Moral conundrum in medical research

David Baltimore interacting with students at the National Centre for Biological Sciences, Bangalore, in January.-K. MURALI KUMAR

Interview with David Baltimore, co-recipient of the Nobel Prize in Physiology or Medicine.

THE second part of Frontlines interview with David Baltimore, the reputed American biologist and Nobel laureate, includes a discussion on a wide range of issues including his own research; funding in health-related research and development; the moral conundrum of high investments in product development by drug companies versus making drugs affordable for the less developed world; intellectual property rights and generic drugs; policies of the United States on issues affecting scientific research; and open access to research communication. The interview, the first part of which was published in the last issue of Frontline dated February 29, was given partly in New Delhi and partly in Bangalore during Baltimores lecture tour of India in January. Excerpts:

The crowd for your lecture in Bangalore on microRNAs must have been quite a surprise to you.

Yes. I was amazed. But what I heard later was that there were so many people who were turned away. Maybe 2,000 people whole lot of them interested in microRNAs (laughs). But look, I know some of this is due to the interest in seeing a Nobel laureate.

Does this sort of a thing happen in the U.S.?

No. It happens more abroad. I did a couple of lectures in China about a year and a half ago. I was mobbed, absolutely mobbed. Thats when I stopped signing autographs. What happens is people start putting stuff over each other to get you to sign, and it becomes a mob scene. And so, I am not really interested in that sort of a thing.

In terms of the overall stature within the scientific community, does it matter that you are a Nobel-Prize winner?

It matters some. When I go to give a talk at any university, I turn out a surprisingly large number of people, and I know that a lot of those people want to say [that] they saw a Nobel laureate. When I was a kid in science, it was a thrill to see that sort of elders of the field even if I didnt expect to learn anything. Francis Crick used to come occasionally to MIT [Massachusetts Institute of Technology] to give a talk, and it used to be in the biggest hall at MIT.

What is your research interest in microRNAs?

[microRNAs (miRNAs) are tiny bits of single-stranded RNA (ribonucleic acid) molecules, of about 21-23 nucleotides in length, that are believed to be highly conserved during evolution. Only recently have these emerged as important regulators of gene expression. Thus, they play a part in how and when genes turn on and off. MiRNAs are encoded by genes that are transcribed from DNA (deoxyribonucleic acid) but are not translated into protein. These are thus non-coding RNA molecules. Approximately, 500 genes that encode miRNAs have been identified in mammals.]

Another whole line of research in my laboratory has been [on] proteins that are involved in the immune system, and we have been working on that kind of question for 30 years. In 1975, I decided to incorporate into the work that I was doing which is mostly in cancer-related viruses research on the fundamental properties of the immune system. And we made a whole string of basic discoveries in the immune system how genes work together and that sort of a thing over a time.

In 1986, we published a string of papers on proteins that are involved in controlling genes of the immune system. We have continued to work on those proteins to this day. A couple of years ago we asked the question, Are there microRNAs playing a role in the immune system, particularly in its inflammatory response? And that turned out to be very productive. We found three of them to be critically involved and we have focussed on two of them. So I have a significant research programme in my laboratory focussed on these two microRNAs [called miRNA-146 and miRNA-155] now actually more than two but initially two. Thats what I talked about. Right now it is the biggest thing that we are doing in basic science.

The bulk of basic research in biology, with potential important applications in health care, largely happens in public-funded laboratories. Would I be correct in saying that private enterprise, particularly drug companies, would be unwilling to take the risks that come with dealing in new paradigms and new ideas?

Yeah. I think private industry, the big pharmaceutical companies, would not like to fund this kind of a thing. It is too uncertain. They work on things that are going to give them drugs. I am sure about this.

But what I find is that the people who are ready to fund these things are the private people. [For instance,] the [Bill & Melinda] Gates Foundation. As I mentioned [see Part I], we developed a lot of the engineering immunity concepts on a grant from the Skirball Foundation. Many of these are wealthy people from the IT [information technology] world, who have set up foundations often trying to do imaginative things, and if you can capture their imagination with your ideas, they may fund you.

Within the publicly funded research system in the U.S., how have government policies such as the Bayh-Dole Act of 1980 been responsible for taking laboratory research to commercial enterprise?

Well, a whole lot of what we do today comes from the universities; lots of drugs had their initial start at the universities. The technology transfer from the universities to the industry is a well-developed process since the Bayh-Dole Act. The patents now rest with the universities, and the system has been functioning quite well.

But in your lecture in New Delhi you seemed to suggest that private institutions and the venture capital mechanism are the ones that are likely to bring about innovation. At the same time, you also feel that they wouldbe unwilling to fund risky research.

Oh no, no. I was saying that pharmaceutical companies are not willing to take risks. The venture capital industry is designed to take risks. Now its true that it has become more conservative in particular in relation to biotechnology it has become more difficult. Because it is true that it takes a very long time until an idea becomes a reality in biotechnology, and lots of them fall by the wayside as you go along.

So biotechnology is actually very risky and very long-term. And venture capital companies really try to get their money back faster than that. So they become much more short-term in their thinking. They would like to have a start-up company have a phase-three product or at least a phase-two product. The idea that its just a platform technology scares them. I have been involved in the last year in the formation of a new venture capital company, which is kind of going back to the old style.

I am saying we are going to fund early platform stage biotechnology, and we have found money to work that way.

What returns can you expect from funding such ventures, especially if they do not really go onto the second or third phase?

They have to go through those stages, but the people who put in their money understand that this is a long-term investment. Tends to be more Europeans who understand that than Americans.

And yet you mentioned that the U.S. has been the most successful country in biotechnology variety. What is that due to?

Well, until now we had venture funds that were willing to take real risks. In recent times, the venture funds have become a little risk averse. But there are still some, like the one that I am starting, which take a long-term perspective, and there is really nothing like it anywhere else.

In India, one of the main problems has been the absence of venture capital companies willing to take risks

You have a lot of wealthy people here. You should be able to develop a serious venture capital industry. But its cultural. And Americans are willing to take risks. Thats why we have such a great history of entrepreneurship.

You also said that there was a moral conundrum between the kind of money that is invested in developing a new product and the product later being available at an affordable cost for public health needs. Industrial R&D, which finally ends up as a successful product in the market, would have ridden on publicly funded research to a large extent. As you also agreed, most private companies do not take up research ab initio, given the risk involved. But the price of the final drug or technology does not reflect the fact that a great deal of public funding has contributed to realising that product.

So much more money goes into the later stage part of the process than the early stage. There is no comparison. There may be $5 million in the early stage and $500 million in the later stage.

But intellectually speaking, the $5 million investment is often the key to realising the final product.

You mean creativity. But creativity is cheap (laughs).

We say intellectual property but this real intellectual property is either not adequately protected because it is public or does not get its due

You can protect the early stages, in fact, we do. But the corporations would say: Thats fine and we are willing to give you returns for that. But we want returns for the money we are putting into it. We are putting in a lot more money at the later stages.

For a whole lot of drugs, the pricing of the product is several times higher than the actual investment a company makes in that product.

Yes, for a couple of good reasons. One is that the research process is very inefficient. So if you try to look at the cost of making one drug, you are not taking into account the cost of all those drugs that failed. And if you are not going to fund the failures, you are not going to fund success. Because we cant tell a failure from a success in the early stages; research is inefficient. And also you need, for instance, for a company like Amgen of which I am a director, to build up a war chest of money so that you can go out into new directions and try to find new drugs. You have to be able to fund all of that before the drug has made any money. So you dont actually get paid back the money that you put in; you need much more that allows you to work forward. And then the next drug you hit, you charge a lot for that drug and that drug would set up the war chest for the next and so on.

So how does one reconcile public health demands and these corporate demands?

I said it. I dont understand. I dont know how to do it. It is such a moral conundrum.

The fallout of this moral conundrum is also felt in the basic approach and attitude of big companies. Given that profit or at least recouping the invested amount is their bottom line, they are not willing to invest in drugs needed to address the problems of the developing world where the returns would be much less.

Thats right. They dont make any money that way.

So how do we even address global health problems?

Well, increasingly there are private sources like the Gates Foundation and other foundations that are trying to fill that gap.

Even if they did, that kind of funding would be substantially less than what is actually required for a full-fledged programme to solve the worlds health problems. I think you also referred to this in your talk.

I was referring to the strategy of offering a prize. This is a strategy that works with the [so-called] X-Prize for a plane that would go into the stratosphere. So they are trying to extend that to cancer prizes, genome prizes . Lockheed would say that this is the way to spur innovation. What I was saying is that you have to have an enormous prize to do this in biotechnology. Basically, [I am] saying that this will not work in biotechnology.

But do you not think that enhancing public funding for such programmes could make a difference?

Yeah. If America wanted to be altruistic and says that we are going to fund big programmes in malaria research, we could. We havent done that. [To] try to say that we have the responsibility to do that is difficult.

But even the international programmes under the WHO, such as its Special Programme for Research and Training in Tropical Diseases, do not have enough funding to undertake the research that deals with the problems of the people of the developing countries, who constitute the bulk of the worlds population.

You are absolutely right. The international world is not going to put up that money. I think there is also the suspicion that the WHO is an inefficient organisation. But international world was willing to put up money for AIDS [acquired immune deficiency syndrome] drugs and we made many fundamental changes.

In retrospect one could possibly say that this probably happened because the disease was affecting much of the Western world

No, no, no. Not true. We can take care of ourselves. We were doing that because there was a sense that we have the drugs and that we really had a responsibility to make them available, to Africa particularly.

But if that was true, why were they never available at affordable prices?

Now prices of these drugs are quite affordable.

That, of course, is because of countries such as India and Brazil stepping in with cheap generic forms of the drugs.

Thats right.

But here again is the moral conundrum. It has happened because the generic drug market for AIDS has been allowed to exist in spite of the patent protection for proprietary drugs. How do you reconcile to this?

Let it happen.

You mean to say that you have no problems with such contradictions?

Exactly. What I am really saying is that we have to live with the contradictions because I dont know any other way. Maybe some shrewd economist will find some other way of doing things. Thats not my expertise.

Can one envisage some kind of international institutional framework where investments from countries that are advanced in science and technology are pooled and programmes for diseases affecting the less developed world are taken up?

Oh sure. Its possible. The U.N. could sponsor something like that, and there are U.N. biotechnology labs, but they havent been well funded and I dont know much about what they are doing ....

Would issues such as intellectual property stand in the way of such a framework because one would need to bring big companies into it?

I think they could be resolved, absolutely. But Ill go back one step. The reason that we dont have drugs and vaccines for a lot of the diseases in the less developed world is not that people havent tried at all. Its because they are relatively hard to do maybe very hard to do and nobody developed it [the research programme] in a large enough scale, and there havent been enough different people involved to have success. You really need a more competitive environment than you are going to get under a government agency. You get the most creative students from opportunities. So I am a little sceptical. I think you can handle all the things you are worried about. But I am not sure that it will be a success.

The projects that are funded by the Gates Foundation apparently require an undertaking that any successful commercial product from the project will be made available to developing countries at an affordable cost. Did you also have to give that kind of undertaking for your projects?

We had to agree that anything developed from our discoveries will be done under contract that assures that it will be affordable in the less developed world.

Did you have to spell out exactly how you would meet that objective because this would involve pharmaceutical companies?

No. Because in my case there wasnt anything precise in the offing. You really cant talk about anything except in generalities.

You have also been involved in policymaking on a whole lot of issues. One of the things concerned the management of HIV/AIDS infection in the U.S. and related policies. How far has that been effective in the containment of the infection?

I wont take any credit for the development of the drugs; that was all done by the pharmaceutical industry and the biotech industry. But what I will take credit for is that in 1986, when we had the first panel and we surveyed the HIV [human immunodeficiency virus] prevalence, the danger that HIV represented and the importance of finding ways to counter it, we recommended at that point a billion-dollar research programme. The country was spending, maybe, 10 per cent of that at that time I dont remember exactly how much but within a couple of years, we had a billion-dollar research programme. So the country did respond to that report. It is one of the most important reports ever written by the National Academy of Sciences and today it is two and a half billion dollars. And we learned an enormous amount we know more about HIV than about any other virus though the fact of the matter is that we still dont know.

Would you say that the money that has been spent on AIDS research in the U.S. is sufficient?

I think we are not limited by money, we are limited by ideas.

But you still wrote that 2004 editorial for Science [the journal of the American Association for the Advancement of Science, or AAAS] in which you were critical of the implementation of the entire HIV/AIDS programme. You were also critical of many other science policy-related issues.

Well, the AIDS issue is different from the general issue of our administration, which is fundamentally anti-science. The AIDS issue where the money has continued to go in and the programmes are there, [but] they are just not rigorous and imaginative. And so at times there is a lot of me-tooism in the HIV research programme. But there are some people doing terrific things. I think this is true of all research everywhere in the world that it is inefficient. It is hard to really rigorously choose the right people, the winners. If you dont have some slack in the programme where you are funding people, who you really dont know if they are going to be good or bad, you probably havent an imaginative programme. Because very often the same stuff comes up.

What are the other areas where you find shortcomings in the U.S. administrations approach?

The biggest problem is climate change, which our administration has simply not recognised as the very severe global problem that it is. So we dont have the right kind of programmes of research in alternative energy, in cleaning up carbon emissions, carbon sequestration and a whole lot of things that we should be doing and we are not or simply not doing with the intensity that the issue demands.

And what about the stem cell issue?

Yeah. The stem cell business is yet another issue in which the administration has allowed patently religious concerns to dominate science. And has really prevented the scientific community from investigating the opportunities that stem cells represent on the scale it ought to be. Now luckily, local private funding has come to fill that gap, and so we are doing much more research than would be [possible] on federal money from the Howard Hughes Medical Institute, from Gates, from other foundations, from wealthy individuals.

But is that sufficient to drive research in the area?

No, it isnt sufficient. But at least it allows progress.

But is privately funded research also limited to existing embryonic cell lines only?

No. If you have private funding you can do anything you want. Because there isnt actually any law against working with any new stem cell line. The only law is actually a regulation that federal money may not be used for any derivation of new [embryonic] stem cell lines.

What about the State legislation in California known as Proposition 71? Does it not violate any law or regulation?

[Proposition 71, called the California Stem Cell Research and Cures Act (SCRCA), was passed in 2004 and seeks to raise $3 billion for stem cell research in California. The Act authorises the creation of the California Institute for Regenerative Medicine (CIRM) and the raising of the sum through State bonds to fund it. The institute, which was formed in 2005, has begun funding California stem cell researchers at universities, medical schools, hospitals and research facilities. Baltimore is on the Californian panel, which will decide how money will be spent on stem cell research.]

The President can make regulations about federal money. But he cannot make regulations against State money. And Congress has never passed a law that bans stem cell research. Congress has the powers and could do that but the President cant do it by himself.

What kind of impact is this law likely to have locally in California?

Now a good deal of money will become available for stem cell research in California, and I expect intense stem cell research in the State in the near future and one could see some interesting work coming out.

What other policy issues have you been concerned with lately?

One of the issues that I have been concerned with involves internal issues of a regulatory nature related to national security. Homeland security people are really trying to prevent us from involving foreign scientists in research in the United States by putting regulations in the way of that, and the scientific community is fighting back. So far successfully; we have been able to hold it off.

Now that you are the president of the AAAS, would this be an issue that the association will fight for?

It is. And the AAAS has made statements about it. Actually I was working on this more with the National Academy of Sciences. For a while I headed a committee of the academy on Scientific Openness Versus National Security.

Are there serious problems of access to certain kinds of research programmes for foreign scientists and is that affecting the research environment in universities?

It doesnt affect basic research, and thats what we are trying to prevent keep basic research open. It does affect more targeted research. There, for instance, as the president of Caltech, one of my responsibilities of managing the Jet Propulsions Laboratory [JPL] which is where all the space research is done they put significant regulations in the way of foreign scientists working at JPL. It used to be much easier to work for foreign scientists earlier. That is one very particular example. Its really counter to American interests. So there are people now really trying to wreck things the whole issue of national security in the context of modern communications because with the Internet, secrets are very hard to keep (laughs). So the matter is to put high walls around important secret areas, and then let everything else be open. And thats what we are trying to make the government understand.

As the president of the AAAS, would you like to change its policy of open access to its journal Science, which has been a ticklish issue?

Ah! (Laughs) Yeah, you are right. Its a ticklish issue. [The] AAAS depends on the Science magazine. If Science magazine were to go away, there would be no AAAS. So all the good things that we do and there are a lot of them are dependent on the income from Science. When I became president, I really investigated whether we can go to open access. But I am convinced that it is difficult. I think we could be perhaps a little more adventurous than we are, but internal people are not very forthcoming. Now there will be a new editor of Science magazine as of March. In fact, I chaired the committee that found him. And he comes from a much more open access background. So there may be changes. Well see.

Does the AAAS get any federal funding?

No. None at all. Well except by grants. Particularly in the education area, we get a fair amount of money from the National Science Foundation.

Does the AAAS have any other publications?There arent any. But that may change too.

Considering that the bulk of the research in the U.S. is through public funding, is there any demand from the scientific community itself that scientific communication should be open?

The real problem is with must-have peer review. So you just cant publish anything you want. Its got to go through peer review. The question is who is going to pay for it? All right. The answer has been you pay for it through journal subscriptions. But you only have journal subscriptions if you have to pay for the journal. So if you have complete open access, then it will be hard to provide quality control. So at the moment we are debating that issue. Are there ways of providing quality control that dont require the journal to be on sale but on open access. Its a continuing debate. Now PLoS [Public Library of Science] journal was started [with open access] and is quite successful. But it is subsidised by the Moore Foundation and others. Could it finally find a business model that will allow it to be self-sufficient? Thats still an open question as far as I know.

You mentioned in your lecture that you were at the end of your career.

(Laughs) It will be my 70th birthday next month [March 7].

Looking back, what from your research work would you say has pleased you the most?

You know, although I was certainly pleased to find the reverse transcriptase, probably the work that was most pleasing was the development of [the anti-cancer drug] Gleevec because it had a huge impact on people. But in its time, the reverse transcriptase was the most important thing that I had been involved in. It had a lot of implications. It really redirected my whole research path. Hard to beat that. But, as I said, in general, I had lot of thrill and I am led by it.

But, besides the idea of engineering immunity that you are currently engaged in, do you still have some challenging problems in mind?

Yeah, I do. As I told you, research is the thing that drives me. Its always been dear to me. Even during times I have been involved in major administration, I have always kept up research. But I dont have anything set out in front like that. Id like to keep up doing the microRNA work. I always end up with students or post-docs who want to do something very different from my work, and if I believe in them and I believe in what they want to do, I let them do it. Find ways to support them. Its just the way I work. Tried two or three like that now. You know, in general, what happens is that they do something really nice. We publish one paper together and then I send them off to assistant professorships somewhere, and they set out on their own and they get on with the topics that are theirs. I got a couple of guys like that.

Did you have students who you consider Nobel class?

I do have some. Fred Alt in Harvard, Owen Witte at UCLA [who was responsible for the work on Gleevec] and Victor Ambros, the guy who discovered microRNA, who is just moving to the University of Massachusetts at Amherst. I think maybe they are the three. Surely, what they have gone on to do is high-class work.

What do you think now are the real challenging problems in biology besides the three intractable diseases malaria, TB and AIDS that you mentioned?

As I said to students yesterday, its really the challenges of neural science.

You mentioned consciousness in particular

Yeah. Thats sort of the ultimate problem. But there are a lot of other problems neural coding remains a very interesting issue; neural circuit interactions; if you have a sensory input to the brain through the eye, that all gets decentralised and then reconstructed how does it get reconstructed and stay in register. Amazing! So many problems I think its a great field. The frustration to molecular biologists is that there hasnt been a nice, clean direct route between the system-level problems in neural science and molecular biological techniques. They are still two worlds. People dont talk to each other; they dont know what to say to each other.

You mean that we do not understand the gene-neuron kind of interaction at the molecular level?

The problem is there are so many different kinds of neurons and so many neurons, and they all have gene differences. Today, we are beginning mapping by the range technique to look at what kind of genes are there in what kind of cells. You can do all that kind of stuff. But linking that to the deep problems of integration in the nervous system just cannot be done. Not today and maybe never. Neural scientists are trying to develop multi-prong electrodes that can read out lots of cells that the brain holds at once try to understand something about the overall system behaviour. But thats so different from the kind of science molecular biologists do. I only know a few biologists who are trying to make that linkage. And I think the ones who do will make major strides. Because molecular biology is so powerful, theres got to be a way to illuminate these problems.

Do you think there is a need for a paradigm shift from the reductionist approach to address these system-level problems?

Maybe there is, but I dont know it well enough to be able to say anything. The only approach I know is from a reductionist perspective.

You visited two institutes in India, or maybe three: the Indian Institute of Science and the National Centre for Biological Sciences (NCBS) in Bangalore and probably the National Institute of Immunology (NII) in Delhi. Was it enough to gain an impression of the kind of research in biology that is happening in this country?

I didnt really visit the NII. I gave a talk there and talked to the people. The science and the people whom I met at NCBS were really world class. Just meeting them, I would guess I would be prepared to hire them for Caltech.