Prof. Inder Verma is a pioneer in the field of creating virus-based gene therapy vectors and has made major contributions in the fields of cancer and immunology. His group uses lentiviruses – viruses to which the Human Immunodeficiency Virus or HIV belongs – to create gene transmitting vectors to generate mouse models of human cancer. His research team is also developing the technologies for gene therapy to generate induced pluripotent stem cells (iPCs) from patients and converting them into hematopoietic stem cells, hepatocytes and lung cells.
On a recent visit to NCBS and inStem, we have a conversation with Prof. Verma near the fishpond at the Southern Laboratory Complex, which he mentions is one of his favourite places on campus.
Prof. Inder Verma, you have been involved with gene therapy research since its inception. Could you tell us what it was like when you first began your work in this field and its evolution?
It started out with our work on viruses which can cause cancer in experimental model systems. The reason these viruses could cause cancer is that they hijacked a part of a gene, called an oncogene – a gene that could cause cancer – from normal cells.
We simply argued that if a virus could get into a cell and cause cancer by virtue of having that gene, why not remove that oncogene and substitute it with a gene of therapeutic value? A gene that could cure conditions like haemophilia, a gene for insulin, a gene to correct muscular dystrophy or cystic fibrosis.
And then we asked the question – if we put the virus back into the same cell with such therapeutic genes, will it make the beneficial protein you want rather than causing cancer? So that is how we got into gene therapy – because it made sense to convert a foe into a friend.
In the mid-90s, we knew that the viruses we were using then were able to introduce genes into cells that were dividing. But you cannot use such viruses in cells of the brain, or with the lung, or the heart. So sometime in the mid-90s, we realised that we had a serious deficiency in making viruses that could introduce genes into cells that are not dividing.
And then, there came this virus, HIV, which was found to affect the brain’s neurons, which are non-dividing cells. It was infecting T-cells and macrophages which are all non-dividing. These viruses were putting genes into non-dividing cells.
Therefore we said, why not take this virus, HIV, which affects non-dividing cells, remove all the genes that cause disease and substitute them with therapeutic entities?
And that turned out to be what we now call lentiviral vectors. And now there are hundreds of clinical trials involving gene therapy. I believe this is an example of how basic science eventually led to clinical applications and eventually to translational medicine. Today, all the immunotherapy that is being done now to treat cancer, is all done by lentiviral vectors. Cancer treatments where people take T-cells from a patient, introduce what are called chimeric antigen receptors, and then put the T-cells back in the patients to fight the cancer, you cannot do any of it without these lentiviral vectors.
Hundreds of patients who are on clinical trials now, many of them in remissions, are in fact using lentivectors. So what we made in 1996 for a purely research activity, it has now become a necessary tool to fight cancer.
One of the major changes that has happened over the last several years has been the rapid availability of high volume data such as those emerging from large scale sequencing projects, repositories of material and information. Do you see value in such efforts?
I think this is fantastic because biology is so complex. I used to call myself mono-gene-ous – working on a single gene. That is now over.
If you are a Drosophila geneticist, and we talk of a gene, ‘dorsal’, you can imagine that the gene supposedly works down one linear pathway which we draw neatly like that. But, it works on another gene ‘Notch’, and Notch in turn is working on the ‘Wnt’ path, and they are all interconnected.
We just do not have the tools to do all those analyses biochemically, or even genetically. Computational biology has the ability to pull reductionist biology back into whole biology. So I think that there is no question about it that the future of biology is in computation biology. We experimentalists will still be needed to verify their ideas.
Here, I think India has a good advantage because we have good mathematicians and statisticians, and so that is a big plus we have.
We need an environment where mathematicians and statisticians can work on biological questions, and we need them to be interested in biological problems. NCBS has an effort along these lines here – the Simons Centre. I met a few Simons Fellows during my visit and I found their work very exciting indeed.
We are used to thinking of labs as standalone activities driven by individual Principal Investigators (PIs). However, these days groups of PIs work on large collaborative projects. On this campus we have NCBS and inStem, with examples of both individual PI-based labs and theme based work. How do you think such developments affect the way science in individual PI driven laboratories is conducted?
You have two models here. NCBS is one-lab-one-leader, but they can collaborate with many other people. Then there is inStem, where there are units, with each unit working in one area. It is an experiment.
I personally think that scientists are never limited for collaborations. Either they are not aware of other people’s work or many times they do not have the funding to carry through collaborative work. One of the best ways to have people work together is to have well-funded collaborative projects that invite many people to work on a problem jointly.
I believe that individual labs will still be doing the verification of a lot of work that is done communally. But what I think is important, is that we have to start rethinking how we give credit. Within individual labs, we know who does what, and so credit is duly given. Then there comes a big project and the worry is that some people will not get the credit they deserve. From the public point of view, they simply want a working product. But it is very important for us in science to be competitive, to have incentives to get our creative juices flowing. So we have start thinking now, about how we allocate credit in such big projects.
How do you think large collaborative projects affect the careers of emerging researchers joining these efforts?
Individual labs should not hesitate about taking on big projects just because they are worried that they will lose the credit. And many young faculty members do feel that way.
Just as an example, when you put salt in a dish, you cannot find out which part of the dish has the salt. But without salt, there is no taste. Similarly, a bioinformatician whose name is among a list of 15 other authors, may have been the one who provided the glue that brought a paper together, but you cannot really pin it down with your finger. So we have to start integrating people’s credit, and I think that will change a lot.
Younger researchers worry about their career trajectory. I have seen people from my own institute say, “I am not going to work on this project until I get tenure.” But by that time, 5 other people would have done it. There is no such thing as a project waiting for that one person. This is where committees can help in assessing contributions.
We recently had a case where a young faculty member was up for a promotion. This person had a major paper with a senior faculty member, so we needed to tease out their respective contributions. We made it a point to have the senior faculty member tell the committee what part of the work they contributed to. The committee came to the conclusion that if the junior faculty member had not started that work, the senior could not have done it all alone. So, in this case, the young faculty member got the promotion.
On the other hand, large collaborative projects can also mean that younger faculty members may be diluting themselves by too many collaborations, and we need to protect them against this. Young faculty members also need to focus on one thing and have a main interest, which once recognised, can broaden up.
As a mentor, you do not want to say “do not collaborate because you are not focussing.” Young faculty members need to find that balance. While mentoring can help, at the end of the day, the individual has to make a decision for themselves.
As you are aware, NCBS turns 25 this year. You have been associated with this journey from very early days on. What are your thoughts on the growth of NCBS, future prospects for NCBS and the extended NCBS campus?
I think NCBS is the shining star on the hill in India. That does not necessarily mean it is equal to Stanford, but it is a shining star. You have and you attract the best students – undoubtedly; you have very good faculty – the young faculty members that I have met were very exciting; you have these marvellous facilities. You have no shortage of equipment. And when I see your students, they are always excited – sitting there, chatting with each other, discussing things. You have a cafeteria that is subsidised, and you have a safe environment to work.
So, this is a Shangri-La. And I think people should be congratulated that they put in enough vision, energy, time – people like Vijay, and Obaid, who were the wise people in the background. And now Jitu, Upi, Apurva, Jayant and Shona and all the people who have really built this institution.
I think when you go abroad, many people equate “science in India” – especially in the biological sciences – with NCBS. And that is pretty good. So this is a good time to have your 25th anniversary celebrations to bring people in and show them this wonderful place for science.
You have had wide ranging experience advising organisations supporting research in India such as the Infosys Science Foundation and the Department of Biotechnology (DBT). Do you have any perspectives on funding for Indian science that you would like to share?
Well, unlike the United States, where there are a lot of philanthropic foundations that give money for research, science in India is almost entirely supported by the Government. So right now, the Government is the strongest supporter of science, and they have to continue to support us scientists. Our job is to convince the Government continuously that the money they put in science is ultimately going to be beneficial to them.
In the United States, every dollar that has been put into science since 1951 has brought in 66 dollars. So that is an enormous investment. All the IT (Information Technology) industry of India did not happen merely because there was emphasis on doing IT. The emphasis was on the IITs (Indian Institutes of Technology), which produced the people who went on to build these industries.
So Governments have to realise that they must invest in fundamental science and education. Anything that comes out of it at the end of the day will benefit the Government and the people.
Think of a person who comes to visit the campus. The aeroplane they came on, the cell phone they use all day long, the car they drove in, the pill they took in the morning for their blood pressure – everything is from science. So everything in their life from morning till evening is due to the gadgetry and knowledge that science brings in. Yet they seem to forget this part. So we, as scientists, have to remind them.
We have to keep reminding people that our lives are so intimately and intricately linked with science and education, that they must all support it. And they must not forget that for the betterment of mankind, all of us must invest in science.
About Prof. Inder Verma
Prof. Verma received his Ph.D. from the Weizmann Institute of Science in Israel and conducted his postdoctoral research in the laboratory of Nobel laureate David Baltimore at the Massachusetts Institute of Technology (MIT). In 1974, Verma joined the Salk Institute for Biological Studies. He dons many hats, including that of editor-in-chief of the PNAS.
During the course of his illustrious career, Verma has been conferred several awards including the NIH Outstanding Investigator Award; the 2008 prize in Biomedical Science from the Vilcek Foundation; the 2010 Spector Prize awarded by Columbia University; and the 22nd Annual Cancer Research Award of the Pasarow Foundation. He is a member of the National Academy of Sciences (US), Institute of Medicine, American Academy for Arts & Sciences, American Philosophical Society, Third World Academy of Sciences and a foreign associate of the Indian National Academy of Sciences.
Verma is also the Infosys Prize Jury Chair for Life Sciences, and has vast experience in advising national and international agencies in funding for science.