of the first human CRISPR trials we will see history repeat itself, and science will be reminded of the lessons that should have been learnt from the death of Jesse Gelsinger less than two decades ago. Or perhaps the trials will be a success, with the researchers responsible heralded as pioneering scientific heroes, paving the way for the creation of cures for thousands of diseases.
The developments in genetics over the past 15 years have undeniably changed the world forever, and governments and lawmakers often struggle to keep up with challenges presented by such rapid advances. In the third article in the series, we will explore some of the legal and ethical pressures facing those trying to balance holding back the floodgates to mitigate the risks of untested treatments, without stifling scientific progress.
We will also delve into the weird and controversial world of self-proclaimed human guinea pigs known as ‘biohackers’, who are taking advantage of the simplicity and accessibility of CRISPR (and the lack of legal and regulatory clarity), giving us a glimpse of what the future of human genetic engineering may look like.
Read Part 1 here.
Allegra Chatterjee works for the NHS as part of their Graduate Management Training Scheme, with a specialism in Policy & Strategy. Her current placement is with the NHS Innovation Accelerator, an organisation dedicated to faster up-take and spread of evidence-based medical innovations for increased benefits for patients, staff and the population. Before this, Allegra graduated from UCL with a BSc and MSc in Natural Sciences, where she majored in Genetics and minored in Organic Chemistry.