The Genetic Revolution

 

Structuring the Topic 

Reading & Understanding the genome

  • Over the coming decades, developing our understanding of the human genome is absolutely vital. We in fact know far less about genetics and their role in shaping who we are, than what some commonly believe. 

Selecting the genome

  • The idea of gene selection, as opposed to editing, has far more potential than we commonly believe. It is possible that most of the medical developments in the coming decades will be in this space.

Editing the genome

  • In the last decade, we for the first time realised the potential to leverage CRISPR to edit human DNA. Although there are still many hurdles to overcome, both scientific and societal, we must approach the possibilities with an open mind.

Human vs Non-Human editing

  • We must be careful to focus too deeply on only human genetic editing. The opportunities presented by CRISPR reach far beyond this space. CRISPR can be leveraged to change an entire species through a gene drive, and is also allowing thousands of scientists to create better models of animal diseases hence improving the quality of their research.

Bioethical implications

  • The genetic revolution in all its forms will pose us with huge bioethical issues. The greatest issue to recognize is that no individual can opt out of the decisions that will be made. This is why it is so vital to have lively, and informed debates on genetics and what possibilities the future may bring.

Key issues and implications

Key Developments

  • 1850s – Gregor Mendel’s experiments on pea plants laid the foundation for modern genetics and the study of heredity.
  • 1953 – Two molecular biologists, Watson & Crick first propose the double helix structure of the DNA molecule.
  • 2003 – The completion of a 13 year long project called the Human Genome Project which for the first time mapped the base pairs that make up human DNA. The cost of the project was $3 billion. Today, companies such as 23andMe offer the same service for a few hundred dollars.
  • 2018, November 25 – He Jiankui announces the first successful human germ-line edit in two young girls, Lulu and Nana, laying the foundation for a new era of genetics.

Understanding the role of genetics

  • We know genes are important, but we do not know how important. There is no scientific consensus on the role of genetics in shaping us into who we are. 
  • Robert Plomin, arguably the world’s leading behavioural geneticist, argues that genetics plays a greater role than any other factor in shaping us as individuals. In his latest book, Blueprint, he presents over 30 years worth of research to back up his controversial argument. 
  • However, Carl Zimmer, one of the world’s best science journalists, uses historical and current scientific research to make a compelling argument that this is not the case. In his 2018 bestseller, She has her Mother’s Laugh he instead argues that we are shaped by a multitude of factors that we inherit beyond our genes.
  • Then there is the lesser known field of epigenetics, which seriously considers the impacts of how our genes interact with the environment, and how our genes may be expressed differently without an alteration of the genetic code.
  • Ultimately, the jury is still out on the magnitude of the role of genetics in shaping us who we are, which makes the development in this space over the coming decades all that more relevant for every other aspect of the genetic revolution that follows.

Selecting for desired genetics – In Vitro Fertilization (IVF)

  • Today
    • Currently, we already commonly do genetic selection. Through preimplanation genetic diagnosis (PGD), or preimplanation genetic screening (PGS), parents can already select for eye color, gender, and ensure embryos with single gene disorders are not implanted. This is becoming more common with a global average of 1.7% of births with Denmark Leading the pack at 10% of births through IVF.
    • It is crucial to acknowledge that one of the most attractive possibilities of CRISPR, the elimination of most single-gene disorders, can already be achieved via IVF today.
  • Future
    • The future of IVF can be seen both in terms of the number of embryos we select from and the power of the information we use to select.
    • Increasing the number of embryos
      • Jamie Metzl, the author of Hacking Darwin, has suggested that in the future, parents may be able to select from not only a few possible embryos, but up to 10,000.
      • In his book, The End of Sex, Hank Greely describes how the science for this is already available: increasing the number of embryos can be achieved by taking skin cells, inducing them into stem cells, the stem cells can then be induced into egg precursor cells, and then into eggs. This process can result in thousands of fertilized eggs, each of which after having grown for a few days can have their own DNA sequenced.
    • Improving the information we select on
      • After the DNA of these embryos are sequenced, they can have their information plotted for parents to select from. Parents may be able to select for higher likelihood of preferred personality traits or intelligence from a range of embryos. 
      • This selection will be based on what are known as Polygenic Scores, a 2018 break through technology, championed by behavioral geneticist Robert Plomin. A polygenic score, at its simplest level determines the probability of exhibiting a particular trait based on genetics. As computing power improves, our understanding of how genetics defines who we are will undoubtedly improve.
  • Implications
    • The implications of a couple paying thousands of dollars to pick the smartest embryo from an IVF dish are huge, and real. We likely will deal with the socio-economic implications of advanced IVF for decades before designer babies (via gene editing) are scientifically feasible and politically approved.
    • Who will have access to this technology? Should the government pay for anyone to have access to IVF? Could the widespread use of IVF with improving accuracy of polygenic scores result in a genotocracy?

Gene Editing with CRISPR

  • How can we edit our genes?
    • “CRISPR” (pronounced “crisper”) stands for Clustered Regularly Interspaced Short Palindromic Repeats, which are the hallmark of a bacterial defense system that forms the basis for CRISPR-Cas9 genome editing technology. For varying levels of explanation, we recommend this video. 

2019_08_01_Human_Genome_Editing_1406x2500

    • It was predicted that the first edit to cross this line (from somatic to germ line) would be in China, and this happened in 2018, when He Jiankui edited two young girls, Lulu and Nana, in order to make them immune to HIV. With the ruthlessness to continue advancing in this space, it is still to be determined what China does next.
  • Therapeutic versus enhancement gene edits
    • The second dimension on which edits are separated are between therapeutic and enhancements. At first site this line may seem clear, but after deeper thought it becomes clear that almost all considerations are in fact grey area. Is better eye sight therapeutic or enhancement? What about healthier bones? It is conceivable that for all traits there would be a benchmark, which if one was to be below, would be legally allowed to use genetic editing only up to that level. What would this level be and who would make this decision?
    • The chart below highlights the four types of genetic edits, with designer babies, the bottom right quadrant, being the most controversial but also the least likely.

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  • Scientific Advancement
    • In the coming years, scientists hope to have further developments in the gene editing space, including:
      • Improving accuracy and reduced off-target edits
      • Increasing the number of changes that can be made per genome
      • Increasing the efficiency of delivering CRISPR into cells
      • Developing precision based editing to allow edits of individual base pairs rather than editing entire DNA sequences 
  • Limitations to CRISPR
    • Complex traits
      • Most traits such as mathematical ability and impulse control are not single gene traits, but instead consist of thousands of small effects in the genome. We are are a long way from identifying all of these effects, and we are even further from being able to make all those edits without an error.
      • This means that in the foreseeable future selecting a partner or using genetic screening methods such as IVF are vastly more realistic.
      • Even if decades from now, we were to be able to identify all of these small effects, we would run into a hurdle – antagonistic pleiotropy. Pleiotropy is the concept that genes are related to several traits. Antagonistic pleiotropy, therefore is the concept that a gene that relates to one trait in a positive way, but another in a negative way. A good example would be ‘a common variant in the gene SLC39A8, for instance, decreases a person’s risk of developing hypertension and Parkinson’s disease, but increases their risk of developing schizophrenia, Crohn’s disease and obesity’. This has huge implications for the edits we may want to make in our child’s genetic make-up.

CRISPR Gene Drive

  • Solving Global Problems
    • As of 2020, gene drives are arguably a more powerful use of CRISPR for the foreseeable future, as it can tackle global problems such as malaria that result in over half a million deaths annually.
  • How does CRISPR gene drive work?
    • “A gene drive is a self-propagating mechanism by which a desired genetic variant can be spread through a population faster than traditional Mendelian inheritance.” 
    • In other words, if there is a trait we would, or would not, like to see in a particular species, a gene drive is able to drive this trait through a species very very quickly.
  • Why should we use gene drive?
    • As Kevin Esvelt from MIT, arguably the leader in the gene drive space, argues – “Our current civilization is not sustainable absent continuous advances.” He means that we need to explore and make use of these scientific discoveries, otherwise our current civilization may become unsustainable and collapse.
    • However, Esvelt also poses important questions on who gets to decide if and when these advances should be carried out, and these are certainly important questions to grapple with.

Regulation & Global Coordination

  • How should we think about regulation?
  • Natural Tendency to Lead
    • Countries naturally want to be leading in this space, as it will become arguably one of the most important fields of the 21st century and beyond. This importance creates an incentive for lack of regulation, and thus low standards.
      • In such a world, the country with the lowest standards (China in today’s world) would lead the way in setting the regulation other nations will inevitably follow. This would happen because of a simple fear of missing out (yes FOMO!) on the potential gains that are on offer from genetic enhancement of the population.
  • Genetic Tourism
    • In a world where some countries maintain what they would believe to be the ‘moral high ground’, it lays the foundation for genetic tourism. People could travel across the world for procedures or edits that are not legal at home.
    • Genetic tourism may pose challenging ethical dilemmas such as whether a citizen who exploits genetic tourism should be allowed to return home?
  • Future Regulation
    • What would it take for a country such as the United States to allow human germline editing? Would there have to be decades of clinical trials? 
    • How high would the success rate of a procedure need to be in order to be implemented? Even a 99% success rate would leave 1 out of every 100 children potentially disfigured. How would we grapple with this?

What are the ethical questions we will face?

  • Biological engineering, of almost any form, will pose some of the greatest ethical, philosophical and religious dilemmas we have ever faced. Some questions we would have to consider:
    • Should we be doing any genetic editing? Should we be ‘playing God’?
    • How will we track edited vs unedited people? Do you get labeled in your passport if you are edited? Does the extent of your edit get labeled? Will it be legal for edited and unedited individuals to reproduce together (particularly if they come from jurisdiction with differing laws)?
    • How do we think about the trade off of the tiny portion that will need germline editing (therapeutic) versus potential larger long term impact to society because of it? 

Argument Nuances

  • Dominant and Recessive Genes
    • When we learn basic biology in high school, we learn the standard Mendelian trait of dominant and recessive alleles. This is most commonly applied to eye color. This is not actually true. In fact, most traits do not work in this simplistic way and are in fact very complex, hence making the creation of designer babies substantially more difficult than we are led to believe.
  •  Designer Babies
    • Even if we were able to completely understand how complex traits come about, the interconnectedness of genes would make it incredibly complex to successfully make gene edits without adverse side-effects.
    • In particular, the mere possibility of antagonistic pleiotropy (addressed earlier), severely hinders the scientific feasibility for designer babies for the foreseeable future.
  • Gene Drive Dangers
    • Many who understand the potential of a gene drive to quickly spread a trait through a species worry about the revolutionary technology being used in a dangerous way. There are two reasons why this is not true:
      • Gene drives are only possible in sexually reproducing organisms, meaning that it has no potential in viruses or bacteria.
      • If a ‘malicious trait’ were driven through a sexually reproducing species, it could be undone, by driving the original gene(s) through in the same way, to create a one-for-one replacement on the malicious trait.

Potential Solutions

For this edition, we do not believe there is a list of potential solutions, but rather there are questions and dilemmas that need to be considered. Those questions have been raised throughout the toolkit and each person based on their own experiences, beliefs and culture may view them differently.

Further Reading

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