How Our Changing DNA Keeps Us Alive: Linda Chelico (Transcript)

Here is the full transcript of Professor Linda Chelico’s talk titled “How Our Changing DNA Keeps Us Alive” at TEDxUniversityofSaskatchewan 2024 conference.

Listen to the audio version here:

TRANSCRIPT:

The Blueprint of Life

Thank you. That’s DNA. It is sometimes called the blueprint of life. I’m sure we’ve all heard that before. Well, in some ways it is true. You can’t change your eye color, for example, but in many ways it really isn’t. Our DNA changes every day. DNA is actually getting damaged every day by external factors like UV rays from the sun or internal factors like chemicals.

Humans do encode in their DNA proteins that can repair that damage, but those processes can’t repair everything. For instance, when you go out into the sun and get exposed to UV without sunscreen, you can get a burn. That is your DNA getting so damaged that it can’t be repaired. The protective effect is to let those skin cells die.

However, most times your DNA repair can repair that sun damage, but my advice is don’t let those proteins work too hard. Mistakes over time can be dangerous. This is best illustrated by some rare diseases where DNA repair proteins don’t work properly. For one of these, a symptom is the onset of skin cancer at the age of eight years old, nearly 50 years younger than the general U.S. population.

Mutations: Good and Bad

This is part of the reason why cancer, a disease of DNA damage that does not get repaired properly, increases with age. The improperly repaired DNA damage causes mutations in the DNA. However, mutations are not all bad. Although mutations can cause cancer, in some situations, in other situations, they can also result in beneficial evolution. Mutations formed humans as a species and every other organism on the planet. Organisms evolve by acquiring mutations.

But how does biology decide what are good and what are bad mutations? I think of it like this. When we encounter uncertainties in life, it incites an uncomfortable feeling, one that can result in an attempt to bring things back to the status quo, repair the damage and bring things back to the way they were. However, sometimes inaction is not an option.

With some uncertainties, we’ve just needed to weigh the risks and make the best decision with the information available. We may have had a plan, a blueprint, but at times we’ve had to throw that out and just wing it, induce those mutations in our life’s blueprint. I think we’ve all been there before.

A Risk That Paid Off

I know I have, maybe too many times. I took a risk near the end of my PhD and I flew all the way from Canada to Australia to go to a conference celebrating the 50th anniversary of the discovery of DNA. All the best people in the DNA repair field were going to be there.

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And I was convinced during this trip that I was going to find a postdoctoral lab to work in in order to help me answer the question of how mutations occur in DNA despite DNA repair proteins and how biology is weighing these risks. Luckily, that risk worked out. And some days I still think to myself, how?

But that is another story for another time. The important part here is that I did find a professor from the United States to work with who studied exactly what I wanted to work on. And this was how bacteria deliberately introduce mutations in their DNA.

He and others discovered that bacteria lacking the ability to deliberately induce mutations in their DNA grew similar to other bacteria under normal growth conditions. But under stressful growth conditions, the bacteria that could not induce mutations died first. Sticking to the blueprint was detrimental. Risk, mutation, and evolution helped the bacteria to adapt and survive in uncertain situations.

A Surprising Discovery

So I show up to my postdoctoral lab to study this process, but instead I arrive shortly after a very surprising discovery had been made by scientists. Humans and other animals were found to encode in their DNA a large family of proteins that deliberately damages and induces mutations. Now this was in addition to the process I just told you about in bacteria.

Humans had evolved an additional way to induce DNA damage. So I took yet another risk and I switched my research focus to study this family of proteins and be part of figuring out the details for this exciting new discovery. And 20 years later, I’m still amazed by these proteins, but I’m sad to say that their name is not as amazing as their function.

Introducing APOBEC

They are called APOBEC. And if I sum up APOBEC to you, I would say that these proteins are experts at winging it. They don’t use a blueprint, they randomly induce mutations in DNA, and surprisingly, most of the time, it works in our best interest.

Biology has pre-calculated the risks. In my postdoctoral lab, I started studying one specific APOBEC family member that helps us make better antibodies. The second time we get an infection, we have a better and faster immune response. And it’s actually this APOBEC family member that’s essential for initiating that process.

During an infection, in real time, the DNA in your antibody-producing cells is evolving by APOBEC-induced mutations to respond to new pathogens that you’re exposed to during your lifetime. Rare diseases that inactivate this special APOBEC protein results in people being immunocompromised and 80% of the time not living to the age of 25. So inducing mutations can be an essential function.

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Returning to My Roots

As now as interesting and important as this process was, I wanted something more. I wanted to determine if this process could affect the whole body and not one specific part. And originally, I was trained as a microbiologist, so I wanted to get back in line with my original idea of studying DNA damage in microorganisms.

And this is where I switched yet again and decided to focus my research efforts, this time back in Canada, when I started my own lab here at the University of Saskatchewan.

There are some viral infections that antibodies don’t do a good job at clearing up. In these cases, there is another mechanism occurring from a larger part of this APOBEC family, seven different APOBEC proteins that do something more risky.

These proteins cause DNA damage and induce mutations in virus genetic information in an attempt to cause mutational catastrophe and inactivate them. Now that’s different than what I told you about in antibody genes and it’s another outcome of mutations. A few mutations and you have no effect, too many and you have catastrophe, and somewhere in the middle is beneficial evolution.

The Risks of APOBEC

There are many mutational paths. Mutational catastrophe happens quite easily in viruses because their genomes are very small in comparison to human genomes, but there’s also a risk for evolution. If APOBECs don’t cause mutational catastrophe, the lesser number of mutations may cause the virus to evolve.

My lab has discovered that these proteins work together to prevent this from being a frequent occurrence. However, they are winging it, so things may still go wrong. This is why a burning question for me and others in the field was how these APOBECs that cause mutations in virus genetic information avoid human DNA.

Sometimes the virus DNA is right beside the human DNA in our cells. As research progressed, it became clear that sometimes APOBECs do induce mutations in our genome. The extent to which this occurred was realized from precision medicine.

APOBEC and Cancer

Precision medicine involves the sequencing of a person’s DNA to find a personalized treatment for many conditions, but especially cancer. Decades of collecting this sequencing information from tumors uncovered that APOBEC-induced mutations are found in approximately 75% of cancer types. Myself and others jumped in the field to find out what this meant.

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This is because the mutations themselves don’t tell us the function of the mutations. Were they causing cancer cell catastrophe, killing the cancer cells like viruses? Or were they causing cancer cell evolution, creating new functions like the antibody genes? The problem answering this question is that if APOBECs cause cancer cell catastrophe, killing the cancer cells, this will never be detected in the clinic.

Only the evolution events that resulted in someone developing cancer is recognized when someone goes in the clinic and is diagnosed. How many times did APOBECs take the path of having the cancer cell evolve versus helping the cancer cell to die? To answer that, my research group followed in the lab the fate of APOBEC-induced DNA damage from the beginning.

Multiple Paths of APOBEC

The results showed multiple paths depending on the conditions that we exposed the cells to. Sometimes APOBECs did cause the catastrophe and killed the cancer cells. Sometimes they made the cancer cells look so different that they were cleared by the immune system like a pathogen.

And sometimes they helped the cancer to evolve. Right now, we are determining the probability of going down each of these paths under different conditions. By knowing the path after APOBEC-induced damage, we can develop new treatments for cancer based on managing APOBEC activity.

We can transform cancer treatment into one that can direct the tumor to go down a certain path rather than chasing what the tumor is doing. Studying APOBECs gave researchers the blueprint of cancer. As the goal to understand the source of mutations in cancer began to focus more on the role of APOBECs in cancer, mutations began to be considered from many different perspectives.

Embracing Change

Detrimental DNA damage, evolution, disease, immune responses. Mutations affect so many aspects of biology, life, our world. Good or bad. These discoveries have helped us to understand that DNA changes every day and over our lifetime. Personally, APOBECs have taught me to embrace change in my everyday life. Several times I had to just wing it to keep following our data and it led to several new discoveries.

Not following the blueprint was uncomfortable at times but I’ve learned to do it. And perhaps we all should. It’s in our DNA. Thank you.