The genome e-volution

In the light of the COVID-19 pandemic it is even more ironic that opposition to vaccination poses a major public health threat in European societies. Unfortunately, for several virus-borne diseases, the proportion of people being vaccinated is no longer sufficient to provide protection. We are witnessing a comeback of severe outbreaks of measles and other transmittable diseases, for which safe and effective vaccines are available. Measles is one of the world’s most contagious infections, which can lead to serious, fatal complications in children. Whilst fatalities may be low in Europe compared to developing countries, numbers have been continuously rising in the past years⁴. Both scientists and the media are partly responsible for the growing opposition to vaccines. While the false claim about a link between certain vaccines and autism made headlines worldwide, scientific research disproving the connection took too long to materialize and failed to resonate. Also, science in this cases did not manage to self-correct efficiently, as it ultimately took 12 years to retract the flawed paper from the prominent medical journal ‘the Lancet’, a vacuum into which the vaccine doubters were rapidly spreading.

On top of these existing challenges, we face a new one: the digital transformation of society. This transformation is affecting a variety of age groups in different ways – from increasing social isolation, to sedentary lifestyle, depression, and miscommunication. The digitalisation of society is leading to new types of disorders, such as the FOMO syndrome (Fear of Missing Out) and Nomophobia (short for “no-mobile-phone phobia”). The World Health Organization (WHO) declared the gaming disorder a disease in 2018. Younger generations’ use of existing and new technologies will have a long-lasting impact on their physical and mental health.

While big pharma’s work with AI is still at an early stage, a rising number of start-ups are moving machine learning further onto the drug discovery stage. In 2017, the BenchSci Blog⁷ identified 37 start-up companies using artificial intelligence to create new drugs. In 2019, the number increased to 177. Together, these companies have 62 drugs in their pipelines, with a few being advanced to late stage clinical trials. Besides helping to design new molecules for targeted therapies, AI should help boost the systematic repurposing of existing drugs for new therapies.

Long term commitment to basic science – HIV example

The history of HIV is a prime example of how public health has advanced through basic science and modern technologies. At the same time, it also tells the story of how scientific progress may take decades to succeed, and how endurance pays off in the end. AIDS emerged as a pandemic in the early 1980s. A few years later, the HIV virus was identified by a team of scientists at the Pasteur Institute in Paris. That discovery enabled the development of the first commercial HIV test by 1985. The knowledge of the nature of HIV infection gave rise to global prevention campaigns, which together with viral tests limited the spread of the disease.

The first anti-HIV treatment, azidothymidine, is a repurposed drug which had originally been developed as a potential cancer treatment, decreases opportunistic infections in HIV patients and thus AIDS-related deaths. While it ameliorates the symptoms and lethality of AIDS it cannot purge the virus from patients; on the contrary, therapy-resistant viruses started to emerge very rapidly. Despite boasting announcements, and heavy financial investment into research, it took almost another decade before the United States Food and Drug Administration (FDA) approved the first tailored inhibitors of other critical HIV enzymes in 1995. More efficient drugs soon followed, and it turned out that HIV can be controlled and reduced below detection level by a combination therapy with several drugs. Besides being a tale of the limits of science, the history of HIV/AIDS is also one of the inequalities of access to healthcare globally. While AIDS-related deaths have decreased more than 55% since the 2004 peak, rates for new infections are still increasing in some countries and pose particular difficulties in Africa, with 25.7 M people living with HIV in Africa, 2.4 M in Europe, and 37.9 M worldwide⁸.

Targeted tumour treatments initially started off with the inhibition of specific onco-proteins implicated in controlling cellular growth. Drugs included monoclonal antibodies¹⁰ that block growth receptors on the surface of cancer cells. A prominent example is trastuzumab (Herceptin®), the first approved molecularly targeted drug for HER2-positive breast cancer. Other drugs include small chemical compounds that disrupt the oncogenic signalling initiated by those receptors. One example is vemurafenib (Zelboraf®), the chemical inhibitor of the growth signalling molecule B-Raf. It is used for melanoma patients displaying a characteristic mutation in the B-Raf gene leading to uncontrolled cellular growth. There are currently more than 20 targeted therapies used in hospitals and these drugs have already helped millions of patients. Yet, the rapid development of tumour resistance to these therapies – usually within months of total apparent remission in patients -  is a major problem. For this reason, attempts are made to use several variants of the original drugs, which are then supposed to be effective in the newly developed tumours that have become resistant to the initial agent. Moreover, a combination of two or more targeted therapies is increasingly used to maximize the efficiency of an anti-cancer treatment right from the start.

Personalized cancer therapies

Another boost in treatment comes from the field of immunotherapy which aims at reprogramming the patient’s immune system to identify and eradicate growing tumours. A variety of new drugs, so called checkpoint inhibitors, turn immune cells into weapons that destroy tumour cells. A similar approach relies on a genetic modification of the patient’s immune cells, turning them into super weapons for finding and destroying tumour cells in the body. Immunotherapy and its molecularly targeted drugs are about to revolutionize the treatment of multiple cancer patients, with extremely positive data from ongoing clinical trials.

Despite these irrefutable achievements, the public is slow to appreciate the advances. One reason is that cancer, particularly when diagnosed at a late stage and already spread to other sites within the body, is still the second major cause of premature death. Unfortunately, tumours are extremely complex and diverse, hardly any two are alike, and identification of the most effective targeted therapy is still a major challenge. At the same time, tumour cells are genetically instable and prone to mutate, causing them to quickly change their composition during therapeutic treatment, which often results in resistance towards applied drugs. With healthcare moving at lightning speed towards personalized approaches, the next decade will witness plenty of fundamental changes in cancer therapy, especially if cheaper technologies allow routine analyses of the full tumour genome and proteome.

Neuronal degeneration is mostly caused by the accumulation of dangerous deposits – often clumped-together proteins – and damages to the functional units within the cells, so called organelles (mitochondria, endoplasmic reticulum, lysosomes) of long-living neurons. These developments lead to slow, progressive damage and eventually death of specific groups of neurons in the brain. Based on this knowledge, scientists now aim to identify very early events in the development of neurodegeneration that can be inhibited before the damage accumulates and causes a massive loss of neurons. Obviously, this is a tricky situation, as therapies – to be successful – may have to start ten to twenty years before the first symptoms appear, at the time when deposits first start accumulating in neurons. Currently, we lack non-invasive diagnostic tools to detect this stage, for example by mass screening the whole population. Once neurons have started dying, there is much less chance to stop the domino effect of disease. For example, approximately 80% of dopaminergic neurons (neurons that synthesize the neurotransmitter dopamine, which is required for the healthy functioning of the nervous system) begin to atrophy before first clinical symptoms of Parkinson’s disease appear, indicating that there is a long therapeutic time window. Similarly, in Alzheimer’s disease, damage within hippocampal neurons, which are critical for memory connections, often accumulates for many years before the nerve cells lose their functions.

So far, none of the aforementioned neurodegenerative diseases is curable and treatment has only dealt with the late stage symptoms, delaying progression of the disease at best. Multiple reasons exist for this. First, we have to consider the incredible complexity of the human brain. It has about 86 billion neurons, each having about 7000 synaptic connections to other neurons. Secondly, the non-dividing, long-lived nature of neurons make them prone to accumulation of damage during their lifetime. Thirdly, the brain is a secluded organ, difficult to approach for diagnostics or to administer conventional drugs. Altogether, targeting neurodegenerative diseases is one the greatest challenges in biomedicine today.

Until now, most drug development for neuronal degeneration focused on using chemical compounds, antibodies, nucleic acids or proteins able to prevent and possibly reverse the build-up of the proteins that can cause the disease, such as synuclein for Parkinson’s and amyloids for Alzheimer’s. However, all attempts to target aggregation-prone proteins through above-mentioned therapies have so far fallen short of expectations. More recently, attention has been focused on the cells’ own quality control systems, which are responsible for removing any dangerous deposits or damaged organelles. Defects in those cellular control systems may contribute to or even cause neurodegeneration. At the same time, boosting the performance of those internal mechanisms may have a protective effect. One of those is autophagy, which enables cells to remove damaged or dangerous material from our body. Novel innovative approaches try to flag dangerous components and target the autophagic waste machinery for their removal.

The CRISPR/Cas9 system was first applied as a tool for genetic engineering in 2012. Six years later, the birth of potentially HIV resistant genetically modified babies, was reported in China and highly criticised around the world for ignoring well-established international norms in research ethics. The scientist behind these efforts was recently sentenced to 3 years in prison for violating research integrity law in China¹⁴. Germline genetic modification, or the process of genetically modifying sperm or egg cells for the purpose of reproduction, is forbidden in 17 of the European Union’s 28 members. European researchers have traditionally been amongst the first to voice concerns about the dangers and ethical implications of genetic engineering for therapeutic purposes, and the problems posed by the large-scale access to and use of genomic data. However, in a globalized world neither technical breakthroughs nor the consequences of misuse can be limited to national borders.

Innovative therapies and societal challenges

Besides the concerns related to gene therapy and the potential misuse of individual genetic data, for example by insurance companies or digital firms, scientific and technological breakthroughs pose other ethical challenges. Many of the innovative treatments come with skyrocketing costs, putting an additional strain on limited health care budgets and raising questions of the accessibility of high-level, individual care and of inequalities in the healthcare system.

There is also a clear medical need to invest more in rare disease research, which is largely neglected by the pharma industry. When innovative treatments for rare diseases are developed, they often come with an astronomical price tag. High prices are only partially the result of a small market for such treatments. Uniqueness, rather than demand, often dictates pricing, and only regulations can solve the issue.

With tailored therapies for common diseases being introduced on a broad scale, physicians will more frequently have to ask themselves: Is it justifiable to cover treatment costs for a single patient while the same amount of money could be used to cure hundreds of people suffering from other diseases? Should this treatment be covered by the public health system or should it be funded privately? To give an example, current cancer therapies with genetically modified patient cells discussed earlier in this article cost several hundred thousand euros. However, to efficiently target the unique personal circumstances leading to a disease, to provide the needed benefit to patients while at the same time decreasing the unwanted effects, individual therapy treatment is a must. We will have to debate how to overcome the financial hurdles. A similar debate arose around the high cost of treating new chronic diseases, which were previously fatal and now require lifelong treatment with expensive medication, such as HIV infection, which can now be controlled by a combination of drugs. And while these developments force us to face some extremely difficult questions, the much more pressing issue of how to ensure acceptable health care standards and accessibility worldwide has not even been touched.