A year ago there was a public furor in the United States when the Food and Drug Administration (FDA) authorized the use of a drug for treatment of heart failure for African Americans only. The drug, called BiDil, reduced heart failure far more significantly among blacks than among whites. This was the first time a drug had been authorized for a specific population group, and it raised anew old questions about the connection between race and biology, race and medicine, and related issues. The debate, which was conducted in scientific journals and across the social and political spectrum, was an extreme illustration of the genetic diversity among people, which dictates, among other factors, their reaction to drugs.

The medical world has known for a long time that one size does not fit all. Two people who take the same anti-cancer drug, for example, may react differently to it. One might develop dangerous, even life-threatening side effects, whereas the other will benefit and experience almost no side effects. The same drug can bring about the disappearance of the malignancy in one patient and have no effect on another. These extreme differences derive from the genetic differences between people. In the same way that a single gene is responsible for different eye colors, a particular gene in different people can lead them to metabolize the same drug either quickly or slowly. People are differentiated from one another in terms of how well a drug is absorbed by the intestines, how well it metabolizes in the liver, how much it secretes in the kidneys - and all these elements determine how much of the drug the individual takes remains in the body and how it will affect him. If the drug metabolizes quickly, its effect will be limited and the dosage will have to be increased. By contrast, if it metabolizes slowly, or is eliminated slowly from the body, it is liable to generate serious side effects to the point of threatening a patient's life.

One of the cardinal contributions of the Genome Project is the knowledge it provides about the scale of genetic diversity. The tremendous technological leap that occurred in the wake of the project now makes it possible to identify the diversity in certain genes. This, in turn, will make it possible to adapt the treatment to accommodate the patient's personal genetic makeup, to accord him the best and safest treatment, to reduce the side effects, to predict the prospects of survival, and more. This is not science fiction. It has already begun to happen. "Personal medicine" signifies not only a trend, but a new sphere in medicine, which is rapidly gaining momentum. In fact, it is one of the hottest subjects in the medical world today, on the agenda of almost every medical conference and described as the medicine of the next generation.

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350 mutations

The revolution in the attitude toward drugs is already apparent today in treatment of a variety of diseases, but most radically in cancer. "In oncology we are talking about differences in both the genetic fabric of the patient and in the genetic fabric of the tumor," explains Prof. Gideon Rechavi, director of the cancer research center at Sheba Medical Center, Tel Hashomer. "The assumption today is that the mode of treatment that was characterized by offering the same treatment protocol, providing the same dosages to patients who suffer from a specific malignancy, is mistaken and too simplistic. Today we have tools to tailor a treatment for a patient that will give him the best chance for a good reaction with a minimum of side effects, to enable a deliberate assault on the tumor and to adjust the drug dosages on the basis of the characteristics of both the tumor and the patient. In recent years, personal medicine has emerged on the medical agenda, and the ways and means are constantly improving."

The case of M.R. illustrates this point. A 73-year-old male who has been suffering for 17 years from a type of blood cancer, M.R. relates: "One fine day I felt a powerful weakness, and after comprehensive tests I was told that I had leukemia. For two years I was treated with pills and injections to stabilize the disease. After it was stabilized, I was able to undergo an autologous [self-generated] bone marrow transplant. I then continued the drug treatment and my condition was stable for a good few years. At a certain stage I stopped reacting to the treatment and I felt awful. The disease affected me seriously. I had dizzy spells, I needed many blood transfusions and I felt that my end was near. Fortunately, a new drug called Gleevec appeared on the market and I was immediately placed in the experimental treatment group to test it. For about six years I took a pill every day, and in that period I had two-three good years when I didn't need transfusions, felt good and functioned without any problems. The disease simply became dormant.

"Last April, the disease returned, because the Gleevec stopped working. The disease progressed, I felt poorly and my condition deteriorated seriously. I was hospitalized for 32 days. I had a spleen infarct, intestinal inflammation, swollen legs and I needed huge amounts of antibiotics on top of the chemotherapy I was receiving to prevent a recurrence of the disease. I was like a doormat. I couldn't move and I lost 14 kilograms. Luckily, last year a new drug came out as a replacement for Gleevec. Now I am being treated with that drug, as part of a study. I have started to return to my old self and have already gained three kilos. The doctor told me, 'You're lucky. The Gleevec wasn't helping you anymore, and without the new drug, it would have been impossible to save you.' This is already the third or fourth trial of new drugs I've been involved in. I take one of the new pills every day, I get injections once a week to maintain the red blood cells, and I don't need blood transfusions. The treatment is a lot easier now. It's looking good."

"M.R. is an exceptional patient, in that he has lived with a lethal cancer for 17 years," notes Prof. Arnon Nagler, director of the hematological division at Sheba. "The fact that he is still alive and functioning, and enjoying a good quality of life, is due to the progress and the developments that have occurred in medicine in the past decade, and particularly the recent development of Gleevec, which was a breakthrough in the targeted treatment of cancer.

"We have moved from general, untargeted treatment with multiple side effects to specific treatment against the substances that coact in the biological process that generates the disease," Nagler says. "Today we are capable of providing personal treatments for many cancer patients, which are adjusted to the genetic repertoire of the tumor and of the patient, and which significantly increase the patient's prospect of reacting with fewer side effects, improvement of his quality of life, and sometimes even a cure. This innovative treatment is based on sophisticated laboratory tests, which are capable not only of diagnosing the precise type of an individual's cancer, but also of predicting the prospects of his reaction to specific drugs. We are thus able to tailor a treatment for him with the maximum prospects of recovery from the currently existing arsenal of drugs."

In the past year the cancer research center at Sheba acquired a Sequenom, an innovative machine that allows for the precise profiling of the mutations that have occurred in the cancerous cell. With this knowledge, it is possible to detect the modifications undergone by the cell at a very early stage and to tailor appropriate, specific treatment against the malignancy, which will improve the patient's survival prospects greatly.

"If a patient stops responding to Gleevec, we have to ask ourselves whether to increase the dosage or change the line of treatment," explains Dr. Yoram Cohen, a senior researcher at the Sheba center. "We scan a DNA sample from the patient's cancer cells with the Sequenom. If a mutation is detected, that means we have to consider changing the treatment."

This is what happened in the case of M.R. The Gleevec stopped working, and the Sequenom test showed that a new mutation had occurred in his malignancy, which was blocking the effect of the drug. Taking advantage of the fact that a number of alternatives have become available in the past year, the physicians were able to adjust the drug treatment for M.R. on the basis of the type of mutation found in his malignancy.

"Using Sequenom, we can now detect 350 cancer-related mutations," Cohen continues. "Detecting the mutations can assist in early diagnosis, in predicting a reaction to treatment and in early identification of a recurrence of the disease after treatment. These processes are still in the research stage and only a few of them are practical, because there are not enough drugs and our knowledge is still limited. Until now it was very expensive to check genetic changes within the cancer cells. With the Sequenom it can be done efficient and at a lower cost, which improves the availability of the diagnosis to the patient. It has come into practical use in the past two years, and Israel is one of the few countries in the world to make therapeutic use of the machine. In the 21st century, a physician has to tell a patient that there are genetic tests that can predict his reaction to treatment with a particular drug. Some of these genes can influence the diagnosis of the disease, and the decision about whether to administer chemotherapy. And if so, which chemotherapy will affect the malignancy."

'The most expensive breakfast'

A.T., 54, was diagnosed with lung cancer in October 2002. "The house I grew up in was a favorite smokers' haunt. Everyone smoked except me," she relates. "My father died of lung cancer at the age of 58. My mother kept on smoking and died at 78. Five years ago, we started to organize my 50th birthday party. Half a year earlier, I had felt weak, I wanted to sleep all the time, I perspired a lot. I felt like I wasn't myself. The doctors attributed all the symptoms to menopause, and when I started to cough they thought it was a virus. Three months later, after I had started to lose weight, they sent me to have my lungs x-rayed.

"They found a Stage 4 tumor in my left lung, which had enveloped the respiratory organs and had spread to the chest cavity. Immediately after the diagnosis, I started to receive chemotherapy at Hadassah Hospital. Naturally, we canceled the birthday party, and at the same time I told all my friends about my disease. They responded with a lot of warmth and love, which supported me a great deal during the hard treatments. The treatments went on for seven months, during which my hair fell out. That is the greatest trauma. The reaction of the tumor to the treatment was not altogether what it should have been, but we continued. I needed more support. Even though I am not connected to the spiritual world, I started to do Reiki, to work on energies, to do breathing exercises and to go to many sessions, which taught me to concentrate on myself. After the treatments ended, I took off the wig and felt healthy.

"The tests showed that the tumor had shrunk, and after two months I started to be treated with a drug called Iressa. It is super-expensive: Each tablet costs NIS 900, and I took one every morning. I was eating the most expensive breakfast in the country. Fortunately, I was part of an experimental group and the treatment was free. For two years the drug worked excellently and I gained two wonderful years. But then the drug stopped working, the symptoms started to reappear, and then pains also started in my hip. The CT showed a metastasis in the chest. I had radiation treatment and now I am going through a new series of other chemotherapy treatments. The symptoms have stabilized, there is nothing active, the tumor is quiet and I feel good and am leading a regular life.

"I see the five years I went through as a gift. Many people don't understand what extending life a little is all about. My answer is that for me every day is a whole world, a whole life for me and my family. During these years my son completed high school and entered the army, and I had a grandson. I am present at home, the children have a mother, and I am living and doing a great many things."

Iressa belongs to the new generation of drugs (among them Gleevec) that inhibit one of the molecules involved in the cancerous process. The drug has not been approved, even though it is known to have an effect on about 20 percent of lung cancer patients. Monthly treatment costs about NIS 30,000, and it must be administered daily as long as it is working.

"A.T. is an example of a patient who has succeeded in coping with deadly lung cancer for five years - an exceptional case by any standards. She is one of the few cases that was helped by targeted drug treatment of the malignancy," says Prof. Tamar Peretz, head of the Sharett Institute of Oncology at Hadassah University Hospital in Ein Kerem, Jerusalem, who is treating A.T. "Both the medical and the nonmedical communities have not yet internalized the fact that cancer is not one disease and that the division according to areas of the body does not reflect reality. It is like saying that all dogs are the same thing. Lung cancer is not one homogeneous disease. It is a variety of diseases. The 20 percent of the patients who are helped by Iressa have distinct genetic traits.

"The question," Peretz continues, "is whether we are ready for a situation in which we can characterize, with 100 percent certainty, the group of patients that react to Iressa. There are already genetic tests that define this group and that are able to detect the gene involved in the reaction to the drug, but there is not yet agreement about which of the genetic tests is the best. Today we characterize this group on the basis of statistical data. We know that the group includes more women than men, nonsmokers and people of Asian origin, and apparently their malignancy is very specific."

How do you decide who will receive the drug?

Peretz: "As I said, we do not yet have unequivocal genetic tests, so I do an evaluation. When someone with lung cancer comes to see me, I first try to evaluate whether he has a chance of reaching treatment, because in some cases the disease is surging ahead and it is impossible to stop. Afterward I examine the parameters I mentioned and examine the type of tumor. After deciding that the patient is suitable, I hold a conversation with him and clarify whether he can sustain the economic burden, as he will have to take a tablet a day until the drug stops working."

Trial and error

Prof. Peretz believes that within two or three years personal medicine will occupy a central place in treatment policy. Already now there are situations in which patients are routinely checked for distinctive proteins in the cancerous cells that are involved in the disease. For example, samples taken from breast cancer patients indicated the existence of subgroups differing from one another in terms of gene expression (the process by which a gene's DNA sequence is converted into functional proteins). These findings contribute to the referral of patients to chemotherapy and hormonal treatments, and the use of "smart" drugs that selectively attack specific targets that exist in the subgroups. Clinical tests are currently examining the suitability of treatment decisions according to gene makeup.

Concretely, two groups of proteins are now being examined in breast cancer patients. One is the group that act as hormone receptors (estrogen and progesterone). Their presence indicates the possibility that hormones in the woman's body are liable to spur the accelerated multiplication of the cancerous cells. Using drugs, it is now possible to block the action of these proteins in order to counteract the effect of the hormones. The second group of proteins, known as HER2, is present in about 20 percent of breast cancer sufferers, and can be blocked by means of the drug Herceptin. Based on this information, a treatment policy is worked out.

A new technology known as "DNA chip technology" makes it possible for tiny chips to examine the manifestation of tens of thousands of genes in parallel and to discover which genes are active in situations of health and sickness. The most impressive examples lie in the detection of different types of cancer. A few years ago, it became clear that the uniform clinical and pathological picture characterizing certain cancerous diseases was in fact an illusion, and that malignancies of the same type exemplify a completely different genetic profile.

For example, in examinations of cases of lymphoma common in the Western world, the pathological diagnosis was ostensibly identical - there was seemingly one disease. However, when the samples were examined by means of DNA chips, there turned out to be three subgroups of the disease. In each, a different pattern of active genes was manifested. The three groups differ from one another in terms of the aggressiveness of the growth and in their reaction to chemotherapy; similarly, the patient's chances of recovery are also not identical. This is meaningful information, which can help physicians choose a treatment strategy and develop new drugs.

One of the most impressive examples regarding the new technology in question involves acute leukemia in children. Thanks to progress in the modes of treatment, about 80 percent of children suffering from it recover from the disease, albeit often in the wake of exposure to aggressive treatment that may cause significant side effects during treatment and serious complications later in life. A few years ago, it turned out, thanks to DNA chip technology, that it only appeared to be a single, uniform disease: In fact, there are seven different types, differentiated by the gene activity in the cancerous cells.

An understanding of the genetic basis of the subtypes of leukemia has the potential to bring about the development of intelligent, individually tailored treatments, which can improve the chances of success and reduce the risk of side effects and later complications.

"We know today that children's leukemia is a 'basket' of many different diseases that differ from one another - among other ways, in the genetic flaw that developed in the cancerous cells and in the genes that are active in the malignancy," Prof. Rechavi notes. "Today, when we devise treatment for a child with leukemia, we rely on a large variety of tests of chromosomes, genes that underwent change in the cancerous cells. In addition, we observe the genetic 'fingerprints' of the malignancy, partly in order to document the rate of disappearance of the cancerous cells."

Personal treatment based on the genetic diversity between people is still in its infancy. A few tests can now be done to help tailor treatment. One of them is a test to identify a group of enzymes known as Cytochrome P450, which are responsible for metabolizing more than 30 types of drugs, including antidepressants, anticoagulants and others, to ensure that they have been removed effectively from the body. Certain genes are responsible for the creation of these enzymes. The genes in question may differ slightly from one person to another; by the same token, the enzymes, which are the products of the genes, do not metabolize the drugs with the same effectiveness in every case. In some individuals, if the drug is metabolized too fast, it fails to do its work, and a higher dosage is called for. With others, the enzymes act slowly and the drug therefore accumulates and is liable to cause serious side effects. These people need a smaller dosage.

Genetic diversity among human beings becomes known in the response to chemotherapeutical substances. We now know of a number of drugs that metabolize at different rates in different people. For example, 5FU, one of the drugs most frequently used in cancer treatment, metabolizes at varying rates in different people because of genetic diversity in the enzyme involved in the process. Knowing this in advance makes it possible to calculate the correct quantity of the drug and to enable effective, safe treatment.

Millions of people around the world take Coumadin, an anticoagulant, but they are walking a thin line. An insufficient dosage will not do the work and the patient is liable to develop severe coagulation. An excessive dosage can cause internal bleeding. There can be a difference of twentyfold in the dosage administered to different people. Nowadays, when a physician wants to prevent bleeding in a patient, he takes a trial-and-error approach. He prescribes a certain dosage, examines the coagulation indexes in the blood afterward, and adjusts the dosage until he arrives at the desirable values of the coagulation indexes. Following hundreds of research studies, major differences have been found between people in terms of the enzyme concentration that metabolizes the drug. As a result of these studies, a formulation was arrived at concerning which genetic variations dictate the reaction to the drug, and future treatment can then be administered accordingly.

However, despite the promises inherent in personal medicine, results of the tests are not yet widely available. In part, this is due to the physicians: Not all of them are curious or updated about the latest innovations. The advanced technology is also not accessible: The infrastructures are expensive and require professional personnel. In Israel, patients very often have to battle with their health maintenance organization. If the procedures are still experimental, they are not funded by the HMOs, and researchers do not always have the necessary budget to use the breakthrough processes, even though they could save lives in many cases.

There are tumors for which there is no clear diagnosis, which are known as tumors of unknown origin. A patient comes in with a metastasis from a tumor that started at some unknown site in the body. He undergoes routine tests but these are unable to determine where the tumor originated. In such situations, the patient is "bombarded" with three or four chemotherapy drugs in the hope that perhaps one of them will act upon the original tumor. Usually, they don't hit the mark, the patient suffers from serious side effects and his condition deteriorates. In Israel, there are about 1,000 such cases annually, accounting for about 5 percent of tumors.

A recently founded laboratory in Holland known as CUO (for Cancer of Unknown Origin) claims that if it receives a tissue sample of the tumor, it can diagnose its source with an accuracy rate of 80 percent and higher. Laboratory personnel collected genetic profiles of hundreds of cancerous tumors of this kind and entered the information into a database. They conduct a comparison between the genetic profile of the tissue sample they receive and the profiles they have accumulated, and in this way can identify the tumor's origin.

"At first I was skeptical, but the last case convinced me completely," says Professor Moshe Inbar, director of the oncology department at Ichilov Medical Center in Tel Aviv. "I had a 50-year-old leukemia patient who'd undergone two bone marrow transplants and who later on developed a large tumor in the chest that was of unknown origin. I recommended to the family that they send the test to Holland and the diagnosis was a testicular tumor - something very atypical for the patient's age and for the symptoms he displayed. After we received the diagnosis, we went back and examined the pathology findings again, which corroborated the diagnosis. I have to say that the accurate diagnosis really impressed me. There was no chance that I could have diagnosed the illness another way."