'Genes are not hard-wired'

Published : May 26, 2001 00:00 IST

"The protracted debate over nature (genetics) versus nurture (environment) in understanding human behaviour is no longer valid, the two go together," says Prof. D. Balasubramanian, Director of Research, L.V. Prasad Eye Institute, Hyderabad, and a popular science writer.

A specialist in biophysical chemistry, ocular biochemistry and protein structure, Prof. Balasubramanian has written three books (on chemistry, biotechnology and human biology), published 130 research articles in international journals and contributed over 200 newspapers articles. A fellow of the American Association of the Advancement of Science, the Third World Academy of Sciences, the International Molecular Biology Network, the Indian National Science Academy, and the Indian Academy of Sciences, he has received the UNESCO Award for Science Popularisation (1997), the Third World Academy of Sciences Award for Basic Medical Sciences (1995), the Khwarizmi Award of Iran in Medicine (1996) and the Bhatnagar Prize in Chemical Science (1981).

Prof. Balasubramanian was in Chennai to deliver the 16th K. Gopalakrishna Endowment Lecture on "The Impact of Heredity and Environment on the Growing Child." (The K. Gopalakrishna Endowment Lecture is sponsored by the Chatnath Trust and the K. Gopalakrishna Department of Neurology at the Voluntary Health Services (VHS) Medical Centre. The family members of K. Gopalakrishna, who was a pioneer of the automobile industry, created an endowment at the department, which has completed 36 years at the VHS Medical Centre.)

Prof. Balasubramanian spoke to Asha Krishnakumar on a range of subjects, including genetics and environment, the human genome project, and state-of-the-art research on genetics. Excerpts from the interview:

How important are genetics (nature) and environment (nurture) in the development of personality and human behaviour?

The biology of human behaviour is broadly determined by three factors. One, genetic endowment - biologically inherited from parents. Two, environmental impact - in terms of perception and so on. And, three, the way the individual collates everything to determine his long-term personality. Each of this is important and very often slides into another. Therefore, in some sense, it is no longer appropriate to talk of nature versus nurture. It is not as if one goes against the other. They go together.

We say this with greater confidence because we now understand that while genes give you the entire physiology - that is, the body or the hardware - what you put in the brain - the software - is not genetically written in the form of gene sequences. The knowledge and perception you gather and analyse from the environment cannot be passed on to your children. They cease the moment you cease to exist.

Will two clones behave exactly the same way?

They cannot. They are essentially carbon copies of one another or are identical. But what you put in their brain, which is really their perceptive ability, could be vastly different and hence their personalities could also vary significantly. Genes, by and large, go for the physiology, not necessarily for the psychology or the knowledge base.

Can music or mathematics, or business 'run in the family'?

In a crude sense, one can talk about families with a certain genetic make-up as, say, a Pentium or a 486 or a Macintosh family. Each would have an innate mechanical capability. To that extent, certain families may be genetically endowed to do some things - not music or mathematics or business. So, it is not quite right to say that music or mathematics runs in the family.

Have the preliminary results of the human genome project and developments in neuro-biology impacted or changed the understanding of human behaviour?

We now know that the brain is quite plastic or mouldable. There are many issues in this. The brain cells, or the neurons, run into billions. With time, they keep dying. Unfortunately, they do not turn over as blood does - every 100 days we get new blood cells. But the turnover time of neurons is extremely slow - taking almost a lifetime. So once a neuron is dead it is gone forever. But now two things can be said with increasing certainty. One, there are in the adult mammalian brain stem cells that can be harboured and called over. And, under appropriate conditions they will differentiate and proliferate. Thus we understand that neuro density is not as static or as one-way as we thought it to be. We knew this was possible in the case of the liver. And, 14 years ago, in muscles. But now we know it is possible even in the case of stem cells.

Have experiments been done on humans to show that it is possible to regenerate stem cells?

We have done experiments on mice, rats and monkeys. As the genetic make-up is similar for mammals, we take it that it applies to humans as well.

Recent research has shown that 98.4 per cent of the genetic make-up of the chimpanzee is similar to that of humans. Yet there is a vast difference between the two. How do you explain this?

This only shows that we have 98.4 per cent of the machinery that the chimpanzee has, but in a slightly modified form. The genes are not entirely identical but are mostly so. The body parts are remarkably similar. It is only the 1.6 per cent variation in the genetic make-up that makes a human. A part of the 1.6 per cent goes into making the vocal apparatus - chimpanzees only grunt. The rest is devoted to making the neuro-cortex, a part of the brain. Thus the brain-body ratio in humans is slightly better than in chimpanzees. That is why humans are able to collect, collate and use information, which is not given only by the genes.

What other recent research has changed our understanding of human behaviour?

First, the plasticity of the brain in terms of the regenerative possibilities of the stem cells and, therefore, the brain cells. Secondly, we now understand that the human brain can rewrite itself in parts in very minor ways and aid in learning and memory. Animal experiments are very clear on this. While looking at magnetic resonance imaging (MRI) when the tasks are being performed, we find neurons, including new ones, being fired. So we know that new circuits are being made. This is another aspect of the plasticity of the brain, which we have understood in the last couple of years.

In the case of humans, unfortunately, no anecdotal inferences can be made on large sets of people. That is why one keeps working with rats and rabbits and monkeys - we can grow colonies of them and work with them. There is thus an inherent inadequacy while translating the results directly into humans. Yet we know that there are situations where humans seem to have some of this behaviour. Two issues are important. One is the motor or mirror neurons. That is, we know that when we do a certain task, certain kinds of neurons fire in our bodies. But neuro possibility discovered in the last two years, that if a monkey is watching another monkey doing a task, not only does the neurons of the monkey performing the task but those of the ones watching also fire. This has remarkable applications.

The third issue is with respect to certain people who are thought to have prodigal abilities in one area. A very interesting experiment was done in France and reported in the January issue of Nature and Medicine. R. Gamm (26) in Paris does remarkable mental arithmetic calculations like Shakuntala Devi and Leelavati. He was put to test in a laboratory. Doctors wired him up and started monitoring functionally through MRI his brain as he performed the mental calculations. At least five or six different areas were activated in his brain than would have in normal individuals. The study suggests that the extra neural areas that are being activated when he is performing the calculations shows that he is parking mid-way calculations in those and calls them back. Therefore, it now appears that it is possible to activate some areas specifically.

Even more striking is the fact that Gamm was not a born prodigy but learnt to do all this at the age of 20. Therefore it is clear that you can actually teach yourself, as it were, to park short-term memories. We are, however, on dangerous ground as we do not have enough numbers.

Another interesting example is of the Hungarian chess family of Judith Polgar and her two sisters. The three girls were taught chess fairly late (in their teens) by their father but became masters. Their father even said: "I can make a genius." He proved what Thomas Alva Edison said: "Genius is only 1 per cent inspiration, but 99 per cent perspiration." It means that you can work towards it. Of course, it does not mean that anybody can become a genius. Only that it is possible to consider territories in the brain that we until now thought were not pliable.

Thus, in the past two years or so we have had three major suggestions - stem cells proliferation, short- medium- and long-term memory parking spaces that can borrow from one another, and that you can actually do so - that seem to point to the possibility of working through the mode of perception and analysis of the brain, which was thought to be non-pliable. The important point to note here is that all these prodigies are so only in specific areas. Otherwise they are normal people.

So it appears that there is far more you can do with what you have got. And one is not imprisoned with what you get from the genes.

Now we know that humans have far fewer genes - 30,000 or so - as against hundreds of thousands of genes suggested earlier. What does this mean?

That means that the 30,000 genes have to do a lot of functions. A gene is a sentence of instruction for the body, which is read and transcribed by RNA (ribonucleic acid) which then translates it into an action molecule called protein. The genotype is the genetic information and the phenotype is what the protein does.

While the number of genes may be around 30,000, the number of proteins may be 100,000 to 150,000 - nobody knows for sure yet.

How are there more products than inputs (genes)?

That clearly means that the rest of the body parts, apart from the 30,000 genes, are also doing some things in a manner that may activate the genes. The other possibility is that the 30,000 genes are repeatedly used in multiple ways. For example, a gene may duplicate itself. In other words, a sentence can be read twice. The protein which comes out of the same gene can differ. Thus the functions of the gene could differ if it is used twice rather than once. How you do that and what is going to happen if you do that depend on the interaction between the genes and what they perceive as the environment.

Genes are also triggered by some diseases and occasionally by some drugs such as steroids. So, genes are not completely hard-wired. There is the give-and-take between genes and the environment, which is becoming increasingly important.

What are the other major discoveries in the human genome?

The human genome tells us that all of us share 99.1 per cent of the gene make-up (some say 99.9 per cent). We only differ in the 0.9 per cent or 0.1 per cent. There are differences even among siblings born from the same chromosomes. These differences are called polymorphism - some large and some only in a single character.

If everyone on earth is 99.9 per cent similar, then why are we talking about races? Are they not more of a cultural construct than a genetic one?

Does the discovery that mammals have significant similarities in the genetic make-up throw more light on the evolution theory?

That there is continuity in the flow of evolution is clear. It flows in one direction. With time, species have moved and we can even date them. There is remarkable consistency and constancy in this. We have genes similar to that of the donkey up to 80 per cent and the microbes up to 40 per cent. Thus, our ancestry can be pulled all the way up from there. It is what one does with those genes and how they are organised that seem important. Different species have taken various methods in organising the genes. For example, a bacterium has a simple chromosome, while a human being has 23 and a hermit crab 137. Thus, it is not the number of chromosomes that is important. From the human genome it is also clear that we seem to have pinched a large number of genes, over 200, from bacteria.

We also seem to have a large number of sequences, which at the moment do not seem to mean anything because they are not yet transcribed and are therefore called 'junk DNA'. Also, the 'jumping or transposing sequences' seem to be abundant, about which we do not know anything. These may be mechanisms by which specific genes could be initiated, stopped or controlled. Humans have the same genes in the blood and the heart. Yet the heart does not make haemoglobin. Thus there seem to be tissue-specific silencing or activating of genes.

What kind of genetic research is going on in India?

A lot on developmental genetics. That is, studies to understand what happens during the development of an organism given its genome. The other kind of work looks at genetics of lower organisms such as bacteria for certain purposes. In human genetics, the push has been with respect to diseases. It was Indian territory some time ago - not any longer. Earlier they looked at the chromosomes. It is possible to take blood, isolate the genetic element from the nucleus of the cell and set apart all the 23 chromosomes (meaning the coloured part of the cell) and stain them in different colours. The chromosomes are then banded in different parts. Thus, some time ago, when work on cell genetics (cytogenetics) was dominant (prior to the development of molecular genetics), significant work was done in India using banding of cells.

Now we have moved into molecular genetics. Significant work is done in human disease-gene connection. For example, we have identified the gene that causes glaucoma (pressure in the eye), and also the mutation in the gene. Other areas of work include muscular dystrophy and pigmentation of the skin.

How far away are we from gene therapy?

Quite far away from everyday experience. But there are some signs of hope from an Indian scientist, Prof. Inder Verma of the Salk Institute in the United States. The problems are three-fold: How do you deliver. Once delivered, how well would the gene express itself. And, how long will it stay.

The first seems to have been solved reasonably by Prof. Verma. The worry is whether the immunity would be affected and so on. But there is hope. In the next few years we would have developed very good methodology for this. But the second and third issues are yet to be resolved. Those would take time.

Would the ban on animal experiments in India affect research in biology?

Of course. All experiments are done on monkeys, rats and rabbits. It is vital that we experiment on them. We know now that we are all one family. And what the monkey does is translatable in some measure to humans. Therefore it is important that the experiments are done. In drug therapy it is crucial as what we do in a cell is not necessarily the final answer, for what happens in one tissue, organ or the whole body may be different from what happens in another - the reactions may be different.

There are fool-proof international guidelines for using animals in experiments. The three 'R's must be the bottomline: Where possible, Reduce the number of animals, Replace the animals with cell culture, and Refine the methods with statistical and mathematical analysis. All these are done in India. The international guidelines are backed by professional guidelines and national laws, as also an institutional animal welfare committee, which consists of a spectrum of people - professional scientists, veterinarians and ethically oriented people and so on. Clearance for any experiment is to be got by the animal ethics committee. Just because there have been some infringement in some places it is not right to stop animal experiments. This notion that we can do away with animal experiments is merely romantic and has, in fact, damaged research efforts in the country. It may also be a hangover from what happened elsewhere in the world.

You can police animal experiments; there must be regulation in anything. But it is also important to understand the qualification of the people involved in the experiments, their background and so on. Just removing a bunch of monkeys from experiments is not a lofty act. These laboratory-bred monkeys are innocent of outside life. The 30-odd monkeys that are taken out and let into the forest face the danger of being killed by other species, even by their own kind. What was thought to be a compassionate gesture might well have backfired.

The rules have made any experiment using monkeys in India extremely difficult. The power of overseeing the experiment should not rest with agencies that are far removed from the laboratories. Ample laws and guidelines exist around the world. We need no further spokes in the wheel. The rule can set back the pace of neuro-biological research.

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