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We are all mosaics

The X chromosome biology provides a beautiful paradigm to study epigenetic regulation.
by Areej Mehdi

Asifa Akhtar, born in Karachi, Pakistan, became the first international female Vice President of the Biology and Medicine Section in the Max Planck Society in 2020. Akhtar received the European Life Science Organization (ELSO) award for significant contribution in the field in 2008. In 2017, she was awarded the Wilhelm Feldberg Prize for outstanding contribution in the field.

Managing Editor Areej Mehdi sat down with Asifa to discuss her work and the exciting prospect of epigenetics.

When did you first get interested in science?

Science was something that interested me during school. I was very fascinated in biology in general; how things are built, how our bodies are working, can we understand something about them? As I progressed through my education, and got to know more and more about chromosomes and cells and genes and how they’re regulating, it got me more interested in following the route of academic research.

Why study the X chromosome specifically?

X chromosome biology provides a beautiful paradigm to study epigenetic regulation. If we look at chromosome numbers, we are all made up of 46 chromosomes, with 22 autosomes and a pair of sex chromosomes. Women have two X chromosomes and men have an X and a Y chromosome. All the other chromosomes always come as (pairs of) two in men and women. If you look at the gene dosage, females have one X chromosome too many in comparison to the men. So how come, despite this difference in chromosome number, we operate more or less the same? Obviously, there are some important differences, but on average, we behave the same way, feel the same, and look at things the same way. How is that regulated? The X chromosome is beautiful because although females have two identical X chromosomes, they actually shut down one of their X chromosomes very early in development randomly.

In essence, we are mosaics. For example, part of our brain on this one side may have one chromosome activated and in the other half another one is inactivated. And this mosaicism stays all over our bodies.

If you look at calico cats, they have orange and black patches. That coat color gene is located in the X chromosome, and that patch originated from a decision that the baby cat made very early embryogenesis – a decision that is remembered through generations. With epigenetics you can study how a decision that was made is remembered throughout generations and is regulated knowing that the two X chromosomes in principle have identical genetic count.

Is this also applicable to fruit flies on a genetic level?

Exactly. X chromosome and dosage problems not only affect humans, but also affect systems like fruit flies. Fruit flies are much smaller but they also have a male and a female and with apparent differences in X chromosome. Since it’s a much simpler model system you use expertise on one system to understand how gene dosage is being regulated. And because the generation time in the flies is only two weeks, and they have a beautiful genetic model system to look at, gene regulation provides us with a means to understand what’s happening in the flies.

Interestingly, there is a difference in X chromosomal doses between flies and humans in that it is the males that have the single X. And they up-regulate their single X (chromosome) two times, in comparison to the females that have two X chromosomes. That provides yet again a very interesting comparison. While human females are shutting down one of their X chromosomes to equalize the males, what the male flies are doing is that the ones that have only one X, double their output, so for example, turn on the radio twice as much.

How are all these decisions being made? We use different model systems to study this. We use flies and mice and more recently also a human patient to look at that. It gives us a very interesting way to try to understand how, in human patients, the genes are being mutated, what is going wrong, and there, the lessons that we learned from the flies are fundamentally important because we can move much faster to understand the mechanism of how things are working.

What are some examples of this research? Could we use this to turn on/off signals to help people with chronic pain for example?

Chronic pain is one example of many types of diseases that occur. What happens in chronic pain is that you have a lot of inflammation, and that is correlated with changes in gene expression programs. Changes in gene expression programs are actually related to epigenetic regulation. If we understand the mechanism of how, in different types of cells, epigenetic factors play a role and if we understand the mechanistic principle, of course in the long run, we have the possibility to understand how we can help situations like chronic pain. That’s why there is a lot of hope for epigenetic therapy because you are able to use the plasticity that epigenetic regulation brings us, to help modify, or have the possibility to modify gene expression programs to at least help in certain diseases. To be able to really do this properly, however, we need to understand the mechanism. We’re at the stage where there is a lot of hype around epigenetics, but I think it’s important to do the basic work first.

What current research at Max Planck Society are you excited about?

I’m very interested in evolutionary comparison, especially fly models which are very basic. If you compare the human genome versus the drosophila genome 75% of the important genes are conserved. There is much less redundancy in the fly system for the same gene that maybe is present three times, or three versions in humans who will have only one in the fly system. Life becomes much simpler because if you take it away, you immediately see the consequence, which in my eyes will be, for example, much more difficult.

What is fascinating for me right now, is to look at the breadth of how we are evolving our functions and to use the appropriate systems. It’s important to do work in model systems, but to be able to really understand what’s happening in a disease state, we actually have to work on the disease cells. So we are very interested in collaborating with clinicians, where they have identified patients with the proteins we work on, to be able to directly relate our work with clinical implications. This is the direction we will be going in. I think the strength of our research is to really combine basic understanding and see whether we can help with applied research as well.

You are a vocal supporter of gender equality in the sciences. What are some steps you are taking as VP at Max Planck Society’s biology and medicine section?

Gender diversity makes us richer as a society – not only as the Max Planck Society, but society as a whole. I think we should make all efforts trying to recruit women in science. There are outstanding women out there. We just have to go and look harder to find them. If you look at the numbers, at student level or even at PhD level, we have almost equal numbers of men and women. But if you go up the hierarchy, there is an inverted pyramid. Of course, for women, the combination of having a family and having a career still remains a challenge. But  we need to tell women that it’s okay. It’s exciting that you’re going forward. It is also okay to say that it will be challenging.

Within the Society, compared to when I started to now, there are definitely more women. We make really active recruitments to look out for women. So definitely the Max Planck Society has increased the number of women over the last 10 years already and we want to move forward even more. If I look at my own career track going from student to now, there are many more women out there than there were 20 years ago. I definitely see that the mindset of people is also different. I think there is a very positive trend and we should really push on that. My effort right now as the vice president, but also as a female scientist, would be to help towards that cause and every one person that we can recruit and motivate to continue and go forward is a success for me.

For students who are interested in this line of work, what skills do they need to develop?

I think the most important asset that you need when you want to become a scientist is that you are curious. You will be able to learn the technical stuff, if you’re motivated and are burning for knowledge. Being a scientist, at least for me, is a job of passion. You have to be wanting to do this, it is one of those jobs where it is very difficult to switch off. For me, it’s not something that you do nine to five and then forget about it.

The projects in biomedical research are centered around discovering new areas where nobody has gone before, and which we don’t know where it’s heading. You should be ready to restructure your thoughts and not be fixed with one hypothesis. You need to be open in the way you think. You need to be creative in trying to shape that, which is a challenge. Of course, it can also be overwhelming at the beginning and that’s why you need a balance of wanting to be creative, but at the same time, also listening.

Do you have any active collaborations with Pakistan?

So far, we don’t we don’t have any active running collaboration with Pakistan. Of course, we are open to that. Usually, they are depending on different countries but are also independent of countries like partner programs, exchange programs, that one can develop in various areas. But what is important for the next generation of scientists to know is that we have a very competitive and international PhD program at Max Planck and we recruit internationally.

I really think that, for Pakistan to move forward, it’ll be very important for the country to invest in science and education. For instance, the German society is very supportive of science education because it sees this as investing in the future. I think it would be fantastic to have forums in Pakistan where one can bring people from different countries to see what people do and learn from that. But the first step is to be interested in going forward in that direction. The mindset has to be there but of course, it goes hand in hand with infrastructure. If you don’t have the infrastructure, you also can’t do anything. Pakistan is full of outstanding people. We can make things happen if we want.

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