Tag Archives: Human genomics

Record approvals of new cancer drugs – what is the role of genomics?

Post by Matt Wasmuth, a postgraduate student at the University of Edinburgh. This post is adapted from work conducted as part of the ‘Biobusiness’ course.

Image of prescription drugs, produced by J. Troha, source National Cancer Institute. Reproduced under a Creative Commons Attribution-Share Alike 4.0 International license. Available online at: https://commons.wikimedia.org/wiki/File:Prescription_drugs.jpg

Over the last decade, the number of new cancer patients in the United States has grown from 1.5 million per year to a projected 1.9 million for 2020. This has also resulted in an increase in spending on cancer treatment. This trend is not just restricted to the US. Global spending on cancer treatment is expected to reach $200 Billion by 2022, constituting 14% of total medical expenditure. This spending has paralleled the unprecedented number of drugs being approved for the treatment of cancer. Here I discuss some key changes within the oncology drug market over the last 10 years and assess the extent to which genomics has altered the dynamics of drug discovery.

Approval rates of cancer drugs continue to rise with an increase from 13% to 17% of novel drugs treatments from 2015 to 2019. What has stimulated this rise? The story begins with Richard Nixon signing the National Cancer Act in 1971, which led to increased funding directed towards oncology through the National Institutes of Health. The research that followed led to the recognition that cancer is not just one disease, but a collection of many – sometimes rare – diseases stemming from one or more genetic mutations. Due to the much smaller markets for treatment, rare diseases attract less investment into the development of potential drug therapies. To ameliorate this, The Orphan Drug Designation Program (ODDP) within the Food and Drug Administration (FDA) was established in 1983. The program aims to advance the development of products that demonstrate promise for the treatment or diagnosis of rare diseases by providing incentives for sponsors. The National Organization for Rare Disorders (NORD), originally spearheaded by patient groups affected by more widely-known disorders such as Huntington’s disease and severe combined immunodeficiency (SCID), gave the necessary impetus for the Act to take shape. Whilst members of these advocacy groups benefitted hugely from the research and products that arose from this movement, so did companies and research groups who develop cancer treatments. With more than 200 kinds of cancer now recognised, most potential treatments for rare cancers (those affecting 1/200,000) are eligible for the program. This also explains why the largest category of these un-profitable ‘orphan’ approved drugs is oncology. As of 2019, 21 out of 44 products approved were orphan drugs.

Figures on R&D spending in the pharmaceutical industry overall have not generally been matched by an equivalent rise in the rate of approvals, especially within Europe. Approvals within the oncology market buck the trend. This may be for a variety of reasons. One is that, as the genetic basis for various cancers become known, treatments have become more targeted. Indeed, they are now often approved with a companion diagnostic test that detects the genetic basis of the cancer.

Clinical trials are then optimised and designed for trial populations in which the genetics of the cancer has been characterised. Smaller patient numbers for rare diseases pose a challenge for clinical trial recruitment and for ensuring that the trials are statistically valid. However, novel clinical trial designs are being explored. For instance, predictive probability is employed to select patients most likely to benefit from treatment, based on their biomarker signatures. In cancer where time is a crucial factor, rather than using clinical end-points (remission rates), adaptive trial designs employ surrogate end-points (such as evidence of tumour shrinkage) or the detection of biomarkers such as HER2 gene overexpression, which is a feature in breast cancer, which exploit the relationship between the severity of the disease and response to treatment. These types of designs often allow for trials to be smaller and for decisions to be made faster.

A collaboration between the European Medicines Agency and the FDA launched in 2009. The product, a standardised application form concerning drugs wishing to enter both markets, yielded reduced approval times and as this approach becomes more refined will continue to do so. The UK government is aiming for regulation to take a more “streamlined, internationally competitive approach” in areas such as clinical trials resulting in further improved approval rates as well as encouraging the use of techniques such as genome editing by CRISPR-Cas9. Genome editing may make it possible to accurately modify the genome to provide a better understanding of cancer biology, highlight potential druggable targets and present a method of synthesising the drugs for these targets in cell factories.

Figure 1: Number of drugs new drugs approved from 1993-2019. Adapted from Mullard, 2020.

Significant developments in the treatment of cancer are not new. Radiotherapy was introduced in the 1900s, and chemotherapy in the 1940s. The next jump with targeted treatments such as monoclonal antibodies and Tyrosine Kinase Inhibitors in the 1980s was a more profound change, shaping the policy and regulatory landscape. Research efforts towards studying the genetics of cancer that began in the 1980s and the genomics of cancer from the 2000s are now bearing fruit, which is reflected in the spike we see in approvals for targeted treatments over the last three years (Figure 1). From the 1980s onwards, oncologists came to understand cancer as a molecular genetic disease by cataloguing different types of mutations found in tumours. These included mutations of the p53 gene, which implicated in cell cycle control and apoptosis, and therefore tumour suppression when active, and the development of tumours when inactivated. Genomic studies of the DNA sequences of particular tumours has enabled better-tailored treatments and also allowed the further stratification of cancer into the individual rare diseases that we know today.

However, the undoubted impact of genetics and genomics on diagnosis and treatment should not lead us to ignore the ongoing salience of monoclonal antibodies, immune proteins that can be designed to selectively attack cancer cells.

Due to the specificity of their targeting of cancer cells, in contrast with radiotherapeutic and chemotherapeutic approaches, monoclonal antibody therapy has taken off over the last decade and is expected to increase further not only as a cancer treatment but also in treating numerous other diseases (Table 1). Recently, antibody-drug conjugates that combine the specificity of an antibody with a cytotoxic (cell-killing) drug compound have been developed to target cancer cells. CAR-T cell therapy (Chimeric Antigen Receptor T cells) involves editing the genome of T cells, immune cells that kill other cells, to enable them to detect specific molecular markers (antigens) on the surface of cancer cells. This causes the T cells to attack those cells with high specificity (Mullard, 2020).

The limitations of particular immunological approaches such as monoclonal antibody therapy have not restricted its growth in all classes of drugs, including oncological. Methods such as genome editing are helping to further improve the specificity and effectiveness of immunological approaches. But genomics has also made its own distinctive contribution. It has enabled the stratification of cancer into multiple rare diseases that has been incentivised by the advantages of orphan drug designation. And it contributes towards the identification of new therapeutic targets, such as this one paper alone highlighting 5 novel gene targets from whole genome sequencing of over 500 patients.


Genetic results – to know, or not to know?

Blog post by Shona Kerr, Project Manager of the Quantitative Traits in Health and Disease group at the MRC Human Genetics Unit, University of Edinburgh. She is also Associate Director of the Edinburgh Clinical Research Facility Genetics Core.

Ever since the hype associated with the announcement of the completion of the Human Genome Project in 2003, a “genomics revolution” in healthcare has been promised. Following a decade or so in which evidence of benefits in mainstream medicine has remained elusive, in the past couple of years the speciality of “genomic medicine” has increasingly lived up to the promises made. This is due to a range of factors coming together in a way that is of enormous economic, cultural and societal importance. Chief amongst these are the implementation of efforts (with significant public funding) in many locations worldwide to embed genomics in healthcare systems, exemplified by Geisinger MyCode. They also include the increased availability (and sharing) of research and clinical genomic data internationally, as championed by the Global Alliance for Genomics and Health (GA4GH). Finally, data on millions of members of the general population has been generated by direct-to-consumer genetic testing companies such as 23andMe and Ancestry.com.


Consumer genetic testing kit from 23andme. Image by Hanno Böck, reproduced from original source under Creative Commons licence.

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The HeLa Cell Controversy In The Genomics Era

Blog post by Robert Eppley. See the video here for more information about the origins of the post. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License


Road marker commemorating Henrietta Lacks. Photograph taken by ‘Emw’. Reproduced under a GNU Free Documentation License license. Available online at: https://upload.wikimedia.org/wikipedia/commons/7/72/Henrietta_Lacks_historical_marker%3B_Clover%2C_VA%3B_2013-07-14.JPG

The HeLa cell line, established in late 1951, is the oldest immortal human cell line. For over 60 years, the HeLa cell lineage has been propagated countless times and played a critical role in the development of vaccines, such as the one to combat Polio. The circumstances under which these cells were obtained from their originator Henrietta Lacks, and the manner in which those cells were monetised, has become a well-known controversy. In this post, I explore how problematic use of the HeLa cells did not stop in the 1950s, but continued into the recent genomics era.

On 1st February, 1951, Henrietta Lacks reported to Johns Hopkins Gynecology Clinic and received a cervical cancer diagnosis. After a failed series of radiation therapy, Henrietta’s cancer spread rapidly and she was pronounced dead on 4th October, 1951. There is no evidence that Henrietta nor her family had knowingly consented to having her cervical cancer cells used for study. Despite this, her cells were collected from tissue samples in Dr. George O. Gey’s Johns Hopkins laboratory. Dr. Gey and his colleagues found Henrietta’s cells to be remarkably effective and efficient at rapid proliferation, and dubbed the cell line “HeLa” as a contraction of the name Henrietta Lacks.

At the time, the only other successful immortal cell line in existence was that of a mouse named L929, which had been successfully produced in 1943. Ironically though, Henrietta’s identity was not as well sustained alongside the cell line as the mouse’s had been, and her name was often mis-referenced to various pseudonyms like “Harriet Lane”. One philosophical scientific perspective posits that Henrietta “has achieved a kind of corporeal immortality through her eponymous cell line,” an immortality that supporters of the Lacks family might argue has allowed a scientific field to possess ownership over and reap benefits from a woman without her consent.

As of 2013, more than 74,000 laboratory studies had used HeLa cells in their procedures. Despite the lack of consent from Henrietta and her family, the Lacks family had, until 2013, received no control over the use of Henrietta’s cells nor major acknowledgment from either Johns Hopkins or any other major research institute that had aided in the commodification of Henrietta’s cervical cancer cells.

Indeed, though Henrietta had died in 1951, it was not until 22 years later – 1973 – that the Lacks family was even notified of the HeLa lineage. In this year, a lab group notified the Lacks family of the HeLa cell line while pursuing familial blood cells to investigate conserved genomic elements in the Lacks family. Following this contact, the Lacks family had trouble accessing more information about the use of their mother’s cervical cancer cells.


The European Molecular Biology Laboratory at Heidelberg. Photograph by ‘Albrecht62’, reproduced here under the Creative Commons Attribution-Share Alike 4.0 International license. Available online at: https://upload.wikimedia.org/wikipedia/commons/8/86/EMBL_au%C3%9Fen.png

A more recent event in the series of HeLa cell controversies came in 2013 when the European Molecular Biology Laboratory (EMBL) published the full genome sequence of the cells in full. The EMBL decision was ethically questionable in a number of ways. Because of the potential implications of a full genome analysis – the potential for it to harbour information indicative of unknown genetic predispositions, for example – the typical procedure for release is one which ensures consent on all parties that may be psychologically affected by the information.

As a result of the EMBL full genome analysis, the HeLa cell line was made more versatile as a component of lab research. Furthermore, the addition of this resource likely enhanced the quality of future HeLa-based research by uncovering previously unknown and abnormal factors about the cell line. In addition, the EMBL claims that the study ultimately highlights the vast number of differences that can be identified between a cell line and another given human reference. Perhaps the EMBL felt that the scientific importance of the study to the biological field was great enough to outweigh the potential deleterious effects it may have on the Lacks family.

Final closure of the public controversy came in the same year, when the United States National Institutes of Health (NIH) and the Lacks family reached a compromise, ultimately allowing the NIH to store the HeLa genome in a controlled-access database for researchers to use, rather than having open and public access to it.

The newer controversy of the sequencing of the DNA of HeLa has stimulated debate on the role of access to genomic data and privacy. However, the NIH has stressed that the agreement with the Lacks family and the solution adopted was tailored specifically to the sequence of the HeLa cells, and did not set a “precedent” beyond that. How privacy and openness is managed in genomics research involving human subjects is a matter that is far from closed.


Sources used:

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The Canadian chapter of the history of human genomics

Post by Miguel Garcia-Sancho, Principal Investigator of the TRANSGENE project and lead investigator of the human genome strand.

In April, I travelled to Toronto, Canada, to conduct historical research into one of the less well-known facets of early human genome research. The reason for visiting Toronto was that the Hospital for Sick Children features as one of the most densely connected institutions in the network visualisations that the TRANSGENE team is now analysing. These visualisations reflect co-authorship relations in articles that describe for the first time new human, pig and yeast DNA sequences in the scientific literature. Finding a Canadian institution in such a prominent role was somehow a surprise. i later found that a collaboration between Francis Collins – who would later become Director of the Human Genome Project in the US – and researchers at the Hospital for Sick Children resulted in the description of the cystic fibrosis gene in 1989.


A fragment of the co-authorship network displaying the University of Toronto Hospital for Sick Children (upper-right corner)

During my visit to Toronto, I interviewed two scientists heavily involved in the cystic fibrosis story: Johanna Rommens and Stephen Scherer. Both of them were young at the time the gene was described and witnessed the events that followed the 1989 Science publication. A striking characteristic of the co-authorship networks was that collaboration between the University of Michigan – where Collins was based during the cystic fibrosis work – and the Hospital for Sick Children did not seem quantitatively relevant during the 1990s. Rommens and Scherer accounted for this by explaining that Collins shifted his interests to other genes and the Hospital became involved in the mapping and sequencing of human chromosome 7.

Scherer, a student during the cystic fibrosis discovery, undertook a leading role in the chromosome collaboration and forged an alliance with Craig Venter, the CEO of Celera Genomics, who was then seeking the involvement of teaching hospitals in his quest to sequence the whole human genome. In 2003, an article describing the full sequence of chromosome 7 was published in Science under the lead authorship of Scherer, and contributions from Venter and other researchers from Celera, the Massachusetts General Hospital and the John Radcliffe Hospital in Oxford, among others. Unlike the publications from the public and charity-funded Human Genome Sequencing Consortium, the article by Scherer and colleagues focused on the variability in the chromosome sequence and its connection to different hereditary diseases.

The oral histories were combined with work at the archives. I explored more than 800 records, among them the annual reports of the Hospital’s Research Institute and Department of Genetics, as well as the Papers and Correspondence of Lap-Chee Tsui, a Taiwan-born researcher who led the cystic fibrosis group. The archival materials also included funding applications, reviews of the different research units at the Hospital and oral histories with retired staff, mainly the former head of the Genetics Department, Manuel Buchwald. These records, along with the oral histories, will be fed into the further analysis of the co-authorship networks, in order to obtain insights from the combination of quantitative and qualitative evidence.


Miguel Garcia-Sancho at the Archive of the Hospital for Sick Children (Toronto).



On John Sulston’s death


Photograph of Sir John Sulston taken in 2006 by Jane Gitschier and originally published as part of the article, ‘Knight in Common Armor: An Interview with Sir John Sulston’ in PLOS Genetics, doi: https://doi.org/10.1371/journal.pgen.0020225. Reproduced here under Creative Commons Attribution License.

John Sulston, one of the driving forces behind the development of the strategy of the Human Genome Project as it evolved in the mid-1990s, died in March. As the head of what is now known as the Wellcome Sanger Institute, he was the public face of the project in the UK, and was deeply influential in steering the public and charity funded effort in three ways. Firstly, in favour of having a small number of centres sequencing vast volumes of the human genome. Secondly, in ensuring that the data produced would be publicly and freely available in open access databases. Thirdly, in tackling the private sector competition spearheaded by J. Craig Venter head on.

At the time, the competition, often depicted as a race, captured the media’s attention. In the manner of parents wanting to keep the peace between feuding siblings, a formal tie was announced at a White House declaration in 2000, at which the head of the US National Human Genome Research Institute Francis Collins played nice with Venter. The tie was declared before the finish line was breached, however, the publications heralding the completed genome sequence only appearing in 2003. The appearance of the separate private and public project publications on the same day was also a negotiated draw, and the definition of completeness somewhat fudged to ensure the announcement of a ‘final draft’ on the 50th anniversary of the discovery of the structure of DNA.

The obituaries of Sulston reflect on the race, but also the openness agenda which at the time was presented as a victory for public access over private control. In some respects, this was the case, and it set an important precedent for the sequencing of other organisms. The free and open access to sequence data undercut the business models of many burgeoning biotechnology companies, while providing a massive informational subsidy to the pharmaceutical industry. In addition, it quickly became apparent that an understanding of the biology of organisms and the ability to intervene in it required far more than sequence data.

The popular press inevitably concentrated on Sulston as a scientific politician, emphasising his socialist beliefs and connecting them to his promotion of openness and advocacy of the public project. Scientific publications gave more prominence to his scientific rather than administrative achievements, most notably his work at the Laboratory of Molecular Biology under Sydney Brenner, mapping out the cell lineage of the nematode worm C. elegans and then undertaking the mapping and then sequencing of the worm’s genome.

The distinction between his scientific and managerial efforts are less distinct when one views them in turns of outcomes. Not only did both projects constitute gigantic efforts to produce resources for use by a wider scientific community, they also helped constitute a community of users in the first place. Brenner’s insight to develop C. elegans as a tool for genetic and developmental biology research and the work done by Sulston and others to make it so enabled a new community to be formed to further develop and use the model.

Similarly, the acceleration and scaling-up of genomics that Sulston pushed, even before the public-private competition became salient, shaped the nascent field of genomics. He, along with National Institutes of Health policies, helped to centralise sequencing, and in so doing shifted the economics and geography of it, and how other scientists interacted with it. The rapid availability of sequence data undermined the economics and rationale for many small groups or individual scientists to sequence. Sequencing work in humans therefore largely (though far from completely) transferred from those who had a direct interest in the functional implications of the sequence data of a genome region of interest towards mass high-throughput sequencing conducted according to strict divisions of labour in large-scale sequencing centres. There was nothing inevitable in this shift; Sulston’s influence in shaping the organisation of this area of biological research was considerable.

The legacy he leaves biology in terms of the particular forms of openness he successfully advocated and the organisation of sequencing is undoubted, but the consequences are not quite as clear cut as his understandably laudatory obituaries suggest.