Interview by Kourosh Ziabari, Ahmadreza Tavassoli

Dr. Saba Valadkhan is a world-renowned biomedical scientist and the Assistant Professor of Case Western Reserve University of USA.

After graduating from the Tehran University of Medial Sciences, Saba Valadkhan moved to New York where she could continue her further studies at the Columbia University upon the fellowship which she had been granted from RNA Research Society.

This young Iranian scientist has won several international awards for her effective, determinant contribution to the field of Molecular Biology such as Peter Sajovic Memorial Award, Harold M. Weintraub Graduate Student Award and James Howard McGregor Prize.

In 2005, she was awarded the American Academy for the Advancement of Sciences (AAAS) award of Young Scientist of the Year for her breakthrough in understanding the mechanism of spliceosomes which was something unprecedented and innovative until that time.

By developing a new strategy to prevent the occurrence of some disastrous cancer types, she identified and determined a slight and insignificant deficiency in the functionality of DNA strands and found an effective way of solving it.

Following is the text of exclusive interview with Dr. Saba Valadkhan in which a stack of interesting subjects around the details of her latest discovery, scientific community of Iran and the prospect of research in Iran and has been discussed.

Dr. Valadkhan; we know that your landmark discovery in understanding the actual function of Spliceosome lead you toward receiving the prominent 2005 AAAS Young Scientist Award which was a honor for all of Iranians, rather than yourself. Would you please elucidate for us that, in a simple and general language, what your discovery specifically was and how much it would be useful to solve RNA-related problems practically?

Human genome has many fascinating features, but perhaps one of the most interesting is the fact that our genes come in fragments. In our genome, we have between 25,000 to 100,000 genes, depending on whom you ask. Now each human gene is on average divided into 8 fragments, but some genes are divided into as many as 100 fragments.

As we all know, our genetic information is stored in DNA strands, which are very long, thin linear polymers, just like very long strings of pearls, except that instead of pearls we have DNA nucleotides adenosine, guanosine, cytidine and thymidine. You can think of them as four different types of pearls, of four different colors, for example. Our genetic information is stored as the sequence of these four DNA nucleotides, for example, two adenosines followed by three guanosines mean: the product of this gene should be taken to the surface of the cell, and so on.

Now imagine that the gene that has the information for making hemoglobin is divided into three fragments, to use a simple example. It means that after a certain combination of nucleotides that indicate the beginning of a gene, we have about 300 nucleotides that constitute fragment 1 of hemoglobin, followed by 5000 nucleotides that are not part of the hemoglobin gene. Then we have another 250 nucleotides that form the fragment 2 of hemoglobin, followed by 3000 intervening nucleotides, and finally, 180 bases that make up the last fragment of the hemoglobin gene, followed by a certain sequence of nucleotides that indicate the end of the gene. Clearly, in order for our bodies to make hemoglobin, these fragments should be put together.

The way that this is done in our bodies is that whenever our bodies need to make hemoglobin, they make a copy of the hemoglobin gene from the start sequence to the end sequence, this contains the three hemoglobin gene fragments and the two long stretches of nucleotides that separate them. Then, the beginning and ends of these intervening sequences are recognized by the cell, and they are removed, and the three hemoglobin gene fragments are attached together. Only then, after all the extra sequences are gone, will this copy of the hemoglobin gene be used by the cell for making hemoglobin.

This process, the removal of the intervening sequences that separate gene fragments, is called splicing, and the group of molecules in the cell that perform this job are collectively referred to as "the spliceosome".

Now imagine what would happen if splicing is performed incorrectly, for example, if the beginning of the second fragment of hemoglobin is mistakenly recognized as part of the intervening sequence. Then, the spliced copy that is used by the cell will lack the information that was contained in the beginning of the second fragment, which can result in a hemoglobin that cannot bind oxygen. Red blood cells are made, but they cannot function. Or conversely, if part of the intervening sequence is by mistake recognized as a piece of the hemoglobin gene fragments. Then, we have extra information that might tell the cells, by mistake, that the resulting hemoglobin protein should be rapidly destroyed by the cell.

The result would be a severe lack of hemoglobin, although the cell is making a lot of it. The clinical outcome of both cases would be Thalassemia. And these were just two of the many possible problems. Remember that each human gene, on average, has 7 of these intervening sequences, and that every time our bodies need to access the information in our genes, they need to make a copy of the gene and splice it correctly.

At any given moment in the cell, there are more than 200,000 copies of different genes that are used for various cellular functions. Now you can see how incredibly critical splicing is. One mistake is enough for one cell to die or become severely ill. Indeed, it is thought that more than half of all human genetic diseases are caused by mistakes in splicing. And splicing-related diseases are not limited to genetic diseases. Any disease with a genetic element, such as cancers, neurodegenerative diseases such as Alzheimer's, etc, can result from splicing mistakes.

I hope I have convinced you by now that splicing is a very important cellular process! The spliceosome, which is the assembly of molecules that perform splicing, is extremely complicated, as expected. However, this complexity prevents us from understanding its function. Thus, despite all the human tragedies caused by splicing-related diseases, we are very far from understanding the problem and curing it. What I did was to make a simple model for the spliceosome, which allows us to understand this critical process. Clearly, this opens the door to understanding how splicing-related diseases happen and hopefully, finding a cure.

With all of your explications, we see that a great respect is being paid to the "Molecular Biology" that is your academic major of study, but seems to be somewhat less known in Iran and the rest of Middle East, as well. What kind of biology branch is it and which sort of subjects it deals with?

Molecular biology is in fact an approach to biology, rather than a field of study. In molecular biology, we try to understand biology at the level of molecules: which molecules are involved in each biological process, how they interact with each other, and how they are made and destroyed by the cell, when necessary. You can use this approach in any field in biology, from neurobiology to botany to microbiology, molecules govern how living cells function, and molecular biology can tell us exactly how these molecules work.

It is an extremely powerful way of approaching biological questions, and these days it is impossible to have an in-depth knowledge of biological phenomena without employing molecular biology. A very large share of new discoveries in medical sciences is based on molecular approaches. For example, in modern cancer therapy, screening of the population for early detection, diagnosis, classification and treatment are all based on molecular biology approaches. Molecular biology has already revolutionized medicine and will continue to do so in the future.

It's more than 15 years that you are far from your homeland, Iran. Do you have still some scientific relations with universities and institutions inside the country? Are you enthusiastic to return to Iran someday if the preliminaries of a substantive scientific environment for you are provided satisfactorily?

I am trying to forge scientific relationships with the Iranian research community, and I am hoping to have a broader interaction with the Iranian scientific community in the future. I am unfortunately not very familiar with the status of research in Iran, but I know that the number and quality of scientific publications from Iran have been on the rise, which is a very encouraging sign Hopefully this trend will continue.

The status of science seems to be improving in Iran, however, the infrastructure is still a concern, and interaction with the broader scientific community is still very limited. These factors prevent the science enterprise in Iran to achieve its full potential. Hopefully with effective planning, sufficient funding, and the cooperation of the scientific community these issues will become less of a hurdle in the future. There are many talented scientists currently in Iran that if given the opportunity will do great things. I want to stress that we don't lack talent or skill, what is limiting science in Iran is the lack infrastructure and the right type of environment. Even if all the Iranian scientists currently living abroad return to Iran, there will not be any significant changes in the quantity or quality of scientific productivity in Iran until these shortcomings are addressed. Now if the government solves these shortcomings, the scientists currently residing in Iran are more than qualified to do cutting edge research.

So is it going to be fair that we conclude Iran lacks the basic fundamentals and accouterments of effective scientific, research works to be carried out in?

See, I have young Iranian scientists in my laboratory that have previously performed research in Iranian universities. They all agree that in terms of equipment, they had all they needed in Iran, that is they had better equipment in Iran than they do in my lab. They also had easy access to research animals and human tissues or samples, for which we need to conduct three months' worth of paperwork in US. What seemed to be limiting their research was access to reagents, many of which were ordered from abroad and took a long time to arrive and perhaps more importantly, not appreciating all they had. We Iranians have a tendency to see the empty half of the glass, and this is something that hopefully will be alleviated by more extensive interaction with laboratories abroad. There are shortcomings everywhere, so we all need to use our talents and energy to overcome them.

Therefore, what causes that a load of young Iranian talents leave the country each year to abroad and make us encounter the phenomenon of "Brains Escape"?

I think this is the wrong way of looking at the problem and in fact, it's not seeing the real problem at all. In Iran, we can't complain about brain drain, we have many more educated, trained forces than can be gainfully employed. We don't need any additional educated work force; we already have more than the country needs. The real problem in Iran is that the country spends a lot of resources training medical doctors or physics PhDs and they can't find jobs that match their training and end up doing carpet business. Our problem is brain inflation, not brain drain. It is not that educated people choose to live and work abroad despite having equally good opportunities in their home countries, the issue is that they don't have acceptable choices at home. Nobody enjoys the often very painful process of emigration, but lack of opportunities forces many to leave their home countries. And let's not forget that after these "overflow" educated forces leave, they often remain committed to contributing to their motherland in any way possible. There are many prominent Iranian academics abroad that have made significant contributions to the human society that have made all Iranians proud, and that continue to contribute to their homeland by transferring their knowledge through teaching in universities and workshops in Iran.

If we put the work force aside, we can take a glance at Iran's scientific stride from the view of scientific indicators including ISI, as well. What are the most remarkable ones among these indicators and what they narrate about Iran's research productivity?

There are many such indices and depending on whom you talk with, they might prefer one or the other. I think a reliable way of measuring the level of scientific productivity in the biomedical field is the number of publications in Pubmed-listed journals. Number of publications in top tier journals in biomedical fields, Science, Nature, Cell and the New England Journal of Medicine, is a good indicator of the quality of scientific work done in a country. I took a moment and calculated these numbers for Iran and a number of other countries in Asia. Although the total level of productivity in Iran is still lower than Turkey, India and China, while we are doing better than all our other neighbors, the rate of growth of our productivity has been excellent, although it has slowed down in the last three years. We need to address this slow down and correct it. In terms of quality, we need to improve but I think as our level of productivity rises, so will the scientific quality.

In your view, what kind of efforts should the Iranian universities, scientific institutions and organizations make in order to attain the international position and authenticity they deserve for?

In every country, science is mainly a state enterprise, most of the funding everywhere comes from the government. If we want to improve our scientific standing in the world, we should ask our government for better planning and more funding.
There are several issues to consider. One is that scientific progress does not happen overnight, it takes time and patience on the part of both the funding agency and the scientist. While the government should made a long-term commitment to a steadily increasing level of funding, the scientists should be given the level of job security they need to endure the many years of effort it takes for a major discovery to be made.

This is both in terms of salary levels that should be sufficiently high to retain the scientists in the workforce and prevent them from going into carpet business!
And also in terms of long-term stability of their jobs, Scientists should feel that their jobs are extremely secure, and they will lose their jobs only if they are not productive scientifically. Although it goes without saying, meritocracy is pivotal as the basis for employment should be scientific credentials and nothing else. The government can encourage the development of the required infrastructure. For instance, the level of chemistry research is very high in Iran; we clearly have many good chemists. Why do we need to import chemicals and reagents? Why not encourage these chemists to start companies and support the needs of the Iranian scientific community? Finally, something else that is sorely lacking in Iran is a spirit of collaboration and self-sufficiency.

Sharing expensive equipment and reagents is a must, even labs in Harvard share! Sometimes during my visits to Iranian universities I hear from doctoral students that although the neighboring lab has such and such equipment that they need, they are not allowed to use it which is unacceptable. Self-sufficiency is also important. We should note that not everything should be bought from abroad. Many expensive reagents are easy to make but unfortunately I hear about these reagents being ordered from abroad, which is a waste of money and time.

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December 25, 2008 Interview by Kourosh Ziabari, Ahmadreza Tavassoli.