More MS news articles for March 2001

Reverse inheritance: What a mother receives from her child

OF THE various magazines that cover happenings in science, my favourite is The Economist. Its science correspondents write well, succinctly and with a sense of humour. The issue of February 24, 2001 covered some of the presentations made by scientists at the annual meeting of the American Association for the Advancement of Science (AAAS) held in San Francisco. These meetings discuss current happenings and fresh research results that are yet to be published in professional scientific journals, and are therefore previews of what will be seen in print shortly. One such item had to do with a class of diseases known as autoimmune disorders. The surprising bit of news about them is that these diseases, which run into as many as 70 in number, may belong to one family and may arise from two sources. One mode is through genetic inheritance or what you get from your parent. The other is the reverse of it, namely what you end up getting from your child even before the child is born. It is thus a form of what The Economist calls as `reverse inheritance'. It is a condition caused not by infection through a pathogenic germ, but a systemic one caused by cells from the foetus making their way into the mother's blood stream.

Reverse inheritance is a catchy term that is just as expressive as the term "reverse genetics" coined in the early 1980's by biologists to describe certain patterns in the occurrence of disease conditions. Diseases occur to us through two routes. The first is by germs that infect our body in order to live off it. The invading microbes use the resources of our body in order to propagate themselves. Some of them behave so well as guests that they actually help our body with its biochemical and metabolic needs. These are termed as symbionts. The body has learnt to understand and appreciate them and accommodates them as paying guests, who play a useful role. There are others who invade the body and parasitize it, with no particular effects - good or bad. These fellow tavellers can be full-fledged cells, or simply stretches of DNA. These could be viruses, which propagate themselves as house guests or often they become part of us, stretches of DNA that integrate into our own genome. When the human genome was read last month in great detail, one of the surprises found by the scientists was the enormous amount of such benign parasitic DNA that our genome carries within. The roles that these repetitive sequences of DNA, called transposons, are slowly getting to be understood. They seem to move in our reposition themselves from time to time in our DNA sequence, and thus provide us with some genetic diversity.

How diseases occur

Then there are germs- cells or bits of DNA - which come in as unwanted guests. They neither lie low nor provide any help, but start using our body as a resource heap to help themselves of. The body recognizes them and mounts a defence reaction, which takes many forms. One is to blast the invader by burning it off or using an oxidative assault. The other is to engulf it within special cellular enclosures and "imploding" it into pieces. A third way is to capture it, shroud it with a set of proteins and dump it as debris to be taken care of by the clearing squad system of the body. In doing all this, the body experiences stress wear and tear.These are expressed as fever, chills, weakness, dehydration and other classic symptoms. Knowing what the infecting germ is helps in containing and getting rid of it, using drugs to interfere with its life processes, and with vaccines which recognize it the moment it enters the body and mount an immune response by `rejecting' it as an alien agent.

The second mode by which diseases occur is called the systemic route. Disorders in the physiological, metabolic, circulatory or transport systems are the culprits. Some of these occur because we eat the wrong kinds of food, exert our body in stressful ways, or adopt unhealthy lifestyles (smoking, drugs, excessive sunbathing). Thanks to self- correcting mechanisms that the body possesses, several of these can be corrected if detected early and treated appropriately. Yet others are genetic in nature. The genes in the body follow a well-regulated system of expression. Occasionally this internal clock or regulatory system can get tampered leading to disorders. Cancer is one such consequence - wherein perfectly normal genes are fired or 'silenced' inappropriately leading to malignancy.

Other forms of diseases that are genetic in nature arise because of errors that have crept in the sequence of letters in the message contained in our genes. Since genes get handed down from parent to offspring, these errors and resultant diseases are inherited in the family. It was over sixty years ago, when we had not yet understood the structure and sequence of the genetic molecule DNA and it sequence, that the chemist Linus Pauling made the insightful discovery that the inherited disease sickle cell anemia is caused by a single error in the genetic message that tells the body to make the blood protein globin. Since then, we have made remarkable progress in identifying single genes that are responsible for a variety of inheritable diseases. Ingenious methods and technologies have been devised, which are helping to pave the way for rapid diagnosis and therapeutic care of many of these genetic diseases.

Reverse genetics

For most genetic diseases, the normal function of the involved gene is not quite known. Localizing a disease-causing gene, without knowing anything about the disease's molecular or biochemical nature, is often called "reverse genetics". Searching for and locating such genes, even before its effects are fully felt, helps in the diagnosis, prognosis and management of the disease. This is a take-off, a turn-about from the traditional way of identifying a genetic defect from studying the symptoms of the disease it produces, that is to go from the expression to the message, or phenotype to genotype. Reverse genetics locates the error in the gene sequence first, and goes from there to the phenotype. This has become possible, thanks to quick ways of comparing DNA sequences by methods such as RFLP (introduced by David Botstein of Boston in 1980 and used first by James Gusella, also of Boston in 1983 to identify the gene for Huntington Disease in chromosome 4), and 'chromosome jumping' (introduced by Francis Collins, of the Human Genome Project fame, in 1989). Reverse genetics helps in rapid and improved diagnosis, and hopefully to implant copies of the 'healthy' gene into the body and thus treat or repair genetic disorders through the emerging field of gene therapy.

The class of diseases called autoimmune disorders has long been thought to be genetic in nature and inheritable from parent to offspring. The diseases arise from a failure by the body to distinguish between what is `self' and what is `foreign' or `non- self'. As a result, the body mounts immune response against its own molecules and cells, leading to extreme discomfort to the individual. Some of these autoimmune disorders can be mild, such as psoriasis or scaling of the skin, while others are quite severe such as inflammation of connective tissues (example rheumatoid arthritis), type 1 or insulin -dependent diabetes, thyroid disorders, and the difficult-sounding and difficult-to- handle disease called systemic lupus erythematus or SLE. That these may be inheritable genetic disorders has been suggested from the observation that SLE is nine times more prevalent in women than in men (X chromosome-linked), and that it occurs far more frequently among the Chinese and the Black population than say the Caucasians or Anglosaxons. To date, as many as 70 diverse diseases have been classified into the category of auto-immune disorders.

Now comes the surprise from the AAAS meeting at San Francisco, which The Economist has reported on. Dr. Noel Rose of John Hopkins University had looked into the prevalence of these diseases among identical twins. If the disease were entirely genetic, then if one identical twin had such a disease, one should expect the other twin too come down with the disorder. His analysis of type 1 diabetes among twins shows the prevalence to be only 5 per cent. Rose has suggested that what is often being inherited is not a genetic predispostion to a particular autoimmune disease, but rather a generalised predispostion to the whole class of these 70 different autoimmune disorders. Which disorder actually develops is more or less accidental. In other words, the other twin may not come down with diabetes, but SLE, psoriasis or arthritis.

Reverse inheritance

Dr. Denise Faustman of Mass General Hospital in Boston also had similar results to show, but in mice. She used a colony of mice so heavily inbred that its members are genetically identical. These animals are prone to develop type 1 diabetes. What surprised Dr. Faustman was the fact that despite their genetic identity, not all animals had the disease. One in every five actually was perfectly hale and hearty.
 
Next, she mated healthy males and females and checked for the prevalence of disease in the litter. Though they did not develop diabetes (one would not have expected it, since the parents were disease-free) but some of the females in the resulting litter became arthritic when they reached reproductive age and were ready to bear and deliver litter. The idea that the same set of autoimmunity genes can produce different outcomes is borne out.

Interestingly she found that these autoimmune diseases affected female mice far more than males. This is quite similar to what was found with humans in SLE, Hashimoto thyroditis and other autoimmune disorders' - that they hit women much more frequently than men. This has led to the suggestion that in addition to genetic inheritance, autoimmunity is also manifest through another, rather odd form of "heredity", namely from the foetus to the carrying mother. As The Economist says "you can get it from your children" as a reverse inheritance.

It is now understood that cells from the foetus can occasionally leak into the pregnant mother's bloodstream and stay there for years. This phenomenon is known as "micro-chimerism", and leads to the mother's body mounting an immune response that can take the shape of arthritis, scleroderma and similar other autoimmune disorders. Scleroderma is a disease manifest as hardened skin and thickening of other connective tissues which can cause extreme discomfort to the body. Women with scleroderma have been found to have at least ten times more fetal cells in their blood after the birth of a baby than mothers who are healthy. These aspects of "minochimerism" (a minuscule form of hybrid - features of the mother - and the child present in the same tissue or bloodstream) seem to be disrupting the normal immune system of the mother. They are thought to be formally similar to graft-versus-host disease in which a mismatched tissue, when transplanted, causes severe immune response and outbreak of adverse reactions. Childbirth is never an easy task - and this discovery of getting it from your own flesh and blood underscores it in a sharper fashion.

D. Balasubramanian

L. V. Prasad Eye Institute

Hyderabad - 500 034