The embryonic stem cells are the ace of medical research *The goal of the prestigious research is to produce tissue cells from embryonic stem cells to cure serious diseases and injuries. The successes in the laboratory are accumulating, says Prof. Karl Skortsky from the Technion
Alex Doron
No one on El Al flight 104 from Chicago to Israel paid attention to the special treatment one of the passengers received. He arrived on a domestic flight from Madison, Wisconsin. With one hand he was dragging a trolley suitcase and with the other he was holding a piece of metal, like a cooler, which he refused to allow to be reflected in the x-ray machine and prevented it from being opened. "There is valuable material inside that could be completely destroyed," he explained, and refused to detail its contents in the ears of the American security personnel. El Al's ground attendants came to his aid. They listened attentively, checked his identity and then very carefully took the can from him and, closely accompanied by a security guard, put him in the first class of the plane. They wrapped the container in blankets and placed it on pillows. One of the flight attendants was ordered not to take her eyes off him during the flight. The passenger himself was sent to his seat in the tourist section.
The passenger and the double-sided metal container he brought with him, cooled by liquid nitrogen, in which there were five test tubes containing "biological material" floating in a pinkish-transparent liquid, launched a new, dramatic era in scientific research in Israel: the path to medical realization of the potential inherent in embryonic stem cells. It happened in the evening of November 1, '98 when they landed at Ben Gurion Airport.
On that day, Israel joined the race between different research groups across the globe in a field where Israel is recognized as a leading world power, whose expert opinion is highly regarded. In other words: Israel has become a central member of a prestigious first class club, some compare it to the "nuclear club", and others say it is much more important.
The goal: cells for transplantation The five small test tubes that Prof. Yosef Itzkovich-Eldor, director of the women's and obstetrics department at the Rambam Medical Center in Haifa and a senior member of the faculty of the Technion School of Medicine, brought with him from Chicago, contained the first five lines of embryonic stem cells of human origin ever produced .
These cells are extracted from a human embryo in the first five-six days after in vitro fertilization was performed. The source of the cells are fertilized eggs that were not implanted in the uterus and were donated to the study. During the development of the embryo, in a process called "differentiation", the cells adjust to form the various tissues and organs of the body. In the first days after fertilization, these cells are still multipurpose. That is, any embryonic stem cell can develop into any organ or tissue.
The goal of today's vigorous research in the world is to control this process, and to create in laboratory conditions cells whose differentiation will be aimed at building specific tissues for medical purposes. For example: creating heart muscle cells, insulin cells in the pancreas or blood vessel forming cells that can be transplanted into the various organs. The latter, for example, will produce new, healthy blood vessels at the place of their transplantation, instead of the damaged ones, where the blood flow is insufficient and is due to a narrowing or a valve. In the heart muscle, the swelling (ischemia) causes angina pectoris.
In the experiments done so far, the initial results are promising. according to which the researchers hypothesize that embryonic stem cells can produce in a deliberate way almost every cell in the human body. The evidence so far is for heart muscle cells, blood cells, insulin-producing cells in the pancreas (see box), liver cells and nerve cells. In most cases these cells were formed spontaneously.
It was recently reported that a Japanese team was able to use adult (non-embryonic) stem cells, derived from a dog, to repair his vocal cords. In the Monash University laboratory in Melbourne, cells of the thymus gland were created from mouse embryonic stem cells. The thymus gland plays a central role in the body's immune system.
Researchers at the University of Kentucky have hailed embryonic stem cells as the "secret to longevity." It is possible that in the future such cells could be transplanted into the bodies of the elderly and extend their lives.
So far, the researchers have faced problems in the field of the basic technology, the "platform" - the one that will allow the growth of human embryonic stem cells under the appropriate conditions. The studies also deal with examining the possibilities for manipulating and introducing genetic changes in the cells. So far, such experiments have only been done in mice, and less so in cattle and monkeys. It is clear to the researchers that an equal derivation should not be drawn between cells of different animal origin and those of human origin, which require a different treatment.
These are fundamental studies for the purpose of characterizing the cells and perfecting the technologies for their creation. Ways to direct the embryonic stem cells for specific differentiation are also being examined. They will be used to discover unknown genes involved in the development of man and his organs: what their role is and what protein substances they produce. These studies may also contribute to the creation of new drugs.
Itzkovich: "It is still too early to determine if it is possible to direct all the cells always and with XNUMX% success to create a certain designated cell, ripe and healthy, for the purpose of transplantation. But the experiments so far provide very great hope. The general public is mainly interested in one question: what use will be made of it. The purely scientific issues are probably less fascinating, despite their far-reaching implications."
America: researchers at risk Prof. Itzkovich flew, as mentioned, from the American laboratory in Madison, the first five lines of embryonic stem cells of human origin produced in the world. These "rows" are embryonic stem cells that have been brought, using biological and chemical agents, to a state where they continue to divide without differentiation. Since then, four more lines of cells have been produced in Haifa - the first "Israeli" stem cells.
That week, the medical community around the world was trained for the publication of an article in the prestigious scientific journal "Science". "Everyone was expecting a big sensation, the first report in the world about the success of the experiment to produce and preserve human embryonic stem cells," says Prof. Itzkovich. "There were then rumors about a possible response, even a very harsh and hostile one, from politicians and clerics in the world, who are opposed to dealing with this issue, claiming that it is a deliberate attempt to interfere with the laws of nature and the act of creation."
In May of that year, the National Institutes of Health of the United States held a special scientific conference on mouse embryonic stem cells. "Since the scientists were prohibited from speaking openly about human embryonic stem cells, mainly because the government prohibited the use of funds derived from federal research and development budgets for the purpose of research involving human embryos, the scientific conference resorted to a language of hints," recalls Itzkovich. "They talked about everything there, only in a very general way; Explain their importance, what can be done with them, how promising the future is."
One of the speakers was James Thompson from the University of Wisconsin, the author of the article in "Science" (Shaitzkovich co-authored it). He was careful not to go into too much detail. "None of his listeners knew that a few blocks away from the gathering place, in a small laboratory, such stem cells already exist."
Since every article in a scientific journal is sent before its publication for preliminary review and comments by a special team of experts, details of the sensational discovery leaked out despite the heavy veil of secrecy. This leak worried quite a few people. It also became clear that the embargo imposed by "Science" itself on the publication had been breached (the newspaper forwarded an extract of the report to the advance notice of the science journalists. They undertook to stick to the schedule established regarding the official publication date. Some of them did not resist the temptation).
The biotechnology company ACT in Boston caught a ride on the rumors that were being spread, and close to the day of the appearance of the "Science" magazine, it quickly issued a press release according to which it succeeded in creating an embryo between species ("inter species") by mixing a human cell with a cow's egg. "The experiment is intended for medical purposes," announced ACT's chief scientist Jose Sibley. He said that he took a cell from his own skin, injected it into a cow's egg, and this is how intersex embryonic stem cells were allegedly created.
Itzkovich: "Only later did it become clear that this publication was reckless; It is intended only to create a commotion and noise about nothing. The achievement itself did not mature at all, nor was it reported to any scientific journal. Just as it did not long ago, ACT-Sach announced that it had genetically cloned a human embryo in a test tube. She won headlines in the world's newspapers and later it turned out that the process stopped in the middle and was not completed at all."
In Wisconsin, they understood well the significance of these exciting events and there was a fear of a harsh reaction from the religious establishment, from conservative politicians and from hot-headed opponents of all kinds. In the United States, quite a bit of bitter experience has accumulated with them.
Indeed, in preparation for the publication in "Science", scheduled for November 6, '98, security personnel came to Madison for a special briefing for scientists and research laboratory workers. "They were instructed how to keep the details of their work a secret, in fact almost going underground. Changed all the locks in the lab, taught the researchers how to evade reporters who might land in Wisconsin like butterflies. How not to stand out, how to avoid identification." All this was done under the very difficult impression that accompanied previous violent events, in which members of the anti-abortion and anti-abortion movement in the United States attacked and even shot doctors to death. The fear of a similar reaction arose when the details of the revolutionary research were published.
Prof. Itzkovich: "For this reason, there was an immediate necessity to transfer some of the lines of embryonic stem cells, which were produced in Madison, to a safe place, so that these cells could continue to be used in the future without fear. Israel adapted to this, because in Israel the approach to this issue was liberal and very considerate, also from the religious-halachic aspect."
In addition to the lines brought by Prof. Itzkovich, several embryonic stem cell lines from Australia also arrived in Israel for research purposes. They were brought by Prof. Binyamin Raubinoff from the School of Medicine of the Hebrew University in Jerusalem and a gynecologist at Hadassah Hospital. In 98, he was on sabbatical at Monash University in Melbourne, which also then entered into the clandestine business of producing embryonic stem cells. Raubinoff brought the valuable biological material to Australia from a laboratory in Singapore, where there are no laws restricting scientists from practicing in the field. Several embryonic stem cell lines from the same source are used in his research, which continues today in Jerusalem and focuses mainly on nerves.
In '99, Itzkovich decided to participate in the research with more Israeli scientists and provided them with the embryonic stem cells from the lines he brought from the United States. "Thus, the laboratories in Haifa of Prof. Karl Skortsky, of Dr. Lior Gepstein and mine, and the laboratory in Jerusalem of the geneticist Prof. Nissim Benvanisti, could together create a huge gap in the great race that is taking place today between the different groups of scientists in the world."
The Pope: It is unthinkable that when the issue of "Science" in question was published, the issue immediately made headlines. "The world's newspapers competed with each other in the use of all kinds of proverbs: 'Scientists have reached the root of life' was just one of them," says Itzkovich. "Others write that by means of embryonic stem cells it is possible to hocus pocus create a heart, bones, liver, what not - and how they will be implanted in a short time in the bodies of patients, thus curing Alzheimer's and Parkinson's, diabetes, heart disease and cirrhosis of the liver. The wave of enthusiastic publications also triggered, as expected, the reactions of the opponents."
The President of the United States at the time, Bill Clinton, was engrossed in the Monica Lewinsky affair, yet he bothered to publish an official announcement, according to which the attempt to mix cells from a human source with a cell from another living creature such as a cow, "is an intolerable act" and demanded that the Senate Ethics Committee hold an investigation on the matter and submit His conclusions. At the same time, he announced his support for research into creating embryonic stem cells of human origin, for medical purposes, based on Thompson's work.
The president's announcements and the public debate that erupted immediately following them soon became mixed up in the presidential election campaign. Not long after George Bush entered the White House, he met with the Pope "and only two subjects occupied them", says Itzkovich, "the situation in Kosovo and the embryonic stem cell problem.
"The Pope demanded from Bush not to approve federal financial support for this research, because it is the destruction of a human embryo. Bush listened to him and returned home. At the beginning of August 2001, Bush went on his famous summer vacation."
From his place of vacation, Bush issued a presidential statement, according to which he categorically denies support for experiments involving human genetic duplication. On August 9, in his first speech to the nation, a new announcement was made, which is an important milestone in contemporary scientific research. According to it, "Government support funds for research will only be given for activity that will be done on all lines of embryonic stem cells of human origin that were created until August 9, and no government support will be given for new lines that will be produced after that."
The world's scientists reacted to the President's announcement: "What hypocrisy!" Elements in the conservative right and the religious establishment were not satisfied and still make their voices heard from time to time. "Too little, too late!", they said, and promised to continue the fight also against research in this field.
A few days before Bush released his second announcement, at the behest of his aides, the Americans launched a "global inventory count" operation, with the aim of finding out which laboratories have embryonic stem cell lines, and how many. They also decided on a careful record of them.
Itzkovich: "One evening I received a phone call to my home and one of the senior officials of the National Institutes of Health of the United States began asking questions. I was not inclined to cooperate with him, but he called again and again and did not stop pressing. Then came a call from the White House. One of the president's aides, a Hebrew speaker, explained the matter to me. As a result, we consulted with Rambam and the Technion and decided to help provide the information. This is how we joined a closed list, which currently also includes research teams in the United States, Sweden, Australia and India, who together have 70 lines of human embryonic stem cells, the research that will deal with them from now on will be supported by federal-American grant funds. More countries are now gradually adopting the American model of reference to this issue. England, Germany and France were the last of them." As a reward for his responsiveness, Prof. Itzkovich was invited to visit the White House.
"I went to Sheffield, England, for a scientific conference, at the end of which I intended to continue to Washington and fulfill the honorable invitation. In a taxi, on the afternoon of September 11, on the way to the airport and the flight to the United States, I heard on the radio about the terrorist attack. I got stuck in Europe. The visit to the White House was postponed to another date - along with the invitation to appear for a hearing at a Senate subcommittee that deals with scientific research budgets for medical purposes. But the invitation to the hearing proved once again how well known Israel's lofty position on this innovative issue is, and how much the opinion of its scientists is considered."
Israel: a center of pilgrimage In recent times there has been a constant pilgrimage of scientists, journalists and other curious people from around the world to laboratories in Israel engaged in embryonic stem cell research. "Germany, for example, shows a special interest," says Itzkovich. "The establishment there is interested in supporting this research. Quite a few scientists want to devote themselves to him. However, some parties and also public opinion, which involves in this issue the aversion to the monstrous idea of human experiments, selection and all that entails, horrible memories from the Nazi era, strongly oppose. There is a law in Germany that prohibits research on fetuses, and anyone who violates it is expected to be imprisoned for five years.
"The absurdity is that abortions are allowed there, but not research on embryos before implantation in the uterus. For example: it is officially forbidden to carry out a pre-implantation diagnosis. It is forbidden to take a biopsy from a three-day-old fetus before it is rooted in the uterus, in order to analyze whether it is a carrier of a genetic disease such as cystic fibrosis. So the pregnant German women travel to Belgium and perform this diagnosis there."
The German researchers, led by Oliver Brussel, have experience working with embryonic stem cells from mice. His team applied for a government support grant, and was rejected. The public debate about this branched off and on. The politicians who were drawn into it looked for neutral experts to brief them for the debates that took place in the Bundestag. Because of this, they come to Israel, usually at the head of a large entourage that includes scientists, businessmen, journalists and television crews.
Itzkovich: "That's how the prime minister of North Rhine-Westphalia, Wolfgang Clement, came to me not long ago, at the head of an entourage that rented 30 rooms at the Dan Carmel Hotel for one night. They met with Sharon and then came to my laboratory in Rambam. And from there, by helicopter, continue to another destination. Clement listened to Hasbari and undertook to support joint research with the University of Bonn and also to convince a German foundation, established by an industrial corporation that employed forced labor during the Nazi period, to pour in the money required to finance the project. This short visit gave birth to bi-national cooperation for research". Following Clement, visitors came from other countries as well, and the respected German newspapers devoted quite a few pages to reporting on the innovative research in Israel and its achievements.
"There is no doubt," admits Prof. Itzkovich, "that we in Israel benefit from Judaism's progressive approach to the subject. Two words, 'rafa yarfa', are the basis for this and also the halachic approach, according to which the fetus before it is implanted in the womb is not considered a living being, and therefore there is no prohibition to conduct research on it."
The expectation: Five years to launch The four research teams in the three Israeli laboratories dealing with embryonic stem cells compete with each other, naturally, but at the same time they also cooperate, among other things in publications in scientific journals. The research grant (two million shekels) that they requested from the ministries of science and health for this subject, should be divided between them. It is estimated that in the near future the teams will be forced to deepen their cooperation in order to face competing teams in the world. At this stage, 80 percent of all scientific publications on embryonic stem cells of human origin are still written by Israeli scientists.
A considerable part of the results of the research that is now being done in Israel will be submitted, it is estimated, within two years for patent registration. Which will require starting to think about this issue in industrial terms; It will be necessary to bring into the picture as quickly as possible companies where the big money is. "If we don't do this, we will lose the lead in the race," says Itzkovich. "Until today, the research grants from local sources ranged around several tens of thousands of dollars per year. The grants from the United States amount to $700-300 for research. We will have no choice but to start talking as soon as possible in millions."
A cautiously optimistic assessment, he says, indicates that within five years from now human embryonic stem cells will be used as medical treatments, first in terminally ill patients and then in others. The pessimists say that all this will only be in ten years.
"Among the problems that must be solved: the degree of safety of this procedure. Its effectiveness has been proven.
When embryonic stem cells were injected into the muscle of a mouse, it was discovered that the cells produced teratomas, benign tumors. It turned out that the injected cells were undergoing a change for some reason. Therefore, if cells that also contain embryonic stem cells are injected into a patient's skin tissue - there will be no accessibility problem when the need arises to remove these tumors. But if they do it in the heart or brain and it turns out that teratomas have formed - that's a different situation."
These benign tumors, which must be dealt with, Prof. Itzkovich explains, may form if not all the injected stem cells have undergone differentiation. It is enough that one of the cells was delayed or that its directed differentiation was not completed.
"The issue of stem cells - embryonic or adult - and their use is an integral part of the dramatic, great revolution that is now taking place in the world of biology and medicine. It is also related to cracking the puzzle of the human genome (locating, identifying and mapping the set of all the human genes numbering about 40 thousand - A.D.) and the 'genetic duplication', cloning, which resulted in the creation of Dolly the sheep, as well as carts and some other animals.
"Who dreamed that one day it would be possible to take an adult cell from any tissue in the body, and 'program' it backwards. That is: to return it to a point where it can start its development anew, like an embryonic cell. That's exactly what happened with Dolly. Who dreamed that stem cells would also be discovered in the brain - which broke many conventions, according to which brain tissues do not regenerate. It is very possible that at this very moment someone, at the other end of the world, has discovered another detail that may change the laws of biology and genetics.
"If someone in a research laboratory succeeds in growing heart muscle tissue cells that are XNUMX percent clean and ready for transplantation - this will be a huge leap forward. And it can happen even within a year."
Prof. Itzkovich further says that among the problems many scientists in the world will have to deal with, and less so in Israel, will probably be opposition politicians and a stubborn church establishment. "This is exactly what happened after the first kidney transplant and also with the pioneering heart transplant performed by Prof. Christian Barnard in South Africa, or when the first in vitro fertilization methods were developed, from which the first test tube girl Louise Brown was born, 24 years ago, and in her wake more than a million healthy children all over the world. All of them are children of couples who were previously considered infertile. The debate about the use of human embryonic stem cells for medical purposes, in countries where it is still conducted and led by politicians and clergy, will end at once on the day when we see, for example, Christopher Reeve, 'Superman', suddenly get up from his wheelchair and start walking again following an injection treatment Fetal stem cells, which renewed his nervous system."*
