WEDNESDAY, 20 DECEMBER 2023A research group at Stanford University has sequenced the human genome in a record-breaking time of under 6 hours. Unbelievably, this is twice as fast as the previous record. Advancements in genomics are changing healthcare as we know it, for better or for worse. Welcome to the Genomic Revolution.
WHAT IS GENOME SEQUENCING?
Genome sequencing allows medical specialists to view the complete set of genetic material in an individual. Now, in as little as a few hours, genomic data is widely accessible and available. The information from the genome is instrumental in identifying rare inherited disorders, characterising mutations that drive cancer progression, and as evidenced by the recent pandemic, tracking disease outbreaks. The interpretation of genetic data requires high-throughput computational analysis which is often time-consuming, expensive, and subjective. Advancements in genomics have been critical for advancing scientific policy and have increased support for the open-sharing of scientific data. However, this has raised many ethical issues surrounding the use of genetic data, particularly in medicine. Who should have access to this data? What could the data incidentally reveal? And how do we communicate this information to patients?
A BRIEF HISTORY OF SEQUENCING
As incredible as it may seem, genome sequencing is a relatively new technology. It all began in 1977 when Frederick Sanger developed the first sequencing method and was awarded a Nobel Prize for his revolutionary work. The first DNA based genome was sequenced in the same year — the genome of a bacteriophage which infects E. coli.
Jumping to the year 2000, the full genomic sequence of the fruitfly was completed. In the same year, the first plant genome was also sequenced.
The launch of the 1990 Human Genome Project set out to sequence the entire genome of humans, and 15 years later established the first ‘complete’ human genome.
Following this, the HapMap Project in 2005 aimed to describe common patterns of human sequence variation, a major stepping stone for large-scale human genome projects such as the 1000 Genome Project.
2009 saw an explosion of new computational tools. Increasing affordability and accessibility to genome sequencing meant that new tools to accommodate the requirements of large-scale genomic projects were required.
The 100,000 Genome Project was the next major stepping stone, a UK initiative to sequence and study the roles of genes in health and disease. The research and analysis of this initiative is still ongoing. Most recently, the Newborn Genomes Programme was introduced. It aims to explore how, and when, offering whole genome sequencing to newborns is appropriate.
Here, we will focus on two important examples of genomic sequences by looking back and reflecting on the aims and outcomes of the Human Genome Project, and looking forward to see how the Newborn Genomes Programme may change the future of healthcare.
GENOME SEQUENCING: ITS PROMISES
THE HUMAN GENOME PROJECT
It is difficult to attend any biological lecture or read any textbook without the Human Genome Project being mentioned in some capacity. In many ways, it has allowed us to gain a complete understanding of the human genome, remarkably reducing the basis of our existence to a sequence of letters on a page. But is our understanding really complete? Although labs all over the world have access to the human genome at their fingertips, each breakthrough presents us with further unanswered questions and reveals an additional layer of complexity.
The Human Genome Project was set up in 1990 with the initial promise of decoding the human genome down to its sequence of base pairs and annotating the genes. It is clear that the scientists involved in the project, and those who funded it, believed that the success of this project would be a momentous step in modern biology and would have an impact on many disciplines, from physiology and medicine to pharmaceutical design. There was also a great amount of excitement from the media and general public about how we would be able to read the secrets of our own lives in an accessible way. Many thought that this project promised to decode the base sequence of our genome and, in doing so, promised to easily identify all disease causing genes, find genes that set humans apart from other great apes, and explain every aspect of our phenotype. It is difficult in hindsight to distinguish between what the scientists ‘promised’ and what the media and general public expected.
The first draft of the human genome project was published in 2003. For many scientists working in the field today, having access to the human genome is as vital to the lab as test tubes and petri dishes. Because of the Human Genome Project, geneticists have a reference genome that they can compare to the genomes of other humans to identify areas of variation, and use to find similarities and differences between our own DNA, and the DNA of other species. The Human Genome Project was a landmark project in many other ways, not least for its public data publishing and the collaboration between multiple labs working towards a common goal.
The data collected from the Human Genome Project has had a significant impact, in the field of genetics and beyond. This is seen both in its direct use and indirectly in subsequent projects that have used similar or adapted experimental techniques. The Human Genome Project has revealed a lot in terms of our past evolution and relationships to other organisms in the evolutionary tree of life. We have been able to disprove suggestions that the more DNA an organism has, the more complex it is — this is the concept of the so-called ‘C-value enigma’. For example, humans and mice have a similar number of genes while some plants, like corn, have many more genes than we do. Through careful analysis of the Human Genome Project data and the 1000 Genomes initiative, we have been able to identify SNPs or small non-coding polymorphisms. These are bases that are different in different people, for example, 80% of a population may have an A nucleotide at a specific position while the other 20% have a C.
HAVE THE PROMISES OF THE HUMAN GENOME PROJECT BEEN FULFILLED?
The Human Genome Project made many claims during its initial stages about its possible future impact on the biosciences and many of these have stood the test of time. However, almost 20 years on from its completion, we must reflect and ask if all these promises have been met. It is very clear that to know the nucleotide sequence of the human genome is to know the human blueprint. But, in the same way a script can only tell us so much about the final film, the base sequence is not the whole story.
The genome is not simply a string of letters to be read chronologically. In reality, DNA is highly compacted through the involvement of histone proteins and nuclear scaffolds. Some parts are highly repressed and are not actively transcribed while other parts are more accessible to the transcription machinery. The more accessible a gene is, the higher the rate of transcription will be. It should be noted that, for a large proportion of the genome, its state of compaction is dynamic and dependent on the immediate needs of the cell. In contrast, genes that are not needed by a cell (for example, liver enzymes in a muscle cell) may be entirely and almost irreversibly repressed. The fact that a neuron, epithelial cell, and muscle cell are so disparate in structure and role while containing the same genetic information proves that knowing the underlying blueprint is limited in its ability to determine how a cell and organism will look and function.
Epigenetics is currently a very fashionable area of research and one that, arguably, is deserving of the attention it attracts. Epigenetic modifications refer to heritable changes to the genome that do not alter the underlying base sequence (and were therefore not sequenced as part of the Human Genome Project). This could be the addition of chemical groups, such as an acetyl group, to histone proteins, or the addition of a methyl group to cytosine nucleotides in the DNA sequence. These modifications can alter how accessible the DNA is and therefore alter gene expression. When we ask seemingly simple questions like ‘why do genetically identical twins who grew up in the same environment develop different diseases?’, we confirm the nucleotide sequence cannot possibly be the whole story. It is probable that epigenetic divergence plays a part in the different phenotypes of genetically identical individuals.
Even if we briefly ignore the issues that gene expression presents, why is it that we have not been able to clearly identify all the genes in the genome and match gene sequence to function? It is clear this process is not as simple as one might have predicted when the Human Genome Project began. Less than 1.5% of the human genome codes for proteins meaning they must be searched for amongst a desert of non-coding sections of DNA. Introns are non-coding regions of genes that are removed from mRNA transcripts by splicing. They appear frequently and can be up to 200 Kb long. To add a layer of further complexity, the term ‘gene’ is actually very difficult to define. Genes can be nested in other genes by being located in an intron. In addition, a ‘gene’ can encode different proteins if the transcript is post-transcriptionally modified in different ways — this is known as differential splicing. Simply knowing the sequence of A,T,G, and C nucleotides is of limited value without an understanding of the proteins they encode and the regulation of their transcription. However, there have been many advancements in transcriptomics (the analysis of the mRNA transcribed from the DNA sequence) through experimental techniques such as microarrays, for which the sequencing of the human genome was necessary for its creation. It cannot be denied that sequencing the human genome was a crucial step in understanding our genetics and was a necessary foundation for subsequent advancements in both knowledge and technology.
We must be aware when discussing the ‘success’ of the original Human Genome Project that the media greatly exaggerated the claims of the scientists involved. The project was fundamentally a success as it succeeded in completing its primary goal — to sequence the human genome. The notion that the Human Genome Project would revolutionise the biosciences did not come from geneticists but rather the journalists of the time. The difficulty in understanding the complexities of the decoded genome could not have been predicted at the outset of the project. Perhaps presenting unanswered questions and lines of further research is as valuable as giving direct insights.
NEWBORN GENOMES PROGRAMME
Fast-forward to 2021, a public dialogue on the use of whole genome sequencing in newborn screening was released. The dialogue’s main findings are summarised below. The recent Newborn Genomes Programme aims to utilise whole genome sequencing in newborns to expand screening from the current nine conditions offered to many more rare diseases.
Professional guidance and advice on whole genome sequencing of seriously ill infants is conflicting. This creates wide-spread controversy on whether the new screening programme is considered acceptable or not. The British Society for Genetic Medicine believes that testing the whole genome is unlikely to be controversial when testing aids immediate medical management. Conversely, the European Society of Human Genetics believe it is preferable to use a targeted screening approach (such as targeting specific genes) to avoid unsolicited or uninterpretable findings. If a reliable method to detect a serious genetic disorder earlier exists, is it not our responsibility to use it? The professional moral imperative of beneficence — doing good to others, including moral obligation — would have you believe so. However, overwhelming patients with complicated genetic results, riddled with uncertainties, may hinder the professional duty of nonmaleficence — to do no harm. The European Society of Human Genetics raises valid concerns regarding potential incidental findings. Whole genome sequencing of newborn babies may reveal unexpected abnormalities, and this raises questions on how, or even if, we report these findings. Despite initial reservations, the design of Genomics England Newborn Genomes Programme is currently underway.
The programme broadly aims to identify rare diseases in babies; to understand how genomic data could be used to improve knowledge and treatments; and to explore the potential risk and benefits of storing an individual's genome over their lifetime. If successful, the programme could provide early diagnosis for childhood-onset rare genetic conditions. In theory, this is a no-brainer. Improving diagnosis and immediate care for infants whilst building a comprehensive genomic database to inform research and knowledge; what could go wrong? In reality, our understanding of the genome is far from perfect and whole genome sequencing in newborns raises many questions. Who will be affected by whole genome sequencing? What information will be shared to patients and to big data sources? And what are the implications for wider society?
A summary of the public dialogue from the Newborn Genome Programme
1) It would be acceptable to use Whole Genome Sequencing (WGS) to identify a wider set of conditions than current NHS newborn screening programmes provided:
- The condition impacts infants in early childhood.
- Treatments and/or interventions are available to cure, prevent or slow progression of the conditions.
2) Genetic Counselling and Mental health support must be available to those who receive a diagnosis.
3) A comprehensive genetic database should be established so ethnic minority backgrounds are not disadvantaged by receiving more uncertain or less accurate diagnoses.
4) The complexities of WGS must be recognised during the design of the consent process. Including:
- Implications of WGS for the wider family.
- That parents consent on behalf of children, but the children may have different views when they grow up.
- The screening tests have the potential to look for more conditions than current newborn screening.
GENOME SEQUENCING: ITS IMPACT
THE HUMAN GENOME PROJECT
Having a reference genome available and being able to sequence an individual’s personalised genome is now very important in healthcare, particularly in treating conditions such as cancer. For example, in certain breast and ovarian cancers there is a mutation in the BRCA1 gene and these patients respond particularly well to specific drugs. In individuals with a mutation in a different gene, this targeted therapy will not work. Introducing more targeted gene therapies for conditions like cancer, where alternative treatments are highly invasive and have many side effects, would be a significant step for cancer research and biomedicine as a whole.
Genetic sequencing technologies have been extended in recent years to more commercial ventures such as home testing DNA kits made by companies like Ancestry or 23andMe. This allows people to understand and explore their heritage in more detail than we could have imagined 50 years ago. The same goes for DNA sequencing tests that allow people to be reunited with family or confirm their biological relatives. This personalised genome sequencing can have a huge impact on an individual’s life and means we now live in a society where relationships can be scientifically confirmed.
Sequencing an individual’s genome has never been quicker or cheaper. In the not-too-distant-future, it seems genomes will be sequenced at birth and personalised medicine tailored to each individual’s genes may be the norm. This could help us identify people who are at risk or predisposed to certain diseases or conditions and potentially offer preventative medicines, advice, or more regular check-ups. However, we must be wary about advancements of this kind. Will this information be available to health insurance providers and healthcare professionals? It seems that in the digital age we live in today, discrimination and prejudices based on a person’s genome could become a devastating reality. Will biological information, like other forms of private data, be protected? The issue of privacy and data protection is very important to any discussion relating to genome sequencing and is something that is already a cause for concern with the DNA commercial testing kits. As technology becomes more advanced and valuable data is stored at such a large scale, can we ever be sure this intimate information will stay private?
To go one step further, editing the genome seems like the stuff of science fiction but the technology is readily available to scientists today. Nobel Prize-winning CRISPR gene knockout technology has been used in experiments for many years now and has proved to be extremely useful. But, will the widespread use of similar technology on humans be a good thing? Genetic therapies could prevent fatal and debilitating conditions being passed onto the next generation but, despite the potential benefits, we seem to be at risk of tumbling down a steep slope of ethical concerns surrounding the commercial use of this technology. We must not disregard the very real risk of data misinterpretation if it fell into the wrong hands that could lead to catastrophic repercussions throughout society, including the risk of a resurgence in eugenics. Such outcomes could not be predicted at this stage. We may look back on these early stages of genomic editing in hindsight and wonder how we did not see these problems coming. Would you want your genome sequenced?
NEWBORN GENOMES PROGRAMME
The Newborn Genomes programme may result in whole genome sequencing being routinely available at birth. Although titled ‘Newborn Genomes Programme’, the results of the initiative will not be limited to affecting newborns. The programme may improve immediate health benefits of seriously ill newborns such as earlier detection and improved care management, however potential harms should also be considered. Due to the complexity of classifying whether a variant is harmful or not, false positives may arise through whole genome sequencing. Another aspect to consider is if information regarding future disease risk is revealed. The so-called ‘Angelina Jolie Effect’ significantly increased the testing of BRCA1 and BRCA2 mutations in women. This resulted in more women opting for preventative treatments to reduce their risk of developing breast cancer. However the difference between these women and newborns is blatant — these women chose to test. If the same mutations are detected in newborns, a child’s right to make their own choices about accessing this information must be considered. A child’s right to an open future should be factored into the design of the programme. Using whole genome sequencing to look opportunistically for a broad range of conditions is generally considered unacceptable in the medical community, but incidental findings may be unavoidable.
Whole genome sequencing also affects parents. Parents may feel entitled to the genetic information of their child, particularly if it reveals information relevant to their own health. The complexity of interpreting genetic information may lead to many uncertainties which, if reported, may overwhelm parents. This may also influence how the child is raised. Other family members may also be interested in knowing information relevant to their health. This creates another question for healthcare professionals — what information from whole genome sequencing should be disclosed to parents of newborns?
Grey areas exist in determining who should access genetic information. Communication of genetic information has been recently classified as belonging to the family rather than the individual — but patient confidentiality still exists. Knowing when to share information, even beyond the wishes of the patient, is not standardised and is assessed on a case-by-case basis. The new programme may over-burden healthcare professionals. Another potential harm is that not all healthcare professionals are trained in genomics. They might not understand the limitations of whole genome sequencing, nor be able to adequately interpret or deliver results. There are many potential benefits and costs of whole genome sequencing in newborns. Increased uptake of genome sequencing could lead to the creation of a more balanced, population wide genome database. Due to the historical imbalance in funding across many scientific disciplines, the genomic databases currently available to researchers are almost entirely representative of the genomes of White Europeans. Whole genome sequencing at birth may help to bridge the gap for minority populations, creating a more comprehensive database. Tackling the discrimination and exclusion within current databases may lead to increased diagnosis in minor ethnic populations. Something to consider is the potential effects on public attitudes towards genetic variation. Major scrutiny has been passed over Iceland’s recent near elimination of Down Syndrome. Since prenatal testing was introduced, close to 100% of women who received a positive test for Down Syndrome terminated their pregnancy. It has been suggested that population genome screening should not be approved until we have tackled negative societal attitudes experienced by those with genetic conditions.
This brief overview of ethical issues of genome sequencing in infants is not exhaustive but only presents a handful of important implications to consider. The potential benefits of the Newborn Genomes Programme has also been briefly explored. Although the major benefits of the programme are evident, the potential issues raised are challenging and not easily tackled. Whether the design team for the Newborn Genomes Programme will address all of these issues is yet to be determined. The sequenced human genome is now a vital tool of any genetic or epigenetic research lab. While the Human Genome Project may not have provided us with an answer to every question, it did provide us with a necessary starting point for further experiments and progress in understanding the secrets of the genome. Whole genome sequencing has an incredible potential to improve healthcare for everyone, hence why sequencing genomes at birth is being explored. However the societal and ethical consequences of the Newborn Genomes Programme are not yet known. How genomic data will be stored, shared, and utilised requires further public consideration. There is an ongoing debate around whether genome sequencing at birth is a step in the right direction and the benefits and harms of the screening programme should be continuously weighed. What is clear, however, is that the Genomic Revolution is well and truly underway.
Rachel Duke is a Second Year Biological Natural Sciences student at St Catharine's College. Her interests lie in developmental biology and how genetic and epigenetic systems influence the physiology of an organism. For this article she focuses on the Human Genome Project. Merissa Hickman, MPhil in Genomic Medicine at Murray Edwards College, University of Cambridge is particularly interested in the ethical implications of Genomic Medicine, here she focuses on the Newborn Genomes programme. Artwork by Sumit Sen.