Women and Science, War and Peace, and the Amazing Spliceosome

Saba Valadkhan was born in a small town just outside of Tehran, and with much encouragement from her parents, she excelled in her studies and then entered medical school at an early age. She found the routines of medical practice fulfilling, but frustrating too. She wanted to do work that would have an impact not just on her patients, but on people everywhere, for generations to come.

That ambition brought her to Columbia University in New York, where her research into the spliceosome—a powerful molecular machine located within the cell—helped to solve one of the crucial riddles of molecular biology. For that work, she has been named to receive this year's $25,000 Young Scientist Award, supported by GE Healthcare and the journal Science.

Valadkhan is now an assistant professor in the Center for RNA Molecular Biology at Case Western Reserve University in Cleveland, Ohio. In a 2 February telephone interview with AAAS senior writer Edward W. Lempinen, she talked about her childhood, her research, the challenges of being a woman in science, and the current diplomatic conflict between the country where she was born and the country where she lives.

I want to start at the very beginning—how you grew up, and how you came to science. Tell me about how you were shaped by growing up in Iran.

I think the aspect about growing up in Iran that is related to my decision to become a scientist would be the general way that the society values education. At least when I was growing up, being educated was the one single important determinant in where you ranked in terms of the social hierarchy. Especially going to medicine was valued greatly. So I think while we were growing up as early teenagers, we were sort of directed toward being educated: getting a good college education, and probably going into medicine.

I think also it was probably partly my family atmosphere. My father is not a scientist—he's an engineer—but he has a very analytical, problem-solving approach to every single thing that happens, that he hears about. That's the way he thinks, it's the approach he's always had, and that makes me feel very comfortable doing science because that's the way I've always seen my parents look at the world.

What work did your mother do?

My mother is a high school teacher. She's been a great role model for me because she always wanted to do so much, much more than she's currently doing. She was always very unhappy with the regular daily chores of life, and she always thought that we've got to be out there changing things, doing science, doing great things for humanity. In her mind, those are the things that are of value and worth doing, and everything else was like boring and repetitive, things you do just to survive. I think that when I told her I wanted to be a scientist, she thought that was the right thing to do, and what she probably would've wanted to do herself.

The impression that's shared by many people in the West, I think, is that Iran is such a conservative society that science would not be valued, and that women in particular would have very limited opportunities to get into science. Is that a misconception?

I think so. You know, it's very difficult—when we talk about these issues, we have to think about exactly what we mean by conservative. Iran is actually not as conservative as people think. To me, coming from Iran, I think the U.S. is also quite a conservative society. Especially because in recent years the Iranian population is mostly made up of the younger generation, I think the general atmosphere of the country is a very liberal atmosphere. Although in the society, like in all traditional societies, there are impediments to women having equal rights with men, but these are never at the level of seeking education. Maybe a little bit afterward, in getting jobs, but never education. In education, girls have much better opportunities than boys. The numbers say that a higher percentage of girls graduate from high school and from college than boys. Educationally, I never felt for myself or anyone else that that we didn't have opportunities. We had every opportunity.

After that, the job market looks at women a little bit with disfavor because traditionally it is thought that women put too much energy into their families—household work and other things that are related to family life—and that they wouldn't be as career-driven as men are. But I think women still have a good chance to break that misconception. You could basically get the job you wanted if you tried hard enough.

The things that they say about women being oppressed in Iran is not about having education or job opportunities. It's mainly at the level of families. Women are really oppressed in their families. Basically, they don't have any rights. And that would affect their ability to be effective in the workforce, because they will be carrying a very unfair share of what is happening at home, of household chores. And also because they would probably have to tolerate a lot of negative attitude toward working from their family. You're not supposed to be putting a lot of time into your work—you're supposed to be mostly at home taking care of things, and that would affect their productivity and their ability to work. So the oppression is something that's coming mostly from home. It's not coming from the workplace.

When you say it's coming mostly from home, and not from work—it doesn't come from Islam, or conservative Islam, that women should stay home and not work?

It does in the sense that conservative Islam affects the way families behave and family laws are written. But the workforce generally—if you are willing to totally fight back, and decide not to put too much time and energy into your family chores, and to do your work seriously, then employers are very happy to have you. Although you sure will be under a lot of pressure from your family.

I guess what I want to say is that there are numerous examples of women working very hard and doing a superb job, but you must first make employers realize that you belong to that category.

Tell me about why you came to the United States, and the process by which you came here.

I went to medical school in Iran. In the beginning I liked it very much, because I was studying all the basic sciences and basic sciences are just so much fun—they're just great. But then we started doing our clinical rotations. In the beginning it was very fun to be with the patients and you feel like you're able to help. But then after a while we'd realize that really, a lot of times we are not able to do much. We could see our patients and do all that's in the books to help them, but a lot of times it wasn't effective enough, and it was very depressing.

And then you read all the journals, and you read things about how people are trying to change that, to create more effective therapies, to understand more precisely how diseases happen. And that just sounded so much more worth doing. Rather than treating patients one by one, you could work to make a change that would affect everybody on earth that has that disease, for all the future generations. That just sounded so amazing.

So I thought that I would want to do science, but it isn't very easy. Medicine doesn't require as much budget as science does. Because it is more immediately related to the well-being of the people, it is much better-funded in Iran than science is. So we have all the best equipment, everything—our hospitals are very, very well-equipped. But science is not faring as well because science is more indirect. Money that you put in now may or may not reach fruition in 10 years, 20 years. So in countries like Iran that have a smaller budget to distribute, science is always very disadvantaged. And the embargoes against Iran don't help the situation very much, either.

The result is that Iranian science, and especially biological sciences, are in no way competitive with what's happening here [in the United States] or in Europe. So if I wanted to do real science, and make a real difference, I just couldn't do it in Iran. I had to come here.

The bad thing is that there aren't any U.S. embassies in Iran, and so you don't have any idea of how to come to the U.S. The U.S. has the best recruiting machinery—if you want to go to a foreign country and study, the easiest place used to be the U.S. Right now, with the visa problems, that's changing. So, obviously, you wanted to come to the U.S. if you could, but we didn't have any means of figuring out how to do that. So that was pretty difficult. Even when you figured out that you have to take standardized tests like GRE and TOFEL, I had to travel to Turkey to take the tests. And then there was all the trouble of finding—in those days the Internet was just starting, it was '95—and it was a lot of trouble finding the schools and the addresses and sending the applications out.

I think the schools sort of were shocked to see our applications. At least Columbia told me that. They said, 'When we saw your application, we thought—whoa! People in Iran are alive! There are women in Iran who do science!' [She laughs.] So I think that means that not a lot of people could actually figure out the way of getting further education in the U.S.

The other funny thing is that, because there are no direct banking relations between Iran and the U.S., you can't send an application fee. So I could only apply to schools that did not have an application fee, and those were Ivy League schools. I had to get into an Ivy League school, or nothing. So I fortunately could get into Columbia.

What specifically did you come to study?

The department that I entered was very broad. We had basically something from everyplace—across the spectrum of biological disciplines. But I wanted to do molecular biology. I thought that was where the most exciting games were being played. I thought the work that was being done in Professor James Manley's lab was very exciting, so I joined his lab. I asked to work on the core elements of the spliceosome, and Jim already had a project working on those, so all went very well.

Tell me about your research at Columbia that helped you to win the Young Scientist Award. Why did you become interested in the spliceosome?

When I started science it was the time that we were starting to realize there are big molecular machines in the cell that do very important tasks. One of them is the spliceosome, which I work on. The spliceosome is the biggest machine in the cell. What it does is preparing the genetic information for use. At that time, the scientific community knew enough about the spliceosome to sort of figure out who the major players are [within that machinery], but still, nobody could exactly figure out what was going on. Because there were these elements that we knew could come together to form the spliceosome, at least part of the elements were known, but nobody knew how these worked. There was a lot of guessing, but nobody had really been able to pinpoint what was the catalytic part, the part that performs the essential function, and what the other parts were, that perform a supportive role for the core element.

I thought that was a very exciting thing because not only would it sort the field out and put everything into order, but it was also very intellectually interesting because it's generally thought that life started on Earth as what we call "the RNA world." It means that the first living organisms on Earth were nucleic acid molecules, of the type that is called RNA. These not only could carry the information that is necessary for life, they also did catalysis. To have a living entity, you've got to be able to carry the information that's needed for enabling you to make another one just like yourself. Not only should you be able to make another one of yourself, but the new one also should be able to replicate itself. So you have to have the information needed for performing the replication function in you.

The RNA molecules could do this—they are not only able to carry information around, but they have the ability to perform catalytic reactions. And so they could catalyze the formation of another RNA molecule just like themselves—like making a baby that's exactly identical to them. This way they could propagate, and there would be a lot of them. And then the theory goes that then, they started to add proteins to themselves to make themselves more sophisticated living creatures. And this went on and on until right now, when in living cells, most of the cell is protein, and the RNA and other nucleic acids—well, RNA is still playing some very critical roles, but it has given up most of its functions to proteins.

Then, something that's very exciting is to figure out where we still have these RNA molecules in the cell because, for example, a couple of years ago it was shown that another very important cellular machine that makes proteins, the ribosome, is really an RNA enzyme, so it was shown that RNAs are really performing the function of making proteins. That's very exciting because it means that this is a molecule that has been around, this is a function that has been around since the start of life, when RNA molecules were doing everything, including making proteins. These RNAs are called molecular fossils, because they have been conserved in evolution since the time that the first living organisms formed on Earth.

That's really interesting.

Thanks. What's interesting with the spliceosome—it's a huge molecule, with over 300 different parts, and five of these are RNA molecules. The exciting thing was, are these tiny RNA molecules the real catalytic players, the real players in the reaction? Are these also molecular fossils from 4 billion years ago?

So I thought when I came into science that there was a chance to address these questions. And so I just went ahead with it and tried to figure out if that was indeed the case.

Was there a moment in your research when you realized suddenly that you'd achieved this breakthrough? Was there a Eureka! moment?

Well, yes, I think so. What we wanted to do was to figure out if these RNA molecules can perform something similar to what the whole spliceosome—this big machine with over 300 different parts—is doing. So we took two of them, which were the most likely candidates, and we tried to see if they behave the right way, in the sense that they interact with each other in the correct way and if they're able to perform the function that the whole spliceosome does.

The exciting moment came when we put these two RNA molecules together and we gave them the substrate of splicing reaction, which is the type of genetic data that the spliceosome prepares for use. We gave them this tiny bit of genetic data and we were able to see that they not only right away recognized the genetic data, but that they reacted with it correctly and performed a reaction that was similar to what the whole spliceosome does. That was a very exciting thing. What's incredible, it just happened the first time I tried it. It was just waiting there to be figured out. I think that had to be the Eureka! moment.

And were you alone when that happened? Were you with colleagues? How did you react?

I think that something we scientists learn very early is to be very, extremely critical of everything that looks too exciting to be true. [Laughs]. And I saw it and I'm like, "This has got to be an artifact." I had this radioactive gel that I had exposed to a sensitive screen so I can see the result, and I saw this new band appearing, which was the product of the splicing I had done with these two tiny RNA molecules. And so I started to re-expose the radioactive gel in all sorts of different angles to see if the band was still there, and I did all sorts of controls to see if it is indeed an interesting thing, a new product.

I think after about a week or so, 10 days, we knew we had something that was really exciting. For about 10 days we were terribly excited but still not terribly happy. I don't remember if I was alone. I guess you're so critical and worried about what you've seen that you just don't remember the details.

How do you think your discovery will be used in the future? What might the practical effects and the practical benefits be?

There are many ways that we can think of it. First of all, they say that about 20 percent or 30 percent of all human genetic diseases are caused by mistakes that the spliceosome makes. If something goes wrong with the spliceosome, it's very likely that a genetic disease happens. And it's so sensitive, because almost all genetic information has to pass through the spliceosome before it can be used. So very large mistakes by the spliceosome, any real big defect with the spliceosome, is incompatible with life. And very tiny mistakes cause the genetic diseases that we're talking about. We've also seen that in a lot of cancers, or in a lot of neuro-degenerative diseases like Alzheimer's, again the culprit is mistakes in the splicing reaction, which the spliceosome performs.

So basically there is this big machine that is sitting at the heart of gene expression and is monitoring all the genetic information passing through it, and if there is something wrong it usually can find it out and discard the wrongful genetic material. But if it doesn't, the wrong thing just passes through it, the mistake, and really creates a lot of trouble in the cell and for the organism.

The problem is that you would like to study these and figure out exactly how these happen, but the spliceosome is so big that it's a lot of trouble to study it. You have these huge, gigantic molecules, these gigantic machines, you have 300 or so different parts, and it is not even static, you know—it's a very dynamic machine. There are other huge machines in the cell, like the ribosomes, the machinery that makes proteins, which is also an RNA fossil. But that is at least more static. But in the spliceosome, things come and go, components switch places, it's just totally crazy. So it's very difficult to study how this machine works. And at the same time it is so important.

So what we are hoping that my research will lead to is that we start to make a very simple, minimal splicing machine—just the core elements and a couple of other elements in addition—and this way we have a tiny, neat machine that's very easy to deal with. It is accessible to a lot of different scientific approaches that the big spliceosome is not.

For example, a lot of cancers are caused by mistakes in the genetic information that results in the spliceosome making mistakes in editing them. But it's not clear a lot of the time how these mistakes translate into mistakes in gene expression. What the minimal spliceosome that we want to make could do would be to create a means of figuring that out, so we can look at genetic information and then we can figure out what happens when the genetic information had this or that defect, how did that result in such an erroneous splicing reaction that would result, ultimately, in cancer or Alzheimer's.

Wow—that's amazing. Are you close to being able to create that small, simpler splicing machine? Will you be able to apply it to research soon?

We hope so. When the machine that we have right now, so far we have been trying to develop the thing basically just to make sure that we have what we think we have. But we are starting now to use it as a model for splicing and trying to figure out why things happen the way that they happen in the spliceosome. So it's already giving us some information. But ultimately we need to add more elements to this machine and we are doing that. But I don't know how close we are. We are going in the right direction.

I want to shift the conversation back to the question of being a woman in science. As a woman in science in the United States, do you find yourself facing particular challenges or particular impediments?

Yes, I think so. The U.S. is not such a traditional society, but still, there is enough of a traditional element in U.S. society that women are taught to be ultimately more of a family-oriented person than a career-oriented person. It's not very obvious, but you do feel that people look at you as a future employee and they think that this woman is going to have a lot of family-related duties and so she's not going to be as active as a guy.

I think that being a woman still makes you be underestimated, though quite a bit less than in a very traditional society, but it's still true.

As a foreigner, I think I get that a lot, because somehow, if you're a foreigner, if you don't speak English extremely fluently, you're sort of thought to be challenged, or less smart or less capable, especially also if you're a petite woman, as I am, and at the younger end of the spectrum for being an assistant professor. So I feel that I'm being looked at with suspicion, whether I can pull it off, or if I'm capable enough.

Will you stay in the United States?

Yes, I really love the science that I'm doing and I think this is the best place to be to do science. If things take a huge turn, I don't know, but if I can do my science, I would like to stay here.

Are your mother and father proud of you?

Yes, I think they're very happy with what I'm doing, and they're very excited. I think my mother is particularly excited because she always thought that her children had to do something that is not mundane or ordinary, and she thinks science is something that qualifies as not mundane or ordinary. And they're excited that I'm making progress, yes.

Right now there are many questions in the United States and the West about Iran's possible nuclear ambitions. Given your contacts back in Iran, what's your sense of the sentiment in the Iranian science and medical community about Iran's nuclear program?

I think it's probably a very mixed feeling. I think people are not very happy with the way these ambitions are affecting their lives because if there are further embargoes against Iran and that results in Iran being further isolated, that would be bad for everybody. But then at the same time, I don't know how to say it, but I'm not sure if people think that Iran is really doing all these nuclear things to develop weapons as opposed to peaceful uses. I think that is something people wonder—are foreign powers too worried about what Iran is doing? Are they making a big deal out of nothing? And also, I don't know, I'm not sure, but I can imagine there might be a sense that so many other countries have nuclear power, why not us? But I'm not sure how prominent that feeling is. Probably there is a small element of that.

I think the main sentiment is that people are worried that this might create consequences that would affect everybody very negatively. And nobody's happy with that. I just think people are hoping that the international community would behave wisely and not foolishly. Iran is a country that I think has things going in the right direction, I think that everyone is hoping that the international community would reinforce that current, rather than by foolish or rash implementation of warlike actions drive everything back to where things were 20 or 30 years ago.

And so you're saying that there would be a strong sense in the Iranian science and medical community, and in the general community of liberal young people in Iran, that U.S. military action or Western military action would be a bad idea?

I think it would be disastrous. Anywhere you look, when a foreign power attacks a country, everybody would be united against the foreign power. That would actually be disastrous to the new liberal movement in Iranian society. Iran is a lot different from Iraq. I guess people have different perceptions of how things are going right now in Iraq. But Iran is very different. In Iraq—I haven't been there, but people who have been there say things are terrible, people are really living in misery, and there was a dictator who was doing all sorts of crimes against humanity.

I know that human rights agencies have a lot of issues with what is going on in Iran, but people definitely are doing much, much better in Iran in terms of quality of life in general and the atmosphere of the society. And so the level of dissatisfaction is not that high. So when people are enjoying pretty decent life standards, if you take that away from them by turning the country into a war zone, nobody is going to appreciate that. Especially if you think that there has been a lot of movements in the right direction in Iran. It has opened up quite a bit. You just hope that with the right kind of reinforcement, things can continue to get better without resorting to force.

— Interview with Edward W. Lempinen

10 February 2005