The major recent breakthroughs in diagnostics and
Even 50 or 70 years ago, personalized medicine existed solely as the talking point of science fiction writers and scientific visionaries. However, as genetic technologies emerged, the individual approach to diagnostics and therapy of many hereditary and incurable diseases became a routine or at least a common solution. These diseases include various cancer types, autoimmune disorders, and numerous orphan (i.e., rare) pathologies. Although such developments are infamous for their high (sometimes exorbitant) costs, they can no longer be considered unavailable.
Genomics and molecular genetics have laid the groundwork for a complete overhaul of the healthcare system, following the P4 principle where both personalization and predictability play pivotal roles.
It is becoming possible to detect genetic predisposition to a disease before conception, prevent an illness during pregnancy, learn about individual genetic specifics, and define a personal healthy lifestyle.
This market is on the upturn: Mordor Intelligence marketing agency forecasts that these services will develop most intensively in Asia-Pacific countries. Europe and North America also demonstrate a slightly lower yet constantly growing demand, while Russia, Africa, and South America are falling behind.
These changes are expected to revolutionize medicine and shift the focus from disease treatment to health preservation.
For patients with orphan and cancer diseases, gene therapy already gives a chance to get a cure. Given the overwhelming amount of global research, this therapy will soon become the ultimate method of treating other non-infectious diseases that cause early death or disability and have a detrimental effect on the quality of life.
In this article, I will provide an overview of major genetic technologies in medicine that proved their effectiveness and became part of clinical practice, as well as of new developments at the final stages of their trials.
The late 1990s were the milestone of cancer diagnostics, as genetic information on mutations became the starting point for specifying a targeted therapy.
Every tumor has its specific mutations, its gene "breakdowns" that the targeted effect of medication seeks to cope with. For example, the information on BRCA1/2 mutation helped establish a targeted breast cancer treatment and prevent this disease among the patient's relatives. Eventually, this experience has converted into the list of most common disorders, both hereditary and acquired, with molecular gene testing becoming a must of all medical guidelines and changing the course
of pharmaceutical development.
There is a gradual shift from developing medications against specific nosologies to adopting the target concept. For instance, the translocation of the NTRK gene can be found in different tumors but can be effectively treated by the same drug. Although this mutation is rare (found only in 1% of all tumors), its therapy can provide a positive response in 80% of all cases.
At first, "damages" in tumor tissues and the blood were diagnosed using low-effective methods that enabled the study of small DNA sequences, such as polymerase chain reaction (PCR) and Sanger sequencing, known since the 1970-the 1980s, and fluorescence in situ hybridization (FISH) of the 1990s. These tools were of great assistance, helping patients
with solid tumors to avoid a needless or mismatching therapy and get a significant clinical effect; besides, oncohematology patients got an alternative to expensive procedures like marrow transplants.
Nowadays, attempts are made to apply gene testing for specifying the diagnosis and even predicting the treatment efficiency.
Another breakthrough happened in the 2010s: the Next Generation Sequencing (NGS) technology made it available to check the whole genome for damages. Here is the classic example of this method's capacities: it took over a decade and 3 billion dollars from the US budget to complete the Human Genome Project that described 3 billion DNA nucleotides using the standard tools. Meanwhile, the NGS sequenator can reveal the whole genome sequence in less than a year, at the cost of several thousand
Higher speed (several days compared to weeks and months) and fewer expenses are the self-evident advantages offered by the NGS. What is also important, this is almost the only way to collect more data from a smaller amount of material, e.g., from the blood plasma. Thanks to the NGS, liquid biopsy could provide information on potential mutations of up to 400 genes and has been approved for use against non-small-cell lung arcinoma and metastatic castration-resistant prostate cancer.
Besides, the NGS makes it possible to perform population screenings and reveal various hereditary mutations, including breast cancer. Scientists believe that in high— or medium-income countries, it is easier and less expensive to test all women above 30, even those without family anamnesis, and then perform additional radiology diagnostics for the mutation carriers.
There is only one problem with the NGS application in oncology — it provides too much information, and we still do not fully understand how to use it, especially if a person is healthy. However, implementation of genome data in the clinical process is not as far away as it may seem — many countries, including Russia, are already considering collecting
and storing large volumes of genetic data, creating specialized scientific
centers, and adopting national strategies for developing genetic technologies.
Attempts to detect the risk of various genetic disorders (Down syndrome being the most commonly known) at the gestation stage were made even before the NGS, but this method made this procedure non-invasive — and thus much safer. Mutations can be found since the 10th week of pregnancy by analyzing the fetus' DNA circulating in the mother's
blood — to do this, only 0.01 ml of the mother's plasma is needed.
The person who revolutionized the embryonic-stage diagnostics of Down syndrome was Dennis Lo, a professor at the Chinese University of Hong Kong. At the turn of the millennium, he discovered the way to distinguish the fetal DNA in the pregnant women’s blood, giving an impetus to the rapid development of NITP methods that are harmless both to the
mother and the future child.
The main prerequisites for NIPT involve chromosome anomalies in the mother's or father's family history. Although this possibility is very low, the testing remains widespread, even though this procedure is not covered by general medical insurance in Russia and many other countries (except for some regional programs).
There is another genetic test that enables risk assessment long before pregnancy. It focuses on gene mutations that cause disorders like mucoviscidosis, spinal muscular atrophy (SMA), and others —
around 24 hereditary diseases in total. An Australian study shows that couples undergoing infertility treatment often turn out to be carriers of CFTR mutations (mucoviscidosis). In some countries, this screening is offered to all couples applying for IVF, despite the ethical ambiguity of this initiative.
While the medical community keeps discussing the potential social and
cultural damage of mass preconception screenings, the IT industry is looking for ways to optimize child diagnostics. It may take days to complete an NGS analysis, so in cases when any delay poses a risk to life and a decision needs to be made within 24 hours, the scientists suggest using artificial intelligence. AI can "notice" a genome decrypted by the NGS faster, even if no description is available. A recent comparative study demonstrates that AI can find a mutated gene in 92% of cases, while other methods fail to pass the 60%-threshold.
The international scientific community began to take gene therapy seriously in the 1970s when Theodore Friedmann and Richard
Roblin published their paper in Science. Back then, there were no tools for specifying the mutations, so Friedmann and Roblin emphasized that gene therapy required a careful approach. However, the outcome was the opposite: the research continued, and the first clinical trials of gene therapy methods were launched for severe and rare diseases.
When one patient died during the trials, those initiatives were put to stop (the US even suspended their specialized federal program) until 2003, when China relaunched the process and licensed gene therapy for head
and neck squamous cell carcinoma (HNSCC). Although this genetic product aimed to affect “broken” genes saw no further development, pharmaceutical companies from all over the world realized their ideas could finally be greenlit.
As a result, gene therapy drugs began to be applied in various branches of medicine. In 2018, for example, the first virus vector-based drug was approved for use in ophthalmology. Luxturna targets RPE65 mutations that cause blindness.
Oncohematology has a pool of developments built around CAR-T technology, the first of them being Kymriah, approved in the US in 2017. This method seeks to modify the patient's T cells genetically and codify the antigen receptor to target tumor cells. Four medications of this type are now used; Russia also has the practice of introducing its developments. Zolgensma, approved in the US in 2019, deserves a special mention, as only one injection of this medicine can cure SMA. It is one of the most
expensive drugs on the market, with one vial costing approximately 2.1 million USD.
The FDA predicts that by 2025, they will be approving 10 to 20 cell
and gene therapy products a year. These expectations seem realistic —
first of all, many clinical trials are undergoing their later stages right now.
One of the examples is von Gierke disease (glycogen storage disease type I) that for years has been treated only by regular consumption of corn starch.
Via a single injection of a virus, a new copy of a gene is delivered to the patient’s liver and “reboots” the body's glucose control. The first positive clinical trial results were published in 2019. The drug has already received orphan medication status in the US and the UK, with its Stage III trial planned to be completed this December.
Meanwhile, we are witnessing the CRISPR gene editing technology in its prime. As I wrote earlier, its founders were rightfully awarded the Nobel Prize in 2020. The method involves "cutting" the DNA using Cas9 nuclease and putting together the ends of this "cut" in a way that makes a defect impossible. The most successful case of integrating CRISPR into clinical practice was demonstrated by Sarah Cannon Research Institute specialists — in summer 2019, they applied this therapy for the first time to a patient with sickle cell anemia.
This disease (a mutation in the β-globin gene) causes red blood cells to deform and lose their elasticity and flexibility, as well as leads to dangerous drops in the hemoglobin level. After a year of therapy, the medics reported qualitative improvements in the patient's life: her hemoglobin level went up, and she needed inpatient assistance less often. In March 2021, similar trials began in several US research centers.
Countermeasures against the COVID-19 pandemic — testing
systems, vaccines, and medication — require the assistance of genetics. In
early 2021, the WHO emphasized the importance of collecting genome data on SARS-CoV-2 and sequencing the virus. To facilitate this process, scientists propose using AI, the way it is applied for disease diagnostics.
At the same time, research has been conducted to find mutations that make their carriers vulnerable to the coronavirus. The COVID-19 Host Genetics Initiative consortium found 40 "candidate genes" that affect susceptibility to this virus. The scientists analyzed the genomes of about 50,000 people affected by the disease with various degrees of severity. They concluded that the TYK2 gene and its variations increase susceptibility to viruses, bacteria, and fungi. Another potentially dangerous "breakdown" was found in the DPP9 gene that also increases the risk of lung fibrosis.
The French scientists have found a set of genes among patients
hospitalized in critical condition, with ADAM9 being particularly expressed.
All these patients did not belong to the general risk group: they had no
chronic diseases and were younger than 50. The study shows that this gene not only determines a more severe progression of COVID-19 but can also be potentially affected by targeted therapy.
As of now, this "COVID" research is more probing by nature than applicable here and now. Advanced technologies enable us to study the coronavirus more assiduously than any other virus in human history; in the next
decade, they can give us many opportunities to defeat dozens of infectious
diseases. How can we do it? We can study how a virus evolves online — so we will know what to be prepared for.
How soon will all these achievements become part of our everyday life?
The answer to this question depends on their availability and cost. The
coronavirus pandemic, with new strains being detected much faster in countries applying advanced genome sequencing technologies, has emphasized the importance of the economic factor.
Furthering the IT progress is the way to make genetic technologies less expensive and more widespread: availability of big data to the global medical and scientific communities helps save time and money by avoiding repetitive studies or therapeutic developments. While the importance of big data has become clear to almost every scientist, data transparency will become the key issue for the next few decades.
Rustam Gilfanov is an IT entrepreneur and a venture partner of the LongeVC fund.
In 2006, Rustam Gilfanov, together with his partners, opened an
international IT outsourcing company in Kyiv. Today, this company is the
largest developer of software for the gaming, marketing and finance industries.
 P4 — predictive, preventive, personalized, and participatory medicine
 von Bubnoff A. Next-generation sequencing: the race is
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