The Tribune, Chandigarh, India

What the genome map means to your health
Enormous potential for both good and bad
by William Haseltine

THE completed mapping of the human genome is an historic feat comparable to sending men to the moon. But the actual feat will have little practical impact on our lives unless we can characterise and isolate the useful genetic information in the genome. After all, there was little utility in the moon landing itself; so far that has come from the associated advances which enabled today’s satellite communications.

Genes are stored in fragmentary form in the human genome. Three per cent of the genome is genetic information; 97 per cent in packaging. The cell is smart enough to assemble that 3 per cent for you to build and maintain your body.

When we know, in effect, what our cells know, health care will be revolutionised, giving birth to “regenerative” medicine — ultimately including the prolongation of life by regenerating our aging bodies with younger cells.

Thanks to the convergence of the information and genome sciences revolution, we are already on the threshold of isolating and characterising virtually all useful genes. The enormous advances during the last decade of the 20th century in molecular biology, laboratory instrumentation and computational capacity have made this possible.

Utilising genes

In molecular biology we have learned how to utilise genes by moving them from one organism to another, by altering them and changing the effect of their protein products. Instrumentation advances have allowed us to manipulate genes in parallel and then to create assembly lines, speeding up the rate of biological discovery by a magnitude of 10,000. Finally, the advances in both computer software and hardware have enabled the storage, retrieval and quick interface of very large amounts of data — essentially what the Internet does for information at large.

Already under way for about four years, is the development of new and more efficient drugs to treat disease based on genetic knowledge. Up to this point, pharmaceutical treatment had been a little like wildcat oil prospecting — digging hopefully for knowledge about migraine headaches or cholesterol based on the extant medical literature. Finding a starting point for drug development was always a hit-and-miss proposition. Now, by isolating and characterising human genes and the way they are actually used in different states of cancer or heart disease or schizophrenia, a systematic means to identify where and when to intervene with drug treatment has been opened.

Long process

This does not mean curative drugs will be available over the counter tomorrow. The process is long and difficult. First, the gene and what it does has to be identified. Then, it has to be shown that, when you perturb that gene, you get the desired effect and only the desired effect. The drug has to be compatible with your body, it has to get in, get around and get out of your body and only stay for the right amount of time. We have to cope with the complication that the body metabolises the drug you take in, like a rocket that bursts into fireworks, and spreads it all around.

All this has to be taken into account and tested through trials that prove the drug safe and effective. But the experience so far is positive.

Within six to seven years, we will see a whole range of new drugs for diseases that have no other treatment today.

Our company, to take one exciting example, has discovered a “receptor” on a protein on the surface of cells that is important for the functioning of the immune system. If you don’t have the receptor, it appears you are less susceptible to inflammation and viral infections. Based on our discovery, a study by the National Institutes of Health has shown that people who are defective — that is, who lack this receptor — not only don’t seem to have any adverse health consequence but, indeed, are not infectible by HIV. A further study in 1999 showed that an unusual form of the herpes virus, like AIDS and probably other viruses, uses this handle to infect a cell.

With this new information in hand, drugs can be developed to inhibit inflammation for viral infection — possibly even to stop AIDS.

It is the action of genes on a single cell and within that cell that leads to the fertilised egg’s production of every organ and tissue in our whole body. We are formed by the action of our genes and, as a mature organism, we maintain ourselves for a long time. Under ideal circumstances, that would be 120 years or more.

Regenerative medicine

And we don’t do this statically, but by replacing our parts. Everyone knows that the skin we have today is different than our skin tomorrow. And that is true for almost all parts of our bodies, including, we now realise, the brain.

Though there are defects, such as among those who can’t clot their blood, our bodies are reasonably effective at repairing themselves.

This understanding is key to the regenerative medicine of the future. Once we have full knowledge of the signals that make this process work, we can create a new medicine. I see four phases in developing regenerative medicine:

1. Gene drugs. The use of our genes, proteins and antibodies — human components themselves as the new pharmaceuticals. In this way we will be able to use our body’s own substances to rebuild, repair and permanently restore ourselves rather than rely on some chemical crutch.

If you now take a pill every day to lower your cholesterol, wouldn’t it be much better to have a treatment of your own proteins that permanently lowers the cholesterol level?

As a result of the first revolution in bioengineering we already have medicines — such as insulin, which is a tiny human part made from the gene of a person and used as a drug — that are essentially body parts. The remarkable fact about insulin — one person’s can be used by everyone — is that it shows how humans are essentially interchangeable at the gene and protein level.

Knowing this, the first phase of regenerative science will be to use our own genes, proteins and antibodies as medicines to rebuild our bodies from the inside out. All we are doing, really, is stimulating the body’s inherent regenerative capacity.

An example: We are testing methods of using a natural protein to enhance the healing of skin for patients with large open wounds or for chemotherapy patients with ulcers in their mouths. This treatment is based upon the cell signal to repair damaged skin (when cells know they don’t have a neighbour, they turn on a receptor that grows new cells). a normal, healthy body doesn’t have these receptors; they only appear when there is a problem.

We will see the first set of these new drugs emerging in two-three years. By 10 years, they will make up 15 per cent of our medicine. In 20 years, they will be at least half of all our medicines.

Parallel revolution

A parallel revolution is taking place in delivering such drugs to our bodies thanks to the power modern materials science. Already under way are technologies enabling drug inhalation for large molecules that look like minuscule whiffleballs, enabling the prescribed drugs to reach into the deep recesses of the lungs. And there soon may be microchips implanted in your body that will release the right dose of a given drug on schedule.

2. Organ replacement. The next phase of regenerative medicine, already with us in early form, involves engineering organs outside the body so they can be implanted. This has already been done for bladders.

If a person has bladder cancer, the bladder can be removed. A matrix made of material similar to catgut is used as a kind of scaffolding to which snippets of the cancer patient’s own cells are attached. These grow into a thin sheet of muscle and lining cells that are stretched over the scaffolding, where they take hold and grow as the catgut-like material disintegrates. That new bladder can then be implanted in the patient without any danger of rejection. In this way arteries, ligaments, new pieces of bone and tracheas are being created.

Within five to 10 years replacement of kidneys will be possible; within 10 to 15 years liver replacements will be a reality. Eventually, entire hearts can be made for reimplantation. In 20 to 30 years, organ replacement will be a major part of medicine.

3. Resetting the genetic clock. The ultimate transgenic medical treatment, only now a gleam in the eyes of scientists made possible by the cloning technology begun by Ian Wilmut and Dolly the sheep, is resetting the genetic clock.

This involves supplanting aging adult cells with younger cells grown from “stem cells” — the originating cells for all body functions. There is one stem cell, for, example, for blood. Another for the skin, the brain and so on.

It will be possible in the future to take a cell from a person, reset its genetic clock and then move it to stem cell status for brains or muscles — in effect, enabling our bodies to rebuild themselves in a younger form. The fundamental process that drives aging is the aging of stem cells that replace tissue worn down by living — reactive oxygen interacting with DNA changing its chemical nature.

The average life of an essential gene in an essential stem cell is about 50 years. But there is nothing intrinsic in that age. It is a result of our body’s evolutionary response to its environment. If we can regenerate stem cells — and get rid of the old cells that turn into cancer — then we can prolong life.

Regenerating bodies

The current medical practice of bone-marrow transplants shows that this idea is not at all far-fetched. In that process, an older person with cancer, whose ability to form new blood cells has been damaged by chemotherapy, often receives marrow donated from someone younger. In effect, that person is an age-hybrid, with a 50- or 60- year-old body, but with blood-derived tissues that are only 20 or 25 years old.

In short, rather than continually regenerate our body with aging stem cells, in the future we can regenerate them with our own younger cells.

I expect this third wave of regenerative medicine to come into being no sooner than the year 2050.

4. The fourth phase of regenerative medicine will be to integrate non-biological substances with our bodies. Already, an older person is a bit of metal with a joint in his leg, a bit of plastic with a valve in his heart, a bit of nylon with a new blood vessel, a bit of an electronic device with a pacemaker or hearing aid.

Miniaturisation and nano-technology (molecular-sized machines) will further enable the creation of prosthetic devices fully compatible with our bodies. One exciting field in rapid development today is neuro-prosthesis where brain implants pick up mental intent and can translate that signal into the movement of muscles independent of the spinal chord.

Already, implants in the brains of monkeys enable them to move robots in the next room — or it could be the next continent. This will make it possible for people to move through bypassing the spinal chord — which may have been ruptured or otherwise injured — altogether.

Though less than a decade in the works, it is already clear that the combination of the genetic and information revolution will change medicine within the next 50 years more than in the past several centuries.

———

William Haseltine, one of America’s leading molecular biologists, is Chairman and Chief Executive Officer of Human Genome Sciences, the firm that is developing a variety of gene-based pharmaceutical products. He is also editor-in-chief of Ebiomed: The Journal of Regenerative Medicine.

(Asia Features)

The terms that matter

IN AN effort to provide our readers with information on the basics of genetic research, we are giving herewith a basic primer, which was prepared by the The Genome Project, USA:

The complete set of instructions for making an organism is called its genome. It contains the master blueprint for all cellular structures and activities for the lifetime of the cell or organism. Found in every nucleus of a person's many trillions of cells, the human genome consists of tightly coiled threads of deoxyribonucleic acid (DNA) and associated protein molecules, organised into structures called chromosomes.

DNA

In humans, as in other higher organisms, a DNA molecule consists of two strands that wrap around each other to resemble a twisted ladder whose sides, made of sugar and phosphate molecules, are connected by rungs of nitrogen-containing chemicals called bases. Each strand is a linear arrangement of similar repeating units called nucleotides that are each composed of one sugar, one phosphate, and a nitrogenous base. Four different bases are present in DNA: adenine (A), thymine (T), cytosine (C), and guanine (G). The particular order of the bases arranged along the sugar-phosphate backbone is called the DNA sequence; the sequence specifies the exact genetic instructions required to create a particular organism with its own unique traits.

The two DNA strands are held together by weak bonds between the bases on each strand, forming base pairs (bp). Genome size is usually stated as the total number of base pairs; the human genome contains roughly 3 billion bp.

Each time a cell divides into two daughter cells, its full genome is duplicated; for humans and other complex organisms, this duplication occurs in the nucleus. During cell division the DNA molecule unwinds and the weak bonds between the base pairs break, allowing the strands to separate. Each strand directs the synthesis of a new strand, with free nucleotides matching up with their complementary bases on the separated strands. Strict base-pairing rules are adhered to; adenine will pair only with thymine (an A-T pair) and cytosine with guanine (a C-G pair). Each daughter cell receives one old and one new DNA strand. The cells' adherence to these base-pairing rules ensures that the new strand is an exact copy of the old one. This minimises the incidence of errors (mutations) that may greatly affect the resulting organism or its offspring.

Genes

Each DNA molecule contains many genes — the basic physical and functional units of heredity. A gene is a specific sequence of nucleotide bases whose sequences carry the information required for constructing proteins, which provide the structural components of cells and tissues as well as enzymes for essential biochemical reactions. The human genome is estimated to comprise approximately 100,000 genes.

Human genes vary widely in length, often extending over thousands of bases, but only about 10% of the genome is known to include the protein-coding sequences (exons) of genes. Interspersed with many genes are intron sequences, which have no coding function. The balance of the genome is thought to consist of other non-coding regions (such as control sequences and intergenic regions), whose functions are obscure.

The protein-coding instructions from the genes are transmitted indirectly through messenger ribonucleic acid (mRNA), a transient intermediary molecule similar to a single strand of DNA. For the information within a gene to be expressed, a complementary RNA strand is produced (a process called transcription) from the DNA template in the nucleus. This mRNA is moved from the nucleus to the cellular cytoplasm, where it serves as the template for protein synthesis. The cells' protein-synthesising machinery then translates the codons into a string of amino acids that will constitute the protein molecule for which it codes. In the laboratory, the mRNA molecule can be isolated and used as a template to synthesise a complementary DNA (cDNA) strand, which can then be used to locate the corresponding genes on a chromosome map.

Chromosomes

The 3 billion bp in the human genome are organised into 24 distinct, physically separate microscopic units called chromosomes. All genes are arranged linearly along the chromosomes. The nucleus of most human cells contains two sets of chromosomes, one set given by each parent. Each set has 23 single chromosomes--22 autosomes and an X or Y sex chromosome. (A normal female will have a pair of X chromosomes; a male will have an X and Y pair.) Chromosomes contain roughly equal parts of protein and DNA; chromosomal DNA contains an average of 150 million bases. DNA molecules are among the largest molecules now known.

Chromosomes can be seen under a light microscope and, when stained with certain dyes, reveal a pattern of light and dark bands reflecting regional variations in the amounts of A and T vs G and C. Differences in size and banding pattern allow the 24 chromosomes to be distinguished from each other, an analysis called a karyotype. A few types of major chromosomal abnormalities, including missing or extra copies or gross breaks and rejoinings (translocations), can be detected by microscopic examination; Down's syndrome, in which an individual's cells contain a third copy of chromosome 21, is diagnosed by karyotype analysis.

Most changes in DNA, however, are too subtle to be detected by this technique and require molecular analysis. These subtle DNA abnormalities (mutations) are responsible for many inherited diseases such as cystic fibrosis and sickle cell anaemia or may predispose an individual to cancer, major psychiatric illnesses, and other complex diseases.

As they look at it

THE genome project, its achievements and its implications have had a world-wide impact. The following are excerpts from editorial comments of prominent international newspapers on the issue.

Beyond ethical dilemmas

Knowing which tiny gene can control which specific human condition — whether it be a disease or a peculiar behaviour — at first seems to be a fundamental tool for progress. Many genetic links will be deduced from this blueprint of the human body. Knowing the links, solutions will be sought to either genetically fix a physical problem or enhance human life.

Both those prospects, of course, are as difficult to sort out ethically as the genes are to decode in the lab. Should, for instance, couples be able to design a baby from the genes up?

But beyond such ethical dilemmas lies a deeper question. Before this new Rosetta stone for deciphering the body’s origins and operations becomes the basic way of thinking about ourselves, it’s worth asking if life is as predestined as all that.

Predestination in genetic medicine may someday go the way it did in religion. Something in human thought fights against the idea that we are already selected to be good or to be bad, to be diseased or schizophrenic.

— Christian Science Monitor

The risks are large; time frame long

Two rival visions of science yesterday met in the White House and declared a dead heat in the race to complete the sequencing of the human genome. ... But the divisions which turned the pursuit of the genome from a plodding ascent of a scientific Everest into an exciting race have not gone away. Scientists still do not know if the genome is to be an open horizon for all mankind, or a new land to be fought over, inch by inch, by rival bands of colonists.

In pioneer fields like genomics, the risks are large, the time frame long, and the costs high. ... To rely solely on the public purse would mean that this new frontier of science would be explored and developed at a far slower pace. If private sector entrepreneurs are to pour money into this vital practical research, however, then patent protection is absolutely vital.

— The Times

Legislate against discrimination

Nobody wants to take medicines that are ineffective. That is true especially if a given medicine has serious side effects. Order-made treatment is certainly attractive. It should not be forgotten, however, that genetic information is property of ultimate privacy.

Legislation against discrimination must be upgraded and arrangements must be made to prevent leakage of genetic information, which should be closely guarded as being in the realm of privacy. Under the current circumstances, the arrangements in our society do not keep up with research that advances at a dizzying pace.

— Asahi Shimbun

Legal safeguards needed

Scientists and doctors are not the only ones with enormous tasks ahead. Without legal safeguards in place, the value of even the most powerful genetic information could be compromised, from misuse or fear of misuse. The latter already dissuades some people from signing up for even the limited number of genetic tests now available. The details of such protection will be complicated, but a few principles are clear. Those obtaining genetic material for a specific purpose—to test the guilt of a criminal suspect or track patients in medical trials—should use only the relevant information and protect the rest from unauthorised disclosure. The president this year signed a laudable executive order barring the use of genetic information in hiring or promotions in the civilian federal work force. A bill in Congress would similarly protect all employees. If people are assured some basic control over this, the most personal information of all, societal benefits will flow more freely.

— The Washington Post

India-Bangladesh rail pact on anvil
From Krittivas Mukherjee in Calcutta

Indian and Bangladeshi railway officials are set to sign a formal agreement next week on the resumption of the international rail link through the Petrapole-Benapole border in West Bengal, according to Indian Railway sources.

The foreign ministries of the two governments have given the go-ahead to their rail authorities to sign an agreement in Dhaka, the sources said adding that the pact was likely to come through next Monday. The railway officials of the two countries would then decide on the date of resumption of the service.

The inauguration of the service, which has been rescheduled at least twice last year, could take place next month as the infrastructure is ready. The sources said the draft agreement on the resumption of the service has been approved by both countries. India is sending a four-member team to Dhaka for the signing of the pact.

Work on track-laying has largely been completed, and only a 10-feet gap remains to be covered on no man’s land. The sources said a round of diplomatic parleys was necessary to discuss track-laying on the uncovered stretch. “That stretch can be put up in just ten minutes once we have the green signal,” the sources said.

Train service between the two countries existed through several points, which was abandoned in 1965 following deterioration of relations between India and the then East Pakistan, which won independence from Pakistan and became Bangladesh in 1971. Talks of resuming the service came up on several occasions, but were abandoned for some reason or the other. But in 1997-98 the two countries formally agreed to resume services through the Petrapole-Benapole border, which first started in 1923.

The resumption of the rail service would be another step in cementing relations between the two countries. The Dhaka-Calcutta bus service was started in July last.

To begin with only goods trains will ply on the Petrapole-Benapole route. Allowing passenger traffic would then be just a matter of time keeping in view the growing traffic volume between the two countries.

Once the railway link is re-established, India and Bangladesh would explore fresh road and rail routes to increase trade volume and ease passenger traffic. According to official sources, the proposal to revive the Gede-Chuadanga rail link between the two countries, which was discontinued following the creation of the erstwhile East Pakistan (now Bangladesh) after Partition, was at a nascent stage. Gede is in West Bengal.

According to sources, West Bengal was interested in the restoration of the rail link through the Gede-Chuadanga point as that would help the state connect better and faster with its northern parts which are considered far-flung. An abandoned rail route exists between Calcutta and New Jalpaiguri in north Bengal through Bangladesh that was being considered for revival. The Gede-Chuadanga border was the transit point for this route. Most of the stretch of this route runs through Bangladesh. If revived, the time taken to travel between Calcutta and New Jalpaiguri will be halved. At present, it takes around 12 hours.

Communication apart, the link would mean higher volume of business. Presently, exports and imports are routed through only two road points in the Petrapole-Benapole and Hili borders. It was expected that with restoration of more rail links, pressure would be taken off the arterial Jessore road that links India and Bangladesh.

Like the Petrapole-Benapole rail link, where portions of track existed even after the service was suspended, a service on the Gede-Chuadanga route could also be started with minimal expenditure, according to Indian Railway sources. India was having to spend only Rs 50 million on the restoration of the Petrapole-Benapole service.

— India Abroad News Service

Canada to amend Human Rights Act
From Ajit Jain in Toronto

A panel set up to review Canada’s Human Rights Act has suggested several amendments to avoid inordinate delays in acting on rights violations complaints and remove perceived bias against the underprivileged.

The government had appointed a four-member panel of experts to go through the 23-year-old Act and suggest changes, if required. The panel has just released a 178-page report containing 165 recommendations.

Harish Jain, an Indo-Canadian who teaches in McMaster University in Hamilton and specialises on employment equity, was a panel member. He said there were inordinate delays in dealing with human rights complaints and that defeated the purpose of having such an Act to protect people’s rights. “The current process is flawed”, he said.

The current approach of the Canadian Human Rights Commission in dealing with individual complaints is not good, Jain claimed. He suggested that the commission investigate the entire system while complaints against employers go to the Human Rights Tribunal, which is a sort of court where complainants go with their attorneys.

In its annual report last year, Canada’s Auditor-General had revealed that 68 per cent of complaints were dismissed by the rights commission and no reason was assigned to such large-scale dismissal, said Jain.

The panel report, titled ‘Promoting Equality: A New Division for 2000’, calls for a major redesign of current federal human rights legislation while placing greater responsibility on all Canadians to promote equality and prevent human rights abuses from occurring.

“What we are proposing is a fundamental re-thinking of the human rights system”, said Gerard la Forest, who chaired the panel. “Today we need a Human Rights Act that is designed to address the more fundamental aspects of systemic discrimination”.

The report says the Act should be expanded to ban discrimination against the poor. Human Rights abuses should be redefined to include business practices that limit access to loans, mortgages, bank accounts, telephone services and other services for poor people, people who are on welfare or are unemployed, or single mothers, the panel recommends. It says discrimination should be banned against people based on their “social condition”.

Jain says the report also moves human rights away from a largely complaints-based model to address potential abuses in the workplace. With greater emphasis on prevention, the panel recommends increased responsibility for employers and service providers to ensure equality and to deal with discriminatory acts that occur in their place of work.

Another important recommendation pertains to human rights protection being extended to people “who are not lawfully present” in the country — illegal immigrants and refugees. But the Immigration Department had warned the panel this recommendation would allow illegal immigrants to use the human rights system to undermine immigration law.

Based on the recommendations of the review panel, the Canadian government may either change the entire Human Rights Act or make suitable amendments to incorporate these recommendations.

— India Abroad News Service