An Overview of Precision Medicine

Personalized or precision medicine are tailor-made individualized therapies that are becoming increasingly popular to treat or prevent diseases based on a person’s genomic variability.¹

The rapid inventions in precision medicine are becoming possible due to simultaneous advancement in next generation sequencing (NGS) technologies. The second and third generation sequencers are efficiently detecting defects in the genome, particularly the protein coding parts of it which is collectively known as exome.²  In the last few years personalized medicines have been topping the list of drugs being approved by the Food and Drug Administration (FDA).³ Nations that were early adopters to invest in research and development in genome sequencing technology infrastructures are now reaping the benefits of the novel therapies available to fight acquired or inherited diseases related to gene mutation, gene expressions, and immune system vulnerability. As the one size fits all generic medicine paves way for molecular therapeutics, it is now a matter of time to observe when it becomes extensively available across borders at a reasonable price.³

Genetic Mutation, Genetic Expression, Genetic Disorders & Gene Editing

Changes in DNA sequence are genetic mutations which can happen either naturally to help species adapt better to the environment or in diseased conditions that may lead to chronic or terminal illnesses.⁴  Access to specific sites in the DNA to switch genes “on” and “off” is genetic expression that is mainly controlled by epigenetic factors. Gene mutation and expression are responsible in the type and frequency of protein synthesis respectively.⁵ Among the multiple steps from switching genes “on” for the genes to be read to initiate the process of synthesizing proteins, the most critical controlling point for therapeutics is at the level of RNA transcription from the DNA template.⁶ Specific genes that are switched “on” can be detected by measuring the RNA expression by RNA modification detection technologies.⁷ Gene expression can also be measured by observing a trait by specific protein activity.⁸ Once genes are identified that either needs to be switched “off” or “on”, gene editing tools are utilized to snip out bases or an entire gene in the DNA and molecular therapeutics can be applied to fight that gene causing disease.⁸

The “Omics” and Precision Medicine

The “omics” are the foundation, and manifestation of “omics” whether hereditary or in response to personal traits, lifestyle, environment is the basis of precision medicine development (Fig-1). Coded information passed from DNA triggers transcription process to develop the messenger RNA which then translates to form protein. Genome is the complete set of DNA, transcriptome is the complete set of coding and non-coding RNA and studies of these are called Genomics and Transcriptomics respectively. Similarly, the study of proteins is called Proteomics, Microbiomics is the dynamics of microbiome, and Metabolomics is the study of Metabolomes which are the metabolites formed from cellular metabolisms. The modification of genome due to diet, environment, and lifestyle through the processes of histone acetylation, DNA methylation, or microRNA destroying the coding RNA which ultimately interferes in protein synthesis are referred to as epigenome and the study of it is called Epigenetics. NGS tools are rapidly discovering changes in any of the “omics” that leads to disease conditions.⁹

Fig-1: Factors affecting the omics ⁹

Genome sequencing, identifying disease causing genes either from mutation or from over or under expression, and study of the proteins synthesized- plays the most critical role in designing customized targeted therapies like precision medicine. More emphasis is given to discovering the biomarkers in body fluids, especially blood and urine, to easily diagnose diseases and invent the right route of delivering the therapeutics.

Next Generation Sequencing Process and Utilization

NGS has been the game changer in unearthing the universe of genomics and the other “omics”. The technology of NGS process broadly encompasses fragmentation of the sample DNA into short segments¹⁰ which are then attached to the sequencing flow cell for library preparation,¹¹ followed by uploading the library into the sequencer. All the fragments are parallelly sequenced at the same time that generates massive data which is then analyzed by bioinformatics where sample sequence information is compared to genome reference sequence to identify mutations or variations. Finally, the result of the full-length sample DNA is compiled for final interpretation to detect mutations or variants.¹⁰ 

NGS for Diagnosis and Clinical Application

NGS’ contribution to accurately diagnose genetic diseases, rare diseases, cancers and noncommunicable diseases is changing the landscape of disease management and outcome.

Cancerous conditions usually have multiple mutations that will require multiple testing and large sample size if each of the mutated genes are to be detected in regular molecular assays. For instance, hematopoietic leukaemia, acute myeloid leukaemia, myelodysplastic syndrome are conditions with multiple gene mutations and NGS is the ideal tool that identifies all mutations at one go and additionally augments targeted therapeutic selection with disease prognosis. ¹⁰

Tumor cells also shed DNA into bloodstream or other body fluids that are the markers for detecting primary tumors. These cell-free DNA samplings testing is known as “liquid biopsy”. The significance of using NGS for “liquid biopsy” is, it is less invasive than difficult biopsies, where tissue biopsy cannot be obtained. Liquid biopsies monitor cancer remission, early diagnosis of cancer, relapse, and further metastasis. ^3,10

Disease causing or disease associated genes are being discovered almost every other day. For only lung cancer, the genes so far discovered are-EGFR, KRAS, BRAF, NRAS, PIK3ca, ROS1, MEK, VEGFA, ALK, MET, ERBB2, and ERBB4. NGS is used to identify mutations in any of these genes and diagnose the type of cancer to apply the targeted molecular therapy. NGS is also crucial in hereditary cancer diagnosis by assessing germline mutations to identify the population at risk of developing cancer. BRCA1, BRCA2, CDH1, PTEN, TP53, STK11, PALB2, ATM, CHEK2, MUTYH, BARD1, MRE11A, NBN, RAD50, RAD51C, RAD51D, and NF1 are breast cancer associated genes acquired hereditarily. ¹⁰

Studies reveal that 12% of women in general population will develop breast cancer in their lifetime but risks increase by 55-75% in women inheriting BRCA1 and 45% in women inheriting BRCA2 mutation.¹³

Pharmacogenomics studies how certain genes in an individual’s DNA are intolerant to some drugs.¹⁴ People having HLA-B*15:02 gene are at risk of developing toxic epidermal necrolysis induced by carbamazepine. Effective and safe medication prescription is essential to avoid adverse effects and pharmacogenomics help clinicians to assess the right medicine for the right patient.^{15, 16}

NGS Guides Precision Medicine Invention

Precision medicine is often termed-“the right patient with the right therapy at the right dose at the right time”.¹  

NGS testing and its accuracy is crucial at discovering the genes and genetic products like protein and biomarkers for the development and application of precision medicines for treatment and better patient outcome. Precision medicine can only be applied after NGS guides the therapies to be used that match the patient’s individuality, state of health, lifestyle, habits, and risk assessment to avoid adverse effects.^{3, 12, 14}

Gene therapy is a kind of personalized treatment mainly used in cancer where a patient’s immune system is “reprogrammed” with their own bone marrow or hemopoietic stem cells which are modified to induce antibodies or T-cell mediated immunotherapy. ¹⁸

Gene therapies also involve implanting normal genes into patient’s own cells to modify cellular function within tumors. ³ In only 2022, the FDA approved 12 personalized medicines and five gene therapies out of the total 37 approved drugs. In the last five years personalized medicine drugs accounted for more than a third of the new drugs approved by FDA (Fig-2). 12 new diagnostic testing were approved in 2022 that target giving treatment to only those who will benefit to increase efficacy and avoid cost. On an average, in the last nine years, more than 30% of all the drugs approved by the FDA annually were molecular therapies (Fig-3). The numbers are an indication of the explosive inventions taking place in gene based human therapeutics. ³

Fig-2: Year to Year Novel Drug Approval by FDA ³

Fig-3: Percentage of FDA approved molecular therapies from 2014-2022.¹⁹

The common cancers where precision medicine is widely used include:

• Colorectal cancer
• Breast cancer
• Lung cancer
• Certain types of leukemia
• Certain types of lymphoma
• Melanoma
• Esophageal cancer
• Stomach cancer
• Ovarian cancer
• Thyroid cancer²⁰

Interdisciplinary Consortium

The genome sequencing reveals the genetic variation which are either inherited or due to epigenetic impacts from personal habits, environmental factors, and lifestyle. These information covers both genotype and phenotype causes of diseases, and along with this patient data from interoperable health records are parts of Big Data which when analyzed through artificial intelligence (Ai) and machine learning (ML) will provide the variables precipitating disease conditions. This complex process will enumerate pathogenesis of not only rare diseases and cancers but also provide new information on underlying causes of chronic diseases like heart disease, obesity, diabetes, immune system diseases and on why some individuals are more prone to infectious diseases.¹³ The vast amount of information generated requires new information technology support for disease stratification and support clinical decision making for medical practitioners. Pharmaceutical companies leading in the field of precision medicine have consortiums where they collaborate with experts across disciplines from tech sectors, molecular scientists, and digital health startups.^18,19 The aim is to move towards a more personalized, predictive, preventive, and participatory health sector. ²²

Elements of Precision Medicine- “Omics”, NGS, Big Data & Bioinformatics

The data of individuals or population group obtained through electronic medical records, radiological investigations, scanners, smart devices with biosensors, social media, and the various “omics” including DNA sequences, transcriptomes, proteomes, metabolomes, epigenomes, and microbiomes are compiled together to form the Big Data. ⁹ Artificial intelligence (Ai) and machine learning (ML) processes the Big Data through bioinformatics to convert to useful information for therapeutic interventions (Fig-4). ⁹

Fig-4: Tools of Precision Medicine⁹

The accuracy of precision medicine outcome is dependent on these factors along with applying companion diagnostics to determine individual patient’s benefit from the therapeutic. ²³ Big Data is the critical element of precision medicine application, and it is rapidly transforming the landscape of traditional medical practice. Researchers are collecting large volumes of data, using algorithms, and observing management effectiveness, calibrating the treatment according to the need of the affected person.⁹

Nations Invested in Precision Medicine

The USA spends the most in research and development of drugs and in healthcare in general. 40 percent of the entire precision medicine market is dominated by them since prevalence of chronic diseases is the highest in the US. ²³

Illumina, a giant in biotechnology industry collaborated with National Institutes of Health in the US and National Health Services in the UK for the All of Us and 100,000 Genomes Project respectively. The All of Us project in the US sequenced over a million genomes and the UK project began with 100,000 genes and now targets to cover 5 million genomes. Both are legendary studies for cataloguing genes that might be responsible for specific diseases and for developing personalized medicines.^24–26 

Illumina’s close competitor BGI is a Chinese gene technology giant that has challenged to sequence 100,000 genes a year at a rate lower than $100.²⁷ China has also developed a one million genetic database project in Nanjing.²⁸

Singapore recognized the under-representation of Asian genome database and launched the SGK10 study by the National Precision Medicine programme. It is generating genome data in Phases I, II and III that will end in 2027 with a completion of sequencing of one million genome. It is already the largest multi-ethnic Asian genetic database. It is aimed at cataloguing and avoiding misdiagnosis and mistreatment.²⁹

Genome Thailand is also involved in developing their genetic database. Their precision medicine application is greatly dependent on their reimbursement system just like in the west.³⁰

Malaysia has also developed framework and accumulated genetic data of over 100,000 participants and focusing on their common diseases like thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, tuberculosis, and Helicobacter pylori infection.³¹

Indian government launched National Genomic Grid which is a national shared network for genomic data. They also have The Genome India Project that aims to collect 10,000 genetic samples to build a reference genome and their private sector investments in precision medicine is gaining momentum. ²³

Challenges

Managing diseases with precision medicine requires stratification of patients on predicted response. For instance, only 30% of patients with chronic lymphocytic leukaemia has shown complete remission when treated with CAR T-cells therapies using CD19 as target. The precision medicine therapeutics require equal and more investments in simultaneous investment in building the full infrastructure in NGS technology, compliance of laboratories with international certification, skilled technicians preparing the samples and analyzing the sequencing, and in bioinformatics, computational and database infrastructure.²¹ Manufacturing, distribution, and logistics are completely different from generic medicine. Molecular therapies are for specific patients, it is dependent on small courier service, and medicines need to be stored and transported in very cold temperature to remain stable. These medicines are also very time sensitive and need to be supplied very rapidly. ¹⁸ Last but not least, precision medicine is expensive.

Opposing Opinions of Public Health Experts

Public health experts express concern about democratizing precision medicine as the whole concept is based on personalized treatment. The central focus of precision medicine is on genomics and the other “omics”.¹³  It has been established that genetic factors are responsible for only 30% of an individual’s health. The other almost two-thirds of a person’s health depends on modifiable factors which includes a person’s behaviour (40%), social circumstances (15%), healthcare (10%) and environmental exposure (5%).⁹

Multibillion-dollar investment was made in precision medicine over the last decade, but public health specialists opine that using family history is an inexpensive tool than genomic screening to assess health risks. Also, it is an opportunity cost against potential investment on population-based preventive programs that consider determinants other than genomics that influence health.¹³

Although the cost of sequencing is going down and precision medicine accuracy is increasing, it is yet to be established if the outcome is cost beneficial compared to existing methods.¹³

The extensive studies already done also requires investments in developing  pharmacogenetics ID card for patients that have done their genome studies; extensive pharmacogenetics course study in medical schools; genotype laboratory services, and multiple other investments for the whole industry.³²

Personalized Medicine- Present and Future

In due course of time precision medicine might be more democratized when it becomes extensively available across the globe.

The future will have national biobanks cataloguing bioinformation of humans and other living organisms in most countries or in some countries, the data of which can become accessible to any person to leverage for their own benefit.  As more consumers seek access to data and tools to keep track of their own health, the decreasing cost of sequencing tests will inspire people to learn more about their “omics” and risks. This personal knowledge, smart phone health trackers, over-the-counter diagnostic tests are empowering individuals to take responsibility for their own health. Consumers themselves will have the tools to match their personal data with the references available in the biobank.²² Precision medicine is the ultimate output of integrating technology, clinical phenotypes, the “omics”, laboratory tests and imaging to treat a disease and the rationale is to develop new classification of diseases based on molecular biology.¹³ Precision medicines are here, and people will seek it. It is important that countries with the financial strength establish regulatory framework and build infrastructure for genome sequencing, along with manufacturing and distributing these medicines as early as possible. The promise of precision medicine is, it can identify novel therapies that can treat diseases that were previously untreatable.¹³