The global coronavirus pandemic has profoundly altered various aspects of life, from economies and education to politics. Its repercussions will likely continue to influence health and scientific fields for years to come, reshaping areas such as international travel and vaccine development.

One crucial yet often overlooked area that has emerged as vital in combating the virus is genome sequencing. This technique enables researchers to understand the virus better, identify its variants, and conduct epidemiological studies. The field is experiencing a significant transformation.

I had the opportunity to speak with Prof. Adi Stern, a specialist in biotechnology and viral evolution. She leads the Stern Lab at Tel Aviv University, where her team was the first to map the genome of the Covid-19 virus upon its arrival in Israel. During our conversation for my podcast "One a Day," I asked Prof. Stern for a straightforward explanation of genome sequencing—a “Genome Sequencing for Beginners,” if you will.

Elad: Prof. Adi Stern, thank you for joining us today.

Prof. Stern: My pleasure.

Elad: Do you recall the day you received the initial Covid-19 samples and began the mapping process?

Prof. Stern: Absolutely. It feels like a long time ago now. I recognized that I was dealing with a serious disease, and that working with these samples could be challenging. Yet, from a scientific perspective, it was incredibly exhilarating.

Elad: How did the process unfold?

Prof. Stern: It felt somewhat like being a detective. We ventured into unknown territory, posing questions and seeking answers. Our first attempts didn't always go as planned; some were more successful than others. However, when we finally succeeded, it was a monumental achievement. We could actually visualize the virus.

Elad: Let’s start with the basics. What is genome sequencing?

Prof. Stern: Every living organism, including viruses, has a genome sequence that serves as a manual. For humans, this manual is our DNA. Similarly, viruses possess a genome sequence, which we can think of as a long string of nucleotides—essentially, a sequence of letters.

Our task in mapping a virus's genome is to interpret what this manual conveys. We must identify the letters it contains, determine their sequence, and translate its meaning.

Elad: What do you mean by a manual? Are these instructions for basic functions?

Prof. Stern: Exactly. This manual outlines what the virus must do once it enters a human body. It instructs the virus on how to replicate or evade the immune system, for instance. A virus is a parasite; it can't function independently. It needs to hijack a human cell, turning it into a factory for virus production. Following the manual—the genome—is essential for this process.

Elad: What insights can we gain from mapping the genome sequence?

Prof. Stern: I can provide two examples. First, by analyzing the data, we can identify changes in the virus, known as variants. We can compare sequences from different strains and ascertain whether mutations have occurred. Research can reveal the significance of these changes, which can be crucial.

Second, by deepening our understanding of how the virus operates, we can identify potential treatments. Mapping a virus’s genome can expedite vaccine development. Understanding how a virus acts and what its manual instructs can allow us to intervene before it causes harm. There’s a wealth of information embedded within the genome sequence.

Elad: What are the steps involved in mapping the Covid genome?

Prof. Stern: We start with a sample collected from a swab. Initially, this sample contains numerous cells that are irrelevant to our study. We need to isolate the virus from these other cells. It’s quite an art form; we mix, add, and dilute until we obtain a clean Covid sample.

The next step is performed by a machine. In our lab, we have sequencing machines that replicate the virus’s genome. This machine mimics the process occurring in our bodies: as the virus duplicates, the machine captures the genome letter by letter, adding colors to each letter. For instance, 'A' might be red, while 'B' could be green. The machine can interpret these colors and generate the letter sequence.

Elad: And you’re able to read this output?

Prof. Stern: It's quite complex. We don’t fully understand the meaning of every sequence. Ultimately, the computer presents us with numerous elements, helping us identify where a sequence begins and ends, which portions are significant, and which are not. It's a complex task, akin to deciphering a 30,000-letter word.

Elad: You've compared your work to detective work, but it also sounds similar to linguistics.

Prof. Stern: I love that analogy! I’ve always seen parallels between genome sequencing and linguistics. The rules governing language evolution share similarities with those of viruses.

Elad: Now that we grasp the fundamentals of genome mapping, how did working on Covid differ from other viruses?

Prof. Stern: The Covid genome is longer, which adds to the complexity.

Elad: How so?

Prof. Stern: The human genome consists of about 3 billion letters, while RNA viruses typically have around 7,000. Covid, however, has approximately 30,000 letters, making it longer than both flu and HIV viruses.

Elad: What implications does that have?

Prof. Stern: It indicates that the coronavirus is more intricate than other viruses, possessing more genes in its genome. One of its traits is that it evolves at a slower rate, mutating less frequently than other viruses. For instance, the flu virus mutates often, while Covid’s size and complexity mean it changes more slowly, which is beneficial for us.

Elad: Yet we do observe variants. How do those arise?

Prof. Stern: When the virus infects a cell, it begins to replicate. This means the genetic code needs to be copied for the new viruses. While the process is generally accurate, it’s not perfect, leading to errors known as mutations.

Consider the millions of infected individuals; each person has a virus replication factory in their cells. Given the vast number of viral replications, mistakes are bound to occur. Most errors are trivial and don't affect the virus's behavior. However, occasionally a mutation occurs that alters how the virus operates, resulting in the variants we see today.

Elad: Can we identify when these significant mutations happen?

Prof. Stern: Experts believe that many of these variants emerged in individuals with weakened immune systems. Most people recover from Covid within a week or two, but some struggle for weeks or months. During this prolonged period, the virus has time to change, which is where many known variants originate.

Elad: Not all mutations are detrimental; some could render the virus weaker.

Prof. Stern: That’s correct. Fortunately, most mutations tend to weaken the virus. It's quite rare for a mutation to enhance the virus. When I say "enhance," I mean that a virus that spreads more easily isn't necessarily more dangerous. The virus's goal is to infect as many cells as possible without killing its host, as it would perish as well. Evolution favors the virus's survival, which is why we seldom see mutations that make it more lethal.

Elad: Genome sequencing seems to be a powerful tool. How significant was its role during the pandemic?

Prof. Stern: We found ourselves involved in various tasks. We leveraged our expertise to investigate major outbreaks and conducted epidemiological analyses. I recall one case where a hospital sought our assistance in tracing an outbreak. They were anxious, as their investigation indicated that a woman was the source, suggesting the virus spread through the air vents.

Upon our arrival, we conducted sequencing and discovered that she was not the source; it was actually a man who had been moving throughout the ward.

Elad: How did you arrive at that conclusion?

Prof. Stern: The coronavirus mutates approximately every two weeks. While most mutations are minor, they can be detected in the genome. The order of letters in the genetic code varies.

We compared the genome sequences of the woman, the man, and the infected individuals. The man and woman exhibited different genetic codes, while those infected shared the man’s variant.

Through sequencing, we could determine that a small number of individuals are responsible for the majority of infections. This insight allowed us to identify significant events that might pose greater risks.

Elad: That’s fascinating! Finally, do you believe the pandemic has transformed the field? Will things change moving forward?

Prof. Stern: Absolutely. Various biological and scientific disciplines have begun to recognize the value of sequencing. People are starting to appreciate the power of this tool. It has applications beyond Covid-19, allowing us to explore why certain individuals might be more susceptible to specific diseases. The possibilities are virtually limitless.

The larger challenge lies in managing the vast amount of information generated. Currently, over a million Covid genome sequences have been mapped worldwide. The key question is how to utilize this information effectively to enhance global health.

Elad: Thank you so much, Prof. Adi Stern.

Prof. Stern: Thank you for having me.