What Is Next-Generation Sequencing?
Next-generation sequencing (NGS) is a massive parallel sequencing technology. With NGS, genomic DNA is extracted, fragmented, and a library is generated by adding adapters by ligation or an amplification reaction (PCR). From there, DNA fragments in that library are simultaneously sequenced. A massive sequenced data set can be created in a matter of days.
In this article, we will explore examples of NGS in drug research, as well as future clinical applications.
In This Article:
How Is NGS Used in Drug Development?
NGS already has many applications in drug discovery research. It is used for:
- Rapid whole-genome sequencing
- Understanding DNA-protein interactions
- DNA methylation analysis
- RNA sequencing (total RNA, mRNA, miRNA, etc.)
NGS techniques make it possible to sequence a genome, identify targets of interest, and test how drugs interact with those targets. Below are four examples of how NGS has already been used in medical research projects.
Testing efficacy and safety of drugs
NGS can identify single nucleotide polymorphisms (SNPs), variations in DNA sequence caused by altering a single nucleotide. These variations occur in individuals and in populations. Researchers can then analyze differences between the genomes of people with a disease and people without. These insights point researchers toward potential treatment targets.
SNP analysis can also identify existing therapies that could work to treat other medical conditions. In a study published in Nature, for example, researchers investigated 10 million SNPs in over 100,000 subjects. Subjects were split into two groups: those with and those without rheumatoid arthritis. Researchers identified 42 new risk indicators for rheumatoid arthritis (RA).
Their research showed that many of these risk indicators are already targeted by RA drugs. It also found three drugs currently used in cancer treatment that could be easily repurposed for RA treatment.
Preventing disease progression
NGS can help develop pharmaceuticals that affect biological targets associated with disease progression. A study from ACS Medicinal Chemistry Letters used NGS technologies to discover a therapeutic target for osteoarthritis. Current treatment for osteoarthritis involves anti-inflammatory drugs (NSAIDS), but this is purely for symptom management. NSAIDS do very little (if anything) to impact cartilage breakdown and disease progression.
Using a DNA-encoded chemical library, researchers identified the metalloprotease ADAMTS-4 as a target for treatment. The study then identified several possible inhibitors that could impact ADAMTS-4 and ADAMTS-5 to slow disease progress. NGS technologies allowed this research to be conducted with faster lead generation.
Combating drug resistance
Next-generation sequencing can be used to identify drug resistance and predict response to medical interventions. This can help researchers and clinicians understand which patients will benefit from specific therapies. Researchers can also use these insights to develop new therapies to treat mutated microbes. Although every project presents unique challenges, many follow a few basic steps:
- A microbe’s genome is sequenced to identify potential targets for therapeutic intervention.
- Clinical trials are conducted to validate these results. Researchers determine if there would be any health benefit associated with treating the identified target.
- Assays are conducted to test and identify potential drugs. Researchers modify drug candidates to make them more effective and minimize negative side effects.
- Preclinical and clinical studies begin in animals and humans. Studies determine whether the drug is functioning as intended and whether there are any unexpected side effects. Information is gathered about the drug’s effect on the human body and how the body processes it. During development, dosage, administration method, toxicity, and ideal patient characteristics are also identified.
For examples of genomics combating antibiotic resistance, take a look at our recent article, Whole-Genome Sequencing in Drug Resistance Research.
Developing precision cancer treatments
NGS is a valuable tool for developing new cancer treatments, and is used in many ways to further that research. One major way this technology is used is to identify biomarkers that make cancerous tumors resistant to certain treatments. In 2017, an estimated 90% of chemotherapy failures were related to drug resistance. This resistance can be present in the tumor at inception. It can also be acquired during treatment as an adaptation of the disease.
The goal of NGS in cancer research is to identify targeted therapies that can stop tumor growth and progression. This approach could potentially provide alternatives to chemotherapy, spare healthy cells, and increase survival rates.
It also sheds light on why some patients fare better than others in clinical trials. One clinical trial found that bladder cancer tumors with a specific TSC1 mutation were more receptive to the drug everolimus. Patients with this mutation experienced a significant improvement in time-to-recurrence. Patients whose tumors did not have the TSC1 mutation did not see the same improvements.
Everolimus did not achieve its progression-free survival endpoint in a majority of subjects. However, the patients it did impact saw phenomenal results. Researchers argue this illustrates a need for a more personalized approach to cancer treatment. It also points to a new way of looking at the success or failure of drugs in clinical trials.
The Future of Bioinformatics and Medicine
Next-generation sequencing has huge potential to transform the way diseases are treated. Although applying NGS at the level of the doctor’s office presents challenges, we are rapidly approaching a future with:
- Routine genomic testing in the doctor’s office or clinical laboratory. Genetic testing will be applied in more and more health care settings, instead of for a select few diseases. Genetic counseling will be more common for people at high risk of certain diseases.
- Increased efficacy of personalized medicine. Doctors will be able to make more accurate, immediate care decisions. Medication decisions will be more informed, and more tailored to a patient’s unique needs. Drug trials will have more nuanced results.
- More accessible bioinformatics tools. The library of sequencing data is ever-growing. To have meaning in a real-world setting, tools need to be developed to give clinicians and researchers timely, relevant insights.
We're just starting to see NGS's benefits in medicine. High-throughput technology and massive DNA-encoded libraries provide information on drug leads, allowing researchers to make decisions with confidence. As these libraries continue to grow, NGS will impact how drugs are tested, prescribed, and repurposed to treat other conditions.
