Basic Instinct

We have entered an era of great hope and promise, of advancing human health and well-being and of social and economic progress. The shape of things to come can be visualised with a rough timetable. Will the new order of things reduce and eventually eliminate the inequities and disparities that characterised our world as we entered the Third Millennium, or as is widely feared, will it accentuate these phenomena heralded by the instrumentalities of liberalisation, globalisation and the gtt? Will the slow-moving Darwinian natural evolution, up to now the heritage of humankind, be replaced by more rapidly-moving, artificially-induced evolution (revolution?) with hitherto unknown, even unimagined, expressions of human characteristics? Will we be able to create, through intervention at the level of the genetic code, an ever more beautiful and graceful human being with an elevated level of consciousness and understanding and a heightened responsiveness which is supremely sensitive to human need and suffering? Will we be able to create a "maximal human-being" with the highest attainable level of caring and compassion? Desired individual human characteristics such as height, body mass, colour and texture of the skin and eyes may be inducible by genetic means in the near term. Genetic enhancement is much in the air.

The notion that genetic modification could confer special advantages on an individual is widely shared, but a persistent concern is how to ensure equal access. What will be the effect of genetic enhancement on human evolution? As Eric Lander and Robert Weinberg said in the 10th March, 2000 issue of Science: "The most serious impact of genomics may well be how we choose to view ourselves and each other...lest we loose sight of why we are here, who we are and what we wish to become."

It is important to remember that genes, while maintaining their pre-eminent position in biology, are not everything. We are not prisoners of an unalterable destiny through our genes. Environmental influences, lifestyles, diet and nutrition can modify genetic destiny positively. The basis of the new genetics is that it is not only single gene mutation that affects health but also interaction between multiple genes and the environment that give rise to complex phenotypes associated with health and disease.

While all this is in the realm of distant vision, nay a dream, there are harvests of the genetic revolution which can be reaped in the near future. They touch many aspects of human development and welfare. Newer vaccines and drugs are likely to be developed to counter emerging and re-emerging diseases and to overcome the spreading problem of multi-drug resistance. Predictive and preventive medicine will become realities increasingly through genes for health as a new strategy in the health care of individuals and populations. In this process, knowledge of the genomic sequencing of pathogenic microbes will accelerate discovery of new drugs and vaccines.

These are exciting times for genetic science to discover new approaches to the control of challenging diseases such as malaria, tuberculosis and hiv/aids: no less challenging are afflictions such as cholera, kala-azar, Japanese B encephalitis and diarrhoeal diseases. Microbial genomics will play an increasingly important role in providing clues to the molecular basis of human diseases. The ultimate aim would be a vaccine that could be given at birth, preferably by mouth, that would immunise children against an array of diseases locally prevalent in different parts of the world. There should be no need for boosters, there should not be undue sensitivity of the vaccines to temperature variations and they should be affordable by all people irrespective of their socio-economic status. The dream for 'Health for All' may then be fulfilled in the 21st century, which the gene technologies can help to fulfil.

-- V Ramalingaswami
National Research Professor, All India Institute of Medical Sciences, New Delhi

The recent announcement is no doubt a milestone made possible by automated sequencing technology and by the powerful capability of modern computers to align the huge data on the order in which the four letters of the dna alphabet tagc occur in the long linear sequences. It is a great technological achievement. However, this accomplishment does not per se bring any immediate benefit to mankind. It just provides a base dictionary.

The meaning of most of the letters has to be learnt. We know only the functions of about 5 per cent of the genes, the remaining 95 per cent have to be discovered. Thus the present achievement by itself has no direct applications but opens the door to the study of functional genomics.

India has unique resource material for the study of functional genomics. By virtue of social customs, a number of communities have inbred for generations in the country with the result that there has been an enrichment of genetic traits in families. Systematic analysis of their dna can help decipher the genes responsible for various diseases, for susceptibility or resistance to infections, for behaviour disorders or for very special abilities. Once these are demarcated, knowledge base computer graphics can help design drugs for specific intervention or stimulation of discrete gene functions. The range of medicinal therapy will then expand in undreamed realms.

In the past few decades, before the present description of the human genome was made, a number of applications based on genetics have emerged. For instance, we recognise the genes responsible for some hereditary disorders caused by a defect in a single gene. An example is sickle cell anaemia. It is possible to perform a predictive diagnosis with the help of a probe illuminating the responsible gene in a tiny bit of cell from an early foetus conceived by parents with a family history of this disease on either the husband or the wife's side. This will provide them with an option of terminating the pregnancy early, so that the new-born is not burdened with a disease for which there is no lasting cure. In course of time, gene therapy will come of age and help in correcting the defect. dna finger-printing is another application offering the most sensitive test for determining paternity or for intricate evidence for detection of crime.

While these derivative applications of the already acquired knowledge carry no hindering patents and these are accessible to both rich and poor countries, the tests are costly because of the sophisticated and expensive technology. Somebody has to pay, the government social security system or insurance whether one is poor or not so poor.

As far as the fear that multinational companies may take out patents on the newly-found gene sequences, the field is open and Indian scientists have the advantage of precious and unique resource material for conducting functional genomics studies. Undertaken at a competitive pace, with proper team work and funding, preferably with co-participation of government and industry, Indian scientists have the talent to establish a worldwide leadership in this area and thereby convert this announcement into an oppurtunity. Venture capital should be available in plenty within India and from nris. It is a call for entrepreneurs.

Functional genomics would lead to identification of genes conferring high susceptibility to certain diseases -- such as diabetes, cardiovascular infirmities, vulnerability to various diseases etc. There will be a possibility for "personalised" genomics, where an individual with adequate money can get tested his particular genes and fashion his lifestyle to ward off an ailment to which he may be genetically disposed. It can be argued that in case the insurance companies get such information, they may not insure high risk individuals or lay high premium on them. These are all possible spin-offs of the new knowledge and technologies. Guidelines on confidentiality and ethics would have to be framed to avoid misuse of such information.

As regards the elderly, whose number is increasing worldwide, every new advance in medicine would have the potential to add years and what is more add to the quality of life. Regenerative medicine has made an entry. By transplanting stem cells (cells derived from the embryo, or aborted foetus or grown from tissues), these cells by virtue of their pluripotent character, can differentiate into insulin producing pancreatic cells, or neural cells making dopamine or cells making blood or immune cells depending on the tissues in which these are implanted. Thus diabetics, patients with Parkinsons disease etc can be imparted the missing ability and thereby a better quality of life. It is another matter whether these would be affordable by all. Social security/insurance systems would have to plug in- something which is happening in economically developed countries.

A question has been asked on whether the new advances will lead to genetically engineered weapons. Deadly viruses and lethal bacteria are already there. There is no need of human genomics to enhance their lethality. If at all, the available genetic engineering techniques (these do not depend on human genome) can be used to make lethal bacterial or fungal toxins in large qualities as proteins in E. coli. The international community is already seized of the necessity of controls on chemical and biological weapons.

To sum up then, the rough description of the entire human genome is a great technological advance. It brings no immediate benefit or harm to mankind. To derive benefits, the functions of most of the genes have to be found. India offers unique resource material for study of functional genomics. It is an opportunity for Indian scientists to establish worldwide leadership in this field. It will require professional team-work and competent management. There will be accompanying entitlement to patents and in course of time to enormous economic returns.

Modern medicine is expensive, even as such, and a price has to be paid for every new advance with the incoming sophisticated new technologies. Social security and health insurance has to be extended, so that the benefits are accessible to those who are economically under privileged.

-- G P Talwar
Director Research, Talwar Research Foundation, New Delhi

It is expected that this breakthrough will lead to the genetic dissection of common diseases which, in turn, will help in discovering drugs and vaccines for such diseases. These drugs will be genetically-engineered (recombinant) drugs/ vaccines, which are expected to be eventually cheaper than the current classes of drugs/vaccines.Initially, this will widen the chasm between the rich and the poor because of patents that will surely be filed and granted upon the discovery of important drugs and vaccines based on genome sequence information, such products will be expensive and probably will not be affordable by the poor. Initially biotech companies will try to recover their r&d investments, so they will keep the costs of their products so high that they may not be affordable to everyone. The poor will probably have to continue to depend on classical drugs/vaccines until such time that the prices of these new classes of drugs/ vaccines come down. I feel that the new classes of products will become cheaply available not long after these are discovered, because their production costs will be lower than those of classical drugs.

Whether this will it lead to the quest for the perfect human being or could genetically-engineered biological weapons be used to target a specific race, the answer is that all these are possibilities. The history of human society is full of such inappropriate deviations. However, humankind has taken strong stands against such deviations whenever these have occurred and has been able to curb such activities. It is absolutely essential now, more than ever before, that those of us who are engaged in genomics, must be extremely vigilant and must take appropriate measures to thwart such possible misuses of genomic information. Already, several guidelines have been formulated anticipating such misuses. It may become necessary to formulate regulations that will prevent such misuses.

On another issue, the prolonging of life and retarding the ageing process could theoretically effect intra-family equations. But this is not particularly related to advances in genetics. Even the improvements in health-care, leading to increased life-expectancy at birth, have affected intra-family equations. I am an optimist and I'm sure that we will devise ways and means of handling such dilemmas that may arise.A problem arising from this is whether we can we provide jobs and resources for the increasing number of people. My view is that unless humankind, especially those inhabiting developing nations, exercises voluntary population control, the situation may soon get out of hand.

Finally, I do not think that raw information on the human genome sequence should become patentable. Everyone should have equal access to it, whether or not they have participated in the human genome sequencing project.

-- Partha Pratim Majumder
Professor, Anthropology and Human Genetics Unit, Indian Statistical Institute, Calcutta

When the news broke we were all electrified while watching the television programmes which announced that a working draft of the Human Genome is now available. My mind went back to the past half century, during which I had, from the sidelines, seen the development of modern biology. I have had the privilege and honour of knowing closely many of the pioneers. I was in England doing research in elementary particle physics and visited Cambridge University often, at the time when Jim Watson and Francis Crick unravelled the structure of the dna in 1953. Since then there have been many path-breaking discoveries that made possible the recent developments.

There has been commercial imperative for companies to be able to get their hands on the information first. Money has, therefore, not been a problem. And then, there is the thought that, in spite of the first tremendous feeling of elation, this draft of the human genome is only a starting point. It is still full of holes. While the wide variety of genes responsible for hereditary diseases have only been identified and cloned over the last few years, we are aware of around 4,000 single gene disorders that follow Mendelian laws. We are now entering the arena of complex polygenic disorders with the work on the Human Genome. What will follow will surely be a completely new area of molecular medicine based on understanding and preventing gene-based disorders and then of gene therapy.

It is clear that such fundamental knowledge relating to human beings would raise ethical, legal and social questions. Because of this, in the United States, right from the start of this project, there has been a specific percentage of the project allocation assigned for elsi (Ethical, Legal and Social Implications). The legendary Jim Watson had a great deal to do with this. Information from the Human Genome Project will not remain exclusively within the scientific domain because it will lead to applications that affect all aspects of the lives of people, including their private life, family life, community life, and life as members of humanity.

One of the key issues that has come up relates to obtaining patent rights -- obtained with massive but routine sequencing efforts. It must be remembered that the most important step, in terms of social benefits, is that of identifying biological functions of a gene. This is a task of great difficulty and complexity, calling for the highest order of creativity. Since patenting sequences, as they are discovered through efforts like the human genome programme, did not appear to be correct, the International Council of Scientific Unions had issued a strong statement opposing this in June 1992. unesco also took a major initiative in support of this view.

In 1993, unesco set up the International Bioethics Committee (ibc) as the world's only international body to study the implications of human genome research and genetic engineering. ibc has discussed many issues relating to genetic screening, genetic testing, genetic engineering, aspects relating to transgenic crops and food, equal access to matters concerning biophysics for woman etc. A major output from the deliberations of the committee was a declaration on the human genome. The most important aspect of this declaration relates to the question of human rights in the age of biotechnology and the trade-offs in scientific research between freedom and responsibility.

To me it is clear that the working draft of the human genome represents the culmination of a scientific effort of monumental significance and must be hailed as such. It must equally be recognised that it will be the starting point for a great deal that is going to happen. Like everything else, in science, it represents an increased understanding of nature with great possibilities for application. It will clearly open up opportunities for not only scientific progress but a much better life for human beings; in particular, it will have a decisive impact on the way the sectors of human health and medicine are shaped in the years ahead.

Craig Ventner pointed out that Celera Genome has mixed the data of the first donor with five other individuals from five ethnic backgrounds, with at least two of them being women. With great and justifiable pride he pointed out that the basic need of the human genome is the same. Science, therefore, demonstrates the universality of the human being. At the same time we have individuality both in our genes and in our upbringing; the latter is nurtured with the environment, culture and society playing their own roles. It is this which gives the rich diversity that constitutes the kaleidoscope of humanity. Let us remember that as we ponder over the implications of this major scientific discovery -- we should sink all our trivial, parochial differences and be proud of belonging to one human race.

-- M G K Menon
Former Union minister of state for science and technology

I have been surprised at some of the statements made by our scientists and science administrators in regard to the announcement of the first draft of the sequence of the entire human genome.

Although this has been a remarkable achievement and successful culmination of one of the largest world-wide team efforts ever made in science -- an effort which extended over a period of over a dozen years -- it is primarily a technological achievement, comparable to the first man on the moon. The genomes of nearly 25 other organisms have been sequenced since the work started on the human genome project. It is just that the human genome is vastly bigger than all the other genomes sequenced so far, taken together.

There are reasons to be excited about the human genome sequence announced recently just as there have been reasons, though different, to be excited about the availability of the sequences of genomes of other organisms such as Helicobacter Pylori. This organism was shown some five years ago to be the major causative agent for stomach ulcers which affect some 4 per cent of our population. The availability of the genomic sequence of this organism has opened up the possibility of discovering new targets in the bacteria for drugs and thus of designing new and active drugs for stomach ulcers.

Not only that, studies over a period will now make it possible for scientists to define environmental conditions, including nutrition and other lifestyle factors, which would make a person who is genetically susceptible to a disease, actually become diseased. Similarly, one would begin to understand the nature of genetic differences between social or ethnic groups and their significance or lack of it. The origin of human viruses, for example, has been an enigma. The information in the human genome may make it possible to have an answer to this intellectually exciting and practically important question.

But these obvious uses of human genome sequence data would be just a tiny part of the top of a massive iceberg. Much of biology in the next few decades will be dominated by scientists discovering new uses of human and other genomic sequence data. These analyses would require an intimate and lasting marriage of molecular biology and information technology.

The Indian Council of Medical Research (icmr) has set up a committee for analyses of genome sequence data. I have the pleasure of chairing this committee, the last meeting of which was held on the 4th May, this year. This committee has made several worthwhile recommendations but they have yet to be consolidated and converted into viable action plans. Unfortunately, we have yet to learn how to work fast and score a goal. If those who sequenced the human genome will have worked at the pace at which we do in our scientific bureaucracy, the human genome sequence would have been available only in the year 2100.

We missed the bus as regards sequencing of human genome or for that matter any genome. We can still be a leader in genome analyses, especially as analyses has been our strength through history. The question is whether our concerned scientific bureaucracy with its tradition of talking too much and doing very little, will allow this to happen in time.

-- P M Bhargava

Former director, Centre for Cellular and Molecular Biology, Hyderabad

When everybody is talking about this as an opportunity my fear is that although its an important event, challenge eof unravelling the functional meaning of the encrypted data set will be the daunting task for the next several decades. it will play a major role for eventual development of new genomic medicines, the expected market for which is us $200 billion starting 2010. Indian it will see the opportunity and get work from large industries and public genome houses, which are likely to outsource it requirement. But we shouldn't take this up without the strategic plan for the nation. For instance, with y2k we got business but the world did not acknowledge our it contribution on the first day of this millennium but the same cannot be said if a disaster had occurred India would have made headlines! In the committee of nations we didn't position ourselves. If we only outsource ourselves for genome informatics, we will not have ipr, we will be contributing in service but won't be partners in international endeavours of functional analysis of human genome sequence. Instead it industries should join hands with our genome researchers contribute substantially in value addition, the result of which can then be traded. India then will be seen as a major r&d player in the post genome era.

To understand the meaning of 3.2 billion sequences, one needs to study mutations. India being one fifth of the world's population endowed with endogamous (intra-marrying) ethnic groups with isolated gene pools, which in genetic diversity, has unique genetic material for research on complex diseases like schizophrenia, asthma, cancer, cardiovascular disorders etc. This genetic resource of India for studying diseases which has an interplay between environment and the gene is going to be important for the international genome function quest. We should therefore organise and participate, and not allow it to go from our clinicians to the genome laboratories outside India, without ipr protection. We need strong ipr, all patents filed using such material much disclosed the source of the material and associated information, so as to protect the economic interest of the original source. It is important that the economic benefit and healthcare reach the needy sections specially those who have contributed their genetic material to the research.

Tomorrow's drugs are going to be genotyped and pharmacogenomics is going to be the new r&d focus. Development of any personalised medicine based on genomic knowledge will need clinical trial. India is already an important place for this as pharmaceutical companies have major collaborative units here because it is cost effective. We must not undertake genotype drug discovery trial without ipr. However, if we do the same in an organised way that knowledge partnership with Indian genome research laboratories, 2010 will see India as a major player in harvesting the health care benefits from human genome sequence which is in the public domain, for its people. Otherwise people of India will not benefit from this new knowledge although its children will contribute in the three niche areas it solutions, genetic material and pharmacogenomics for the world. We need it training institutions to join hands with genome labs for new training of manpower. Pharma companies should join hands with genome labs to work on pharmacogenomics. Clinicians should network with labs and create a genetic databank for utilisation to generate wealth that will be fed back to the people of India. We need to do value addition to generate ipr in these areas and not encash tomorrow's wealth today.

-- S K Brahmachari
Head, functional Genomics Unit,Director, Centre for Biochemical technology, CSIR

By looking at the genome sequence as pieces of a jigsaw puzzle that had to be put together, scientists have succeeded in getting fragments that cover 97 per cent of the genome. The exact sequence has been determined for some 85 per cent (this includes two huge stretches of dna known as chromosome numbers 21 and 22). This is what they mean by a 'working draft'. The press release at this stage was partly for its publicity value and stock market implications. Also, given the inevitability of technical mistakes, waiting until the entire genome is known with 100 per cent accuracy doesn't make sense. An accuracy of 99.99 per cent over the entire genome is expected to be attained within a few years.

There are many implications of knowing the human genome sequence. First and foremost, this opens up the possibility of understanding, at least in principle, a part of what it takes to make each one of us uniquely what he or she is. This is because a great deal of what we are also depends on early nutrition, how we were brought up, in short, on everything that comes under 'nurture'. To say that we now have, or will soon have, 'the complete set of instructions for making a human being' or 'the human blueprint' is, to put it mildly, an exaggeration.The 'draft' helps to know what makes us -- if only genetically -- unique to the extent that genetic differences predispose us to different ailments, or predispose us to resistance against infections, it would be useful if we could pin down the differences to a small number of genes. For one thing, this will help in diagnosis -- ideally, prenatal diagnosis. For another, it may be possible to transfer 'advantageous' genes from one person to another (though the procedure is not without potential pitfalls, some of them inherent in the ambiguity associated with the word 'advantageous'). Finally, it may be possible to design drugs to treat individuals after taking into account their genetic makeup.

As with any form of information, knowledge of a person's genetic makeup can be misused. There is the risk that people will come to think of some genes as 'desirable' and others as not; and as a consequence, will label someone possessing 'undesirable' sequences as a lesser human being. Insurance companies are sure to make use of any knowledge that they possess about a person's predisposition to illness to assess how much they will charge for insuring him or her -- or whether they will deny insurance altogether. What makes this unfair is that predisposition is not the same thing as certainty. The most immediate potential for misuse is biopiracy: thanks to the connivance of the us patenting authorities, private companies can patent dna sequences -- whatever their origin -- that they think might be of commercial value. We may find ourselves spending ill-affordable time and money fighting for our rights as in the case of the neem and turmeric patenting affair.

At the moment a rough analogy to what has been accomplished can be provided by saying that now we have a cookbook in which each recipe consists solely of ingredients. How the ingredients should be put together, and which dish will result from a particular recipe, remains by and large unknown. What makes the situation worse is that a great deal of each 'recipe' may consist of gibberish, or at the least, of repetitious or trivial information. To get back to the genome sequence: what remains is to work out the information contained in the sequence. This will be an enormous enterprise, far more difficult than the sequencing itself -- which is impressive but essentially no more than a technical feat.

Among the skills needed to decipher the meaning (or meanings) contained in the human genome will be sophisticated computational analyses. There is the problem of handling up to 100,000 gene sequences and their interactions with one another. Here is one direction which an Indian contribution might take. Next, the Indian population is made up of a number of sub-groups, which marry among themselves. Therefore, the genetic structure of our population is very likely fragmented in interesting ways, making us ideal subjects for spotting patterns of genetic differences. In short, a concerted effort in the areas of computer-based genome analysis and human genetics is one that we should get ready for.

-- Vidyanand Nanjundiah
Developmental Biology and Genetic laboratory, Indian Institute of Science, Bangalore

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