Tag Archives: genome editing

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.


Can genomics and genome editing assist in wildlife conservation?

Blog post by Caroline Mortelliti. 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


Facsimile of 1626 painting of the now-extinct dodo by Roelant Savery. Public domain image.

Our planet is in the midst of its sixth mass extinction, with loss of faunal and floral species at rates unseen since the extinction of the dinosaurs over 65 million years ago.¹ While extinction events can be naturally-occurring phenomena, the current mass extinction is of exceptional concern as it is driven by human activity. Today, some scientists think they have developed a solution to mitigate this extinction crisis: the de-extinction project. In this post, I comment on the strengths and weaknesses of this controversial solution.

What is paleogenomics & de-extinction?

Paleogenomics is an approach that allows whole genomes to be recreated from long-dead or extinct species. The practice includes obtaining the DNA of the extinct species, sequencing its genome, and matching the extinct DNA to the DNA of its closest living ancestor. Scientists may then edit the living ancestor’s genome to match that of the extinct genome, insert the newly edited DNA into a host stem cell, and grow an in vivo clone of the once extinct animal.²

However, the success of paleogenomics and de-extinction relies on the integrity of ancient DNA. Under ideal conditions, a sample of DNA can last a long time, potentially millions of years, but less ideal environmental conditions can hasten the degradation of DNA’s chemical bonds, or it can become contaminated with the DNA of other organisms, ruining the sample. Therefore, little gathered DNA is viable for palaeogenomics. As a result, de-extinction’s impact on conservation efforts is currently limited.

Genome Editing

The genome editing tool, CRISPR-Cas9 (CRISPR), can assist conservation genomics in a number of ways. First, CRISPR (see image below for an explanation of how it works) can help bring select animals back to life. More effectively, however, genome editing can tweak the genes of endangered species or species that have reproductive difficulty, so that their chances of survival are enhanced. Genome editing can also be used to lessen the invasive tendencies of destructive invasive species. For example, CRISPR can be used to introduce sterility genes in select members of invasive species and disease-carrying vectors, eventually lowering their population numbers and therefore enhancing  biodiversity.


Guide to CRISPR-Cas9, produced by ‘J LEVIN W’. Reproduced under a Creative Commons Attribution-Share Alike 4.0 International license. Available online at: commons.wikimedia.org/wiki/File:CRISPR-Cas9-biologist.jpg

Advocacy for Genomic Approaches

Those who advocate for de-extinction and associated genome editing techniques are often geneticists and molecular biologists who are comfortable with the use of highly technoscientific approaches. By using technoscience to address the extinction crisis, advocates believe that wronged animals and ecosystems will receive their due justice. Additionally, and perhaps moreover, the extinction crisis presents a unique field of opportunity for making advancements in technoscience that could change the face of genetic engineering.

Biodiversity is recognized as a hallmark of a healthy ecosystem, and so many scientists feel they have a moral obligation to act to prevent and reverse loss of biodiversity. Paleontologist Michael Archer believes that since new technologies give us the capabilities to resurrect extinct species, we as humans have the “moral obligation” to right our wrongs and bring these animals justice. “If we’re talking about species we drove extinct, then I think we have an obligation to try to do this”. Alternatively, some critics claim the practice takes on new levels of ethical misconduct and hubris by challenging divine order. To this point, Archer rebuts: “I think we played God when we exterminated these animals”.³

Some scientists believe that de-extinction will increase biodiversity and thus the likelihood of finding natural compounds that can be used to develop pharmaceutical drugs. In some cases, advocates support de-extinction simply because it’s revolutionary. Bioethicist Hank Greely supports the de-extinction process having extensively studied its ethical and legal implications. “What intrigues me is just that it’s really cool. A saber-toothed cat? It would be neat to see one of those”.³

Challenges to de-extinction efforts

The de-extinction process can be interpreted as a threat to conservation efforts in two ways.

First, the de-extinction project distracts from the very successful and reliable conservation efforts that are currently in place, mainly by reallocating funds for de-extinction research.

Second, that de-extinction distracts younger generations from concerning themselves with conservation matters. The implementation of de-extinction practices might provoke a careless attitude among the public. If people believe that animals can always be ‘brought back’, then there would be little incentive for anyone to protect them from extinction in the first place. This attitude is dangerous, say conservationists. Furthermore, even more species could be saved if that money was put towards existing conservation efforts.

In summation, the money would be better spent supporting the programs that keep species from going extinct in the first place. “It’s better to spend the money on the living than the dead” says the lead author of one study, biologist Joseph Bennett.⁴

Conservation biologists and rewilding specialists raise another interesting objection against this application of genomics. They claim that reintroducing an animal into an environment that has changed since it was naturally abundant there is a risky endeavour. “Without an environment to put re-created species back into, the whole exercise is futile and a gross waste of money,” says environmental philosopher Glenn Albrecht.³


Arabian oryx (Oryx leucoryx) in the Dubai Desert Conservation Area, UAE. Photograph by Charles J. Sharp. Reproduced under a Creative Commons Attribution-Share Alike 3.0 Unported license. Available online at: https://commons.wikimedia.org/wiki/File:Arabian_oryx_(oryx_leucoryx).jpg

One example of where rewilding has failed is with the Arabian oryx, a straight-horned antelope. A huge effort went into restoring the Arabian oryx in the wild, but after the animals were reintroduced into their previous habitat in 1982, they met a quick demise from poachers, disease, and mating complications. “We had the animals, and we put them back, and the world wasn’t ready”.³ Returning a species to its natural environment requires the coordination of multiple scientific and non-scientific actors.

Moving Forward

Many scientists have significant concerns with using the de-extinction project as a legitimate wildlife conservation solution.⁵ De-extinction practices do not address pressing ecologic matters; resurrecting one animal will not keep another from meeting the same fate.

However, while de-extinction may not be a solution, through genome editing some species could be responsibly and successfully re-introduced. De-extinction is in many respects a luxury, an exciting idea for scientists to pursue, to be explored so long as it does not interfere with or compromise current conservation efforts.²

The concepts of de-extinction and genomic engineering reveal human’s insatiable need to demonstrate a mastery of living things.

How far will we allow the technosciences to develop? Geneticist George Church once remarked, “Maybe some people thought polio vaccines were a distraction from iron lungs”.³ It is difficult for us predict what might be an obstacle, and what might be a cure.

Sources referenced:

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