The coronavirus pandemic changed the world. It changed economies, it changed education, it changed politics. The pandemic will continue to have a long-term effect on health, and science. There are many fields that won’t stay the same, from International travel to the development of vaccines.
Among those, there’s one field, not widely discussed, that has become the forefront of the fight against the virus. Genome sequencing allows researchers to learn about the virus, find variants, and even perform epidemiologic investigations. The field is going through a massive change.
I spoke to Prof. Adi Stern, an expert in biotechnology and the evolution of viruses. She is head of Stern Lab at the Tel-Aviv University where Prof. Stern and her team were the first to genomically map the Covid-19 virus when it arrived in Israel. In our talk for my podcast ‘One a Day’, I asked Adi for a simplified explanation of genome sequencing — a ‘Genome Sequencing for Dummies’ if you will.
Elad: Prof. Adi Stern, thank you for having this talk with us.
Prof. Stern: Gladly.
Do you remember the day you received the first Covid-19 samples and started the work of mapping them?
Sure. It was a long time ago, it feels like a long time ago. I knew that I’m dealing with a dangerous disease and that dealing with these samples could be unpleasant, but in terms of science, it was all very exciting.
How did it go?
It was actually like being some sort of a detective. We had to find our way in uncharteredterritory, ask questions and find answers. Our first few attempts didn’t all go as planned, some worked better than others, but when it finally did work it was a huge success. We could actually see covid in our own eyes.
Let’s start from the beginning. What’s genome sequencing?
Every living organism, and in this case I’ll include a virus as a living being, has a genome sequence that functions as a kind of manual. We, humans, have DNA, that’s our manual. Viruses have a genome sequence too, it’s their manual. It’s basically a long string of nucleotides, for the sake of simplicity let’s say, a long string of letters.
Our job, when trying to map a virus genome sequence is to decipher what that manual says. For that, we need to uncover the letters that it contains, find their order, and translate the sequence’s meaning.
What do you mean by manual? Are these instructions for where to go and what to do, basic stuff?
Yes. The so-called manual defines what the virus should do once it gets into a human body. It translates the actions needed for the virus to duplicate or evade our defense systems, for example. The virus is a parasite, it can’t actually do anything on its own. A virus needs a human’s cell to take control over, and then it turns that cell into a virus-producing factory. That’s what a virus aims to do, create more viruses. The way to do that is to follow the manual, the genome.
What can we learn by mapping the genome sequence? By deciphering the manual, to continue with our analogy.
I’ll give you two examples. Firstly, by looking at the data we could find changes in the virus, which are known as variants. We could compare two sequences from two strains of the same virus, and see whether a mutation happened. There are studies that could tell us what is the actual meaning of these changes. They could be significant.
Secondly, by understanding the virus better, the way it operates, we could find more useful treatments. Mapping the genome of a virus could, for example, help us reach a vaccine faster. When you know how a virus acts, what its manual tells it to do, you could stop it before it does anything. There’s a lot of information hidden in the genome sequence, a lot of information.
So how do you actually do it? What are the steps to mapping the covid genome?
We first get a sample from a swab. The sample we receive is full of cells we don’t need. Other than covid there are other cells coming from our noses, we don’t want those. So initially there’s a lot of work to separate the virus from all the other cells. It’s a form of art really, we mix, and add, and dilute, until we get a clean covid sample.
The second stage is done by a machine. In our lab we have sequencing machines, they copy the virus’s genome. What the machine basically does is mimic what’s happening in our bodies. The virus duplicates itself, and if we said that the genome is a string of letters, the machine copies the genome one letter at a time. The thing is, when the machine does that, it also adds colors to the letters. The letter ‘A’ will get a bright red color, ‘B’ will get bright green, and so forth. The machine knows how to translate these colors and gives us an output of the letter sequence.
And you can read this output? Make sense of it?
Well, it’s very complicated. We don’t really know what every sequence means. Eventually, the computer shows us many elements and we could tell where a sequence begins and where it ends, which part is important and which isn’t. There’s much we could say and much we couldn’t. It’s very complicated. It’s basically a 30-thousand-long word, it’s hard to understand all of its meaning.
You said that your job is like detective’s work, it actually sounds more similar to what a linguist would do.
I love this analogy! I’ve always seen similarities in people who look at genome sequencing and linguistics, it’s definitely similar. There are rules to the evolution of a language that are similar to those of viruses. There are some resemblances.
So now that we understood the basics of mapping the genome, let’s talk about covid. Was it any different working on this virus compared to others?
It’s longer, it made it more difficult.
How do you mean?
The human genome has around 3 billion letters, that’s its length. RNA viruses usually have around 7,000. Covid is significantly longer, it measures at around 30,000. That’s longer than the flu or HIV.
What does that mean?
It means that the coronavirus is more complicated than other viruses. It has more genes in its genome. One of its characteristics is that it evolves slower, it is rarer for it to mutate compared to other viruses. The flu, for example, changes often, but covid, due to its size and complexity, takes more time to change. This is good, it’s good for us.
And yet, it does change, we do see variants. How does that happen?
When the virus enters a cell it starts duplicating itself. It actually means that the genetic code, the manual as we called it, needs to be copied onto the new viruses that are now being created. When the virus copies the code it's pretty accurate, but not 100% accurate. Mistakes do happen. That’s what we call mutation. It’s a mistake in the copy of the genetic code.
Think of covid. There are millions of people sick, each one has a covid factory inside his cells. The amount of viruses copying themselves is huge, there bound to be mistaken at a certain point. Most of these mistakes are meaningless, too small for any real change in the virus behavior. But every now and then a mistake comes along that changes the way the virus behaves. That’s what we are seeing in the recent variants.
Do we know when these more significant mistakes happen?
What experts believe today is that these variants were created in people with a low immunity system. Most people are over covid after a week or two, most people beat the virus fast. However, there are those who are fighting the virus for weeks and months, all of this time the virus is inside their bodies. When the virus has so much time, it changes. That’s where most variants we know of were created.
I guess not all changes are necessarily bad, the virus could change in a way that makes it weaker.
That’s correct. Luckily we know that most of the virus mistakes actually make it weaker. It’s very rare to see a mutation that ‘improves’ the virus. I’m putting quotes on ‘improve’ as a stronger virus is not exactly what we think it is. A virus that changes and is now spreading more easily is not necessarily more dangerous.
What’s the virus’s interest? To spread to as many people as possible, to conquer as many cells. Its interest is not to kill its host, us, as it will die too. These are matters of evolution. The virus needs us alive, we hardly see a mutation that turns a virus into more deadly. It’s rare.
It sounds like genome sequencing is a very powerful tool, how big of a role did it play during the pandemic?
We found ourselves doing many different things. We used our knowledge and expertise to investigate large outbreaks. We used genome sequencing to conduct an epidemiological investigation. I have a story about one. we were called by a hospital to help them investigate an outbreak. They were very nervous, it was the beginning of the pandemic, and their investigation showed that the source was a woman and that meant that the virus traveled through the air vents.
We came in, we did the sequencing, and we found that she was not the source but actually a man. It made perfect sense as well as he was walking all over the ward.
How did you come to that conclusion?
The coronavirus changes, on average, every two weeks. As we said, most changes are minor, they don’t change how the virus behaves. Whoever is infected wouldn’t know the difference, but those changes could be seen in the genome. The order of the letters in the code, what we called the manual, is different.
And so, we checked the woman’s code, the man’s code, and the code of those who were infected. The man and the woman had a different genetic code, those who were infected had the man’s version of the virus.
Through sequencing, we could reach a conclusion that a minority of the people are responsible for the majority of infections. We could show that major events are potentially more dangerous than others. We did many different things.
That’s amazing. Lastly, I wonder if the pandemic changed the field, do you think things will seem different from now on?
No doubt. Many fields in biology and science have started looking at sequencing today. I think people have understood the power of this tool. It could be used to examine many other diseases as well. We could examine why certain people are potentially more vulnerable to certain types of diseases. There are endless possibilities.
I think the bigger question is what to do with all the information. The more you sequence the more information you get. Today, there are more than a million genome sequences of covid that were mapped all over the world. The challenge is knowing what to do with this information, and how to best use it to help improve the world.
Prof. Adi Stern, Thank you very much.
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