World of Genomics: The Netherlands

Home to 90% of the world’s tulip fields and over 1,000 windmills, we travel to the Netherlands in our latest World of Genomics. Translated to “The low countries”, one-third of its land mass sits below sea level. The Netherlands thrives as Europe’s major shipping port, and their soil fertility means they are the second largest food exporters in the world. Not to be mistaken solely as an agriculturally-driven country, the Netherlands’ advanced infrastructure has provided a long archive of genomic sequencing records and they are partnered with multiple organisations to further genomics guided precision medicine.

The population of The Netherlands

The earliest known human life to inhabit the Netherlands was “Krijn,” a Neanderthal fossil found on the Dutch coast that dates back 60,000 years.

From 800BC, the Netherlands was invaded by Celts, Romans and Germanic tribes and from 57BC, the Roman Empire prospered for approximately 500 years. In 1556, the Netherlands was under Spanish rule.

After the Eighty Years’ War, the Netherlands gained independence from Spain in 1648. This marked the beginning of the Netherlands’ rapid growth and development, an era known as the “Golden Age.” Despite the territorial hardships from neighbouring countries and the German invasion in WWII, the Netherlands has sustained economic growth. International migration and rapid population growth have played key roles in shaping the Dutch population.

The Netherlands is known for its very low-lying topography and the country possesses a flat terrain comprising of coastal lowlands, farmland and grassy dunes.

According to the World Population Review in 2020, the Netherlands ranked 8^th in the world for most developed country.

**Figure 1 |** Map of the Netherlands (Source: Encyclopaedia Britannica)

Geographic and demographic information

Summary statistics

Land area: 33,720 km²
Gross domestic product (GDP):
- Total: USD$1.02 trillion
- Per capita: USD$58,061

Population statistics

Population size: In 2020, the total population size of the Netherlands was 17.4 million.
Crude birth rate: In 2020, the crude birth rate was 10.1 per 1000 people.
Crude death rate: In 2020, the crude death rate was 8.95 per 1000 people.
Infant mortality rate: In 2020, the infant mortality rate was 3.8 per 1000 people.
Life expectancy: In 2020, the average life expectancy was 81.
Ethnicity: In 2018, Dutch nationals made up 76.9% of the population, the remaining distribution comprised of EU 6.4%, Turkish 2.4%, Moroccan 2.3%, Indonesian 2.1%, German 2.1%, Surinamese 2% and Polish 1%.

Healthcare system

The Netherlands has a universal healthcare system where every Dutch citizen must have basic level health insurance. The system is managed by the Dutch government and supplemented by private insurance companies. All primary healthcare and long-term services are provided on a fixed price.

The Health Consumer Powerhouse 2018 report on healthcare systems in Europe ranked the Netherlands as having the 2^nd best healthcare system in Europe. The Netherlands has 3.7 physicians and 11.5 nurses per 1,000 people. In 2020, the Universal Health Coverage of the Netherlands was deemed to be 83, in comparison to the global score of 57. Universal Health Coverage is a score measured by the World Health Organisation monitoring to what extent all individuals and communities receive the health services they need without suffering financial hardship.

The Dutch healthcare system has developed over a long period, with the introduction of the first health insurance funds to aid low-income households dating back to the 18^th century. At the beginning of WWII, the German mandatory health insurance system, “Krankenkasse,” was introduced in 1941. After the occupation, the Dutch government decided to keep the system of mandatory health insurance.

However, as health insurance institutions become professionalised, the addition of supplemental services has caused a separation between private and public health service sectors.

The Netherlands also face spending challenges. The Netherlands’ expenditure on healthcare is equivalent to 12 percent of GDP, ranking them 3^rd highest amongst all 38 OECD countries. Resources have been stable to date, but high costs have prompted cost control measures. This could threaten the affordability of the system long term and influence the system’s resilience, especially as high-cost technologies are introduced, the population ages and a likely increase in chronic diseases is foreseen.

Health priorities

In the Netherlands, the most widespread causes of death in 2019 were cancer, diseases of the circulatory system, mental and behavioural disorders, diseases of the respiratory system and injury.

The Dutch national screening program for colorectal, cervical and breast cancer was introduced in January 2014. However, participation rates have seen a slight decline in the last 5 years. In 2020, the Netherlands Cancer Institute introduced VMware technology. Hospital staff can access medical data and applications quickly, safely and easily, accelerating treatment decisions and improving patient care.

The Netherlands plays a key role in promoting health and wellbeing around the world. They have developed a longstanding partnership with the World Health Organisation (WHO) by funding crucial activities in the areas of mental health, response to disease outbreaks and humanitarian crises, water sanitation and hygiene, primary healthcare and antimicrobial resistance. The Netherlands ranks 4^th in the WHO’s largest financial contributors.

One of the key goals for the Netherlands is attaining the highest level of sexual and reproductive health and rights for all girls and women. The Netherlands serves as a key financial contributor to the WHO’s Human Reproductive Programme (HRP) established in 1988 and has twice served a Chair for the programme. A study conducted by the HRP achieved with Dutch support was the introduction of Carbetocin, a drug used to prevent post-birth haemorrhage, saving the lives of thousands of women.

The Netherlands also supports the WHO’s lifesaving work in response to health emergencies and humanitarian crises. They have contributed 12.5 million US dollars to the WHO’s contingency funds for emergencies which allow the WHO to immediately respond to disease outbreaks.

As of June 2022, the Netherlands had 8.22 million confirmed COVID-19 cases and 22,401 confirmed COVID-19 deaths.

Genomic medicine capabilities

The Netherlands has a commitment to open collaboration, leading to its success in genetic research. Introduced in July 2015, the Government Information Reuse Act mandates that the archives of medical data are to be freely accessible to the public. This openness and transparency has created a sense of community among researchers, which has led to better cooperation and innovation. Genealogists have benefited as open, free access to genealogical records has enabled research that was previously too time-consuming and expensive. However, as archives once used the proceeds of the downloads to finance digitisation projects, without compensation for the loss of income, fewer sources might be available in the future.

The Netherlands is also a strong supporter for the WHO’s response to COVID-19, contributing a total of 11 million USD. The Journal of Infectious Diseases reported the Netherlands as one of the 5 countries to show great performance for sequencing efforts in response to the pandemic, in addition to the UK, the USA, Iceland and Australia.

In 2018, the Netherlands signed a declaration enabling access to at least 1 million sequenced genomes in the EU by 2022. They became the 18^th EU Member State to participate in the joint European effort to deliver cross-border access to genomic health data. The Netherlands values EU cooperation on health and having access to a larger cohort of genomic data will allow for more clinically impactful research.

At the Netherlands Cancer Institute, datasets of whole genome sequencing have allowed the Netherlands to discover new biomarkers and investigate cancer therapy resistance mechanisms. An example is the identification of the KRAS mutation in chemotherapy resistance and the role of antigen-presentation machinery in immune responses.

Notable projects

Genome of the Netherlands (GoNL): GoNL is a project within the Biobanking and Biomolecular Research Infrastructure. It is a whole genome sequencing project consisting of 250 trio-families across all provinces in the Netherlands to characterise DNA sequence variation in the Dutch population.
Netherlands Genomics Initiative (NGI): NGI creates societal and economic value from genomics through a network of large-scale genomics centres.
Mobile DNA-Lab: An educational outreach project launched in 2006, the ‘Language of a Tumour’ programme educates high school children on cancer genomics.
Genetics, Arthrosis and Progression (GARP) Study: A database of over 200 sibling pair both affected with osteoarthritis and non-affected partners in The Netherlands, which has been used for many osteoarthritis studies. The patients and their partners have undergone periodic testing over a period of decades, providing a mass of longitudinal data for statistical analysis. A large number of participants have also provided blood and urine samples for testing of DNA, RNA and proteins.

Notable organisations and companies

The Biobanking and Biomolecular Research Infrastructure- Netherlands (BBMRI-NL): BBMRI-NL is a national node of the European BBMRI, a research infrastructure for biobanking that aims to bring together leaders in the biobanking field to boost biomedical research.
Dutch Society for Human Genetics (NVHG): The NVHG is a scientific association for those active in researching human genetics. The organisation unites medical specialists and facilitates meetings, conferences and collaboration.
Erasmus MC- Institute for Genetics and Medical Research (EMC): The EMC aim to understand the function of the genome and to identify causes of metabolic diseases, cancer, neurodevelopmental disorders, cardiovascular disorders and congenital malformations.
Netherlands Cancer Institute: Established in 1913, the Netherlands Cancer Institute includes an internationally acclaimed research institute and a dedicated cancer clinic, aimed to deliver rapid translation of basic research into clinical applications.
Integraal K ankercentrum Nederland (IKN): Founded in 1980, the Integrated Cancer Centre of the Netherlands is an independent knowledge institute for oncological and palliative care. IKNL’s mission is to reduce the impact of cancer.
Cancer Genomics (CGC.nl): Established in 2013, CGC.nl is a consortium of research groups that combines expertise to understand cancer genomics and integrate benefits into the clinic.

Notable individuals

Anton Berns: Berns is a molecular geneticist known for his pioneering work on generating and utilising genetically modified mice as a tool to search for new cancer genes.
Piet Borst: Borst is a molecular biologist and former Director of the Netherlands Cancer Institute. His work focused on chemotherapy resistance in cancer cells and the biosynthesis and function of DNA Base J.
Titia de Lange: Lange is an award-winning biochemist known for her work on telomeres. She identified the Telomeric-repeat binding factor protein 1 and discovered the t-loop structure of telomeres.
Helga De Vries: Vries is a neuroimmunologist and leader in the field of the blood brain barrier. She led the discovery about the importance of microRNAs in the blood brain barrier and finding targets for multiple sclerosis.
Jan Hoeijmakers: Hoeijmakers is an award-winning molecular geneticist known for his work on the mechanisms of DNA repair and the effects of defects on genetic stability in aging, cancer and hereditary diseases.
Karst Hoogsteen: Hoogsteen was a biochemist famous for noting a new base paring form in DNA, now called Hoogsteen base pairs.
Roel Nusse: Nusse is a biologist who is famous for the discovery of Wnt signalling and researches stem cell development and tissue repair.
Eline Slagboom: Slagboom is a geneticist specialising in aging and osteoarthritis. She is founder of the Leiden Longevity Study and the GARP study.
Cisca Wijmenga: Wijmenga is former leader of the GoNL project. She is a Dutch professor of Human Genetics at the University of Groningen and the University Medical Center Groningen. She has been Rector Magnificus of the University since September 2019.

The future genomics landscape

The Netherlands is eager to be a part of boosting the access of precision medicine to patients globally. Dr. Cisca Wijmenga, Professor of Human Genetics at the University of Groningen and the University Medical Centre Groningen said, “In the next ten years, whole genome sequencing will become a standard tool in research and molecular diagnostics. We hope to kick start the nationwide implementation of such tools and build up the expertise needed to enable our scientists and the public to benefit from these future developments.”

Organisations such as BBMRI-NL aim to build genomic capability in the Netherlands by prioritising findable, accessible, interoperable and reusable projects. However, there are some reservations on the future of genomics research. There are concerns that research financed by the Dutch government and universities would lead to a brain-drain of scientists from other disciplines, as scientists set up companies on the back of discoveries, instead of remaining in pubic research.

As cell and gene therapies are still relatively new areas of research, there are many opportunities for expanding its potential application areas and for optimising its production processes. The Netherlands’ Cancer Institute is now constructing a database by adding digital pathology and imaging data in the hope that utilising machine learning technologies can contribute to better patient selection for therapy.

References

Amsterdam Info. A history of the Netherlands. AmsterdamInfo. 2022.
BBMRI.nl. Integrative Omics data set. BBMRI.nl. 2019.
European Commission. State of Health in the EU: Netherlands country health profile. European Commission. 2017.
European Genome-Phenome Archive. Genome of the Netherlands. EGA Consortium. 2022.
How the Netherlands allows cell and gene therapy businesses to scale-up. Invest in Holland. 2022.
Netherlands Cancer Institute. Precision medicine. NKI. 2022.
Riyazi et al. Risk factors in familial osteoarthritis?: the GARP sibling study. Osteoarthritis and Cartilage. 2007.
University of Groningen. Genome of the Netherlands. University of Groningen. 2016.
Wise. Healthcare in the Netherlands: A guide to the Dutch healthcare system. WISE. 2017.
World Health Organisation. Ensuring equal access to health services to all people. WHO. 2022.
World Population Review. Netherlands population. World Population Review. 2022.
Zorgverzekering Informatie Centrum. Origin of health insurance. Z.I.C. 2021.

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Image credit: canva