Good Medicine : Chapter 4 - Medical Innovations in Israel
The Strengths and Innovations of Medical Research in Israel — Overview
Israel is renowned for its excellence in medical research. It boasts an infrastructure of medical and paramedical research and bio-engineering capabilities facilitating a wide range of scientific inquiry.
As the scope of medical research in Israel covers a huge spectrum of clinical and basic research activities, presenting a comprehensive overview of medical research and innovations would be a mammoth task. This is not our aim. Instead, the present effort aims to convey highlights of medical innovation in Israel today. We report on activities that we feel best represent the reality and potential of medical research currently being conducted in Israel.
The innovations described here are diverse — from the development of a cardiac device to open arteries, to a laser technique to improve in-vitro fertilization success rates; from gene manipulation designed to equip cells with the ability to withstand chemotherapy, to bone marrow transplant techniques that may eliminate the need for chemotherapy entirely; from prenatal diagnoses for a rare but lethal hereditary disease to pre-implantation diagnosis for one of the most common hereditary diseases. We hope that these examples will give readers a taste of what the Israeli medical research community has to offer.
Our choice of projects was influenced by a desire not only to demonstrate innovation but also to illustrate the characteristics common to Israel's research field. Such features include:
- The will to unite clinical and basic research to find solutions more quickly and the allocation of the resources needed for creating the underlying organizational infrastructures to support this aim.
- The interdependent relationship between the national culture, demographics and the health care system on medical research.
- The fact that collaboration with groups abroad is standard practice and that regular contacts are maintained on a reciprocal basis with major medical and scientific research centers abroad.
- The fact that in Israel the action is taking place in different fields of endeavor and in different geographical locations, in both basic science and clinical work, in both diagnostics and therapeutics, and in scientific institutes throughout Israel.
Our starting point for tracking medical achievement in Israel was a unique survey of medical research conducted by the Chief Scientist's Office of the Ministry of Health. Headed by Professor Donald Berns, Director of the Medical Research Organization, the goal of the survey was to characterize the medical research field in Israel and to provide a database of active medical research. The end product, the publication Directory of Medical Research in Israel: Institutions and Scientists, was first published in 1996 and is currently being updated. It has been an invaluable tool for the completion of this report. We also thank Professor Berns for his valuable input and guidance in the report's preparation.
We draw upon data from the Directory to give a very brief overview of the medical research community in Israel. Profiling more than 90 percent of the active investigators in Israel, the Directory surveys all personnel involved in medical-related research in universities and institutes throughout Israel. Survey results are based on a response of more than one thousand investigators engaged in forty research areas.
Israel has four world-class medical schools, which together with some 30 hospitals of all types, constitute the major institutions engaged in medical research in Israel. Each of the medical schools; Hebrew University-Hadassah in Jerusalem, Sackler in Tel Aviv, Technion-Israel Institute of Technology in Haifa and Ben Gurion University in Beersheba, supports a basic science staff employed by the University and in addition has a large clinical staff employed by affiliated hospitals. A significant trend in medical research in Israel is the notable amount of basic medical research taking place. Although well over half of medical research investigators surveyed for the Directory had a hospital affiliation of some kind, 40 percent did not. Of this sector a significant number of researchers came from the Weizmann Institute and from Bar Ilan University, universities without medical schools that have very active groups involved in medical research in their basic science faculties. Other institutes include the Army Medical Corps, JDC-Brookdale, the Israel Institute of Biological Research and the Wingate Institute.
Professional publication is prolific. The survey's analysis of publications over a three- year period revealed an average of more than seven publications per investigator. A Medline search over the past five years shows that Israel puts out a disproportionate number of publications. Whereas Israel's total population is approximately 2.5% that of the United States, her publication rate is 5% of the U.S.'s
Data regarding investigators' funding sources are less than complete and thus conclusions must be drawn with caution. Despite this reservation, a certain picture does emerge. Nearly 60 percent of funded investigators reported that they receive at least some funding from sources in Israel. Research grants from the Ministry of Health's Chief Scientist's Office was the most frequently reported source of funding. Of funding received outside Israel, the United States was the largest source, funding over 40% of investigators. Ten percent of US grants came from the National Institute of Health.
Our emphasis is on emerging innovation. This partially explains why the focus is at the level of university and hospital and to a lesser degree on the industrial sector. While industry is a key player in the process, often working hand in hand with academic researchers, the research continuum in Israel as described by Asher in Breakthrough Dividend: Israeli Innovations In Biotechnology That Could Benefit, has the universities as its main bedrock. It is within this framework that the phases of basic and applied research plus commercialization take place. It is only with maturation of the product that we exit the university sector and proceed to industrial R&D, process engineering, production and marketing.
Gene Therapy — Getting the Message Through
Genes are made up of DNA, and their sequences dictate the assembly of the thousands of proteins that constitute our bodies. Today molecular biologists are well on the way to cracking this code and elucidating the human genome — the entire human gene map. As this progresses, it becomes possible to isolate the genes responsible for diverse human characteristics, physical appearances, personality traits, and not least — the disposition to diseases. With this knowledge, efforts are now being focused on gene therapy — the treatment of a disease by the manipulation of genes in somatic cells.
Researchers in the Hematology Department of Hadassah Medical Center in Jerusalem are at the forefront of Israeli gene therapy technologies. Recently they developed a promising new method to deliver a drug resistance gene into bone marrow tissue, a procedure that could help to advance cancer therapy.
The DNA sequence of a gene determines the protein's structure and form. When this sequence is corrupted it can result in a malfunctioning protein or no protein at all. Gene therapy aims to introduce genetic material into a cell to counterbalance the effect of a corrupted sequence. The inserted gene may act in one of several ways: it may compensate for a non-functioning gene; it may delete a corrupted gene, or, alternatively it may introduce an entirely new gene to the cell that conveys a property beneficial to the cell's survival.
Whatever the final effect, a crucial part of gene therapy technology is getting the gene into the cell in the first place. In their search for an efficient method for delivering genes into target cells, scientists have discovered that they can harness the experience of small organisms such as viruses containing DNA. These organisms excel in the transmission of genetic material, as their survival hinges on their ability to do exactly that. Once disarmed of their toxic features, viruses can be converted into vectors — the scientific term for a gene delivery vehicle. Indeed viruses such as those from the retrovirus and adenovirus families are proving to be excellent vectors for genes in many types of human cell.
Despite these advances, there are still some tissues that have evaded gene manipulation attempts. Failures have been largely due to a clash between the tissue's attributes and the essential conditions of the virus vector. One of these elusive tissues is the bone marrow. The bone marrow is a key tissue to penetrate as it is here that basic stem cells differentiate into the diverse cellular components of the blood, and thus it holds the key to the therapy for many diseases. Bone marrow gene therapy has hitherto been limited, as existing vectors require the target cells to be in a proliferative state. Bone marrow cells are not naturally in this state, and biochemical agents needed to induce the state complicate the procedure as well as add substantially both to costs and labor requirements.
Under the leadership of Professor Ariela Oppenheim, the Hadassah team have developed a vector that can transfer genes into bone marrow tissue. Known as the SV40 pseudovirion, the vector was developed from the Simian virus family and has an almost unlimited host range. It is suitable for bone marrow because it can transfer genes even when cells are non-dividing. The vector also has the advantage of being unconnected to human disease and thus apparently unable to trigger an immune response.
The Hadassah group has been working on the SV40 virus since the mid-eighties. A major breakthrough came when they demonstrated the potential use of SV40 pseudovirions to protect bone marrow cells from intensive cancer treatment. The group, headed by Dr. Deborah Rund, demonstrated in transgenic mice that SV40 can successfully introduce the gene MDR1 into bone marrow cells. MDR1 — multi-drug resistance gene — confers resistance to anti-cancer drugs commonly given to patients undergoing chemotherapy. Bone marrow toxicity is the dose-limiting factor when treating cancers with chemotherapy and radiation, as the bone marrow can only withstand certain levels of treatment. Introduction of the MDR1 gene into the bone marrow would allow patients to undergo higher levels of treatment and consequently increase their chances of recovery.
Like any method, the SV40 vector has its flaws, and the Hadassah group is working to overcome them. In fact the group has succeeded in converting a former weakness of the vector to a strength and a key to its further development. Production or packaging of SV40 pseudovirions is notorious for its high rates of contamination by a "helper" version of the vector essential to the packaging process. The "helper" is toxic to humans, so prepared vectors contaminated with the "helper" have to be discarded. As contamination rates can be as high as 90%, this often translates to a very poor output in relation to effort. The Jerusalem researchers have eliminated this problem by moving production from bacteria or cell culture to an ex vivo environment. Oppenheim explains that production in the test tube is safer and cheaper and results in "clean" vectors. Additionally, packaging supervised ex vivo allows increased control over the process at each stage. This is especially important for refinement of the production technique. The new ex vivo approach brings the SV40 viral vector to the safety level of non-viral vectors, an achievement in itself. However, the Hadassah group is not prepared to settle for this. They are currently working to improve its efficiency for large-scale vector production, by speeding up rates of integration within the cell.
As Dr. Rund explained in a recent editorial published in the prestigious journal Human Gene Therapy, the use of SV40 vectors in cancer gene therapy using MDR1 is part of a larger program aimed at using SV40-based vectors for the treatment of many diseases. Other potential applications currently being researched include therapy for the hereditary blood abnormality ß-thalassemia and Gaucher's disease. Research on ß-thalassemia, conducted by Dr. Nava Dalyot-Herman and others, focuses on findng methods to compensate for a fault in the hemoglobin gene that results in failure of part of the molecule to be synthesized. Proposed therapy using the SV40 vector would involve inserting a gene to replace the non-functioning one. Work on Gaucher's disease, a rare hereditary metabolic disease, is being carried out in collaboration with Dr. Ari Zimron of Sha'are Zedek Medical Center.
Whereas the focus of SV40 so far has been its use in bone marrow cells, it is apparent that this vector has wider potential uses. Dr. Eitan Galum, Head of Hadassah's Liver Department, is already investigating possible application in the hepatic cells of the liver. Similarly, Israel is preparing for the wider potential of gene therapy with the opening of the National Center for Molecular Medicine and Gene Therapy.
The aim of the National Center is to ensure that the pathway from basic research to clinical use is smooth, guided and supported. The national center will have a core facility in which ideas can be generated, evaluated and tested through animal studies, then moved into an FDA-level lab where gene-based medications can be tailored to meet the needs of the individual and then to those of the general patient population.
The Center's establishment is an innovation in its own right. It was described in the Journal of Investigative Medicine last year (1997) as an example of how medical management can meet the challenge of academic research. Advancing medical research is very important to an academic hospital institution, but as the cost of implementation rises, all decisions require careful scrutiny. As Michal Roll, director of research in the R&D division of the Hadassah-Hebrew University Medical Center, explains, their aim was to apply business analysis to such decisions.
Just as an important part of gene therapy is to make sure the gene is inserted into the target cell, the National Gene Therapy Center aims to ensure that the proper resources are being channeled to gene therapy research. This will hopefully ensure fruitful outcomes at all levels.
The Wedding of Surgery and Technology
The increased employment of advanced technological devices and methods to enhance the effectiveness and capability of the surgeon is a global phenomenon. The Operating Room of the 21st century will see the inclusion of many more machines and tools to help facilitate more advanced procedures and possibilities.
As a leader in the high-tech field, Israel is no exception to this trend. Efforts in this area are also enhanced by the recognition that one way to really encourage achievements is to provide a forum where parties from all the relevant disciplines can work together.
A prime example of such an initiative is found in Jerusalem. Professor Aaron Lewis may not come from a medical or biological background, but through his position in the Hebrew University's School of Applied Physics he has significantly contributed to the development of one of the latest microsurgical tools. Lewis is head of the Hadassah Laser Center. The center is a joint endeavor of the Hebrew University and the Hadassah Medical Organization, in collaboration with Cornell University, and its purpose is to link basic research in applied physics with the technological needs of medicine.
An example of the Center's work is their project on new laser applications in medicine. These include uses as diverse as in-vitro fertilization and corrective eye surgery. Lewis recognizes the unmistakable advantage that the interdisciplinary Center gives. Comparing his situation to that of competitors abroad, he notes that the delay between the initial discovery of a technique in a physics or engineering department and its application in the clinical arena is notably longer in other countries. He believes that this is because the competitors provide no common ground and no opportunity for the leaders of different disciplines to meet prior to a discovery — just the opportunity that the establishment of Hadassah's Center provides.
The use of lasers in surgery and medicine has advanced greatly since the advent of the laser surgical knife as an alternative to the scalpel. According to Professor Lewis, the focus today is to develop surgical lasers that cause minimum collateral damage to the target tissue. Earlier types of lasers, such as the Carbon Dioxide and YAG lasers, enriched existing surgery techniques but still resulted in certain levels of iatrogenic damage.
A third kind of laser, the Excimer Laser, is extremely promising. Exhibiting positive features such as strong absorption, heatlessness and lack of mutagenic effect, it is already being used as the basis for radial keratotomy, corrective surgery to the cornea. Such surgery can eliminate the need for glasses in near-sighted patients. Together with Professor Nery Laufer of the Dept of Obstetrics and Gynecology of Hadassah-University Hospital, Lewis has adapted this technique to perfect an in-vitro fertilization method. Forming a tiny hole in ova increases the chances of a fertilized egg implanting in the uterus. Drilling with the Excimer Laser is superior to other types of laser or to the application of chemicals, as these methods can harm the ovum. The first babies born by this method made their entrance in May 1997. The laser is also being applied to treatment of throat polyps and other facets of ear, nose and throat surgery.
One pitfall of the Excimer Laser has been the difficulties encountered in its transmission through optical fibers and biological fluids. This has restricted experience with the laser up until now to relatively dry tissues. Lewis and his colleagues at the Laser Center have recently developed a microsurgical delivery system to allow the Excimer Laser to transmit through fluids. The new system circumvents previous problems through the adoption of an articulated arm and specialized tip. When applied to vitreoretinal surgery, the system's features facilitate transmission of the laser into the eye, allowing the tip to reach almost all regions of the eyeball. Following preliminary experiments with animal models, human trials on patients with vitreoretinal proliferative disease began three years ago. Researchers at the Center are now working on future applications stemming from this achievement. These include improved microdissection and the expansion of methods of cutting biological material under liquids.
Jerusalem is not the only place in Israel where the forces of the basic and clinical sciences are being brought together in the name of "High-Tech". This year the Sheba Advanced Technology Center is due to open on the grounds of the Tel Hashomer Medical Campus in Ramat Gan..
Professor Ari Orenstein, a plastic surgeon and laser expert, is to head the new center. One of the first projects to be undertaken is within his particular field of expertise: Orenstein specializes in a novel cancer therapy known as photodynamic therapy (PDT).
PDT is an increasingly popular cancer treatment modality that exploits characteristics of tumor cells to destroy them. Photosensitizing agents are administered to the area of the tumor. Certain molecules present in tumor cells then cause the photosensitizer to accumulate more in tumor cells than in normal, non-malignant cells. This effectively marks the cancerous cells. When laser emissions of an appropriate wavelength are administrated, they activate the photosensitizer within the tumor cells so it absorbs the light energy, produces a singlet oxygen and destroys the tumor.
The advantages of PDT over old cancer treatment methods involving surgically excising cancer cells and administering strong anti-cancer drugs around cut areas are clear. PDT is minimally invasive and far more precise. Orenstein and his colleagues have been working on refining PDT techniques even further. One method involves administering a biochemical precursor of a photosensitizer instead of a photosensitizer itself. This offers the advantage that the precursor, 5-aminolevulinic acid (ALA), can be applied topically, reducing invasiveness and complexity even more.
The major drawback of PDT, however, is getting light to the tumor. The Sheba center is now working on a project that will capitalize on its radiological technology to reach targets previously unattainable. The aim is to devise a protocol which instead of relying on light markers to differentiate between cancerous and non-cancerous cells agents would use a radiological tool to distinguish between them. Once the tumor cells have been located, a light source can be administered endoscopically and trigger the sensitizing action that destroys the cells. Such a development would be a great breakthrough and would allow a larger variety of tumors to be treated. The prime candidate radiological tool is the MRI (magnetic resonance imaging) scanner because of its ability to contrast between soft and hard tissues. The Sheba Advanced Technology Center owns one of the most advanced MRI models in the world, manufactured by General Electric. With its innovative cylinder shape, the latest in MRI scanners uses a super-conducting magnet that increases its stability and field strength. There are only ten such machines in the entire world.
This project is attempting to bring surgery procedure and essential tissue research together under the same roof. And the staff at Sheba is already learning that one thing is clear about the operating room of the 21st century: As techniques become more sophisticated, it is not only the machinery that is changing but also the roles of the human players within. For example, the GEC MRI scanner is used to see inside the body in real time. Although the surgeon sees the image transmitted through an infra-red detector on the scalpel, the MRI operator, who is able to keep her eye on the image at all times, acts as the surgeon's director throughout the procedure.
Part of the Sheba Center's funding will come from its involvement in a larger national project. The Ministry of Trade and Finance operates a Magnet program to encourage research into novel developments with good industrial potential. For the first time, a consortium is being organized whose focus is surgical imaging technology. Sheba Advanced Technology Center will be one of the main participating clinical centers.
The original idea for the consortium, named Izmel — scalpel in Hebrew — began in the Rambam Medical Center in Haifa. There the Image Guidance Surgical Oncology Center (IGSO) was set up along the same rationale as the Sheba center. Surgeons familiar with the limitations and problems in their routine work in the Operating Room aspired to bring surgery and imaging together, both in time and space. The aim of the IGSO is to develop new strategies for integrating imaging into surgical procedures so that images are seen in "real time," enabling better control and evaluation as well as providing better guidance to the surgeon.
In their quest for resources, the IGSO discovered the option of presenting their projects for R&D funding to the Ministry of Trade and Commerce through the Magnet program. Headed by Dr Doron Koppelman, a consortium was set up in accordance with the program's stipulations, consisting of a number of clinical centers, academic centers, and, most importantly, Israeli industrial companies — all willing to work together toward a shared objective. The consortium will work on a large number of projects where any project coming under the consortium's auspices qualifies for inclusion as long as there is both industrial and academic interest plus cooperation and synergism between the two sectors. This is the main object behind the Magnet program. The focus is not on finished products but rather on an R&D infrastructure for generic technologies. Sheba and Rambam are the two major clinical centers involved. They are joined by Hebrew University, Tel Aviv University, the Technion and at least twelve Israeli companies, making Izmel one of the largest Magnet consortia around. After the initial phase of proposals and budget clearances, the Izmel consortium has received pledges totaling $40 million over 5 years. It is now in the final states of the approval process.
In Koppleman's opinion, the Magnet program is an unrivaled form of funding. "The fact that the government is giving support toward the development of generic technologies to encourage the medical industrial sector in Israel is unique." More prominent perhaps is a valuable side product of the program, increased inter and intrasectoral cooperation. As Koppelman adds, such cooperation is not always easy to achieve.
If that was once the case, then the initiatives we have described here go to show that in Israel researchers are learning that even in the field of high technology, advance will only come through the basic principles of collaboration and team work.
Genetic Diseases — Looking For the Potential
Tracing the genes responsible for hereditary diseases is an essential phase in the development of our understanding of their mechanisms as well as in the development of treatment and prevention programs. The first step is to find their relative positions on the chromosomes. This can be done through cytogenetic and molecular studies of family members known to have, or to be a carrier for, a hereditary condition.
These genetic studies rely on close family structures, and thus Israel is fertile ground for gene research. The immigrant character of the population produces a natural experiment where many genetic structures are preserved due to the closed nature of some of the ethnic groups living in Israel. In addition, a centralized health system makes medical records far more accessible and reliable for patient tracing, a basic necessity for gene mapping.
There are many research groups in Israel trying to unlock the secrets behind genetic diseases, some concentrating on diseases unique to the region and some working on diseases prevalent worldwide. Some groups focus on genetic research in the laboratory with minimal patient contact and others focus almost entirely on treating patients with these diseases.
As space limits do not allow us to describe the work of all these groups, we will focus on one outstanding example that demonstrates many of these options.
The Genetics Institute of the Soroka Medical Center in Beersheba is producing ground-breaking work on many of the rare hereditary diseases endemic to the neighboring Bedouin population. The research group, headed by Professor Rivka Carmi, is learning more than just the genetic secrets of these rare diseases; however, they are also learning how to capitalize on their discoveries to benefit the study population.
Based on the Soroka Medical Center campus in Beersheba on the edge of the Negev desert, this genetic research is being carried out alongside hospital clinical genetic services that include prenatal screening and genetic counseling. The genetic research involves two realms - one clinical and another sociological.
The basic clinical research focuses on dissecting the genetics behind rare hereditary diseases. It is concentrated almost exclusively on the Bedouin community of the Negev region. This highly traditional population displays a preserved genetic structure due to the high rate of consanguinous or interfamilial marriages. The high rates of intermarriage amplify the frequency of genes with mutations responsible for rare diseases within a small population, making it very efficient for gene mappers to work with this group.
Through a systematic approach, the research aims to identify genes responsible for the many hereditary diseases and syndromes prevalent within the Negev Bedouin population. The first step is to find the gene's location on the chromosome. Once it is located, the next step is to identify the mutation in the gene that causes the disease. Ultimately the researchers wish to elucidate the molecular basis of rare genetic diseases so they can prevent their very occurrence. To date, Carmi and her group have identified twelve genes responsible for various diseases; in the case of one syndrome, they have already detected the mutation. The gene for deafness was already known from studies of a different disease and the Beersheba group found the mutation through analysis of a Bedouin family in which the disease was common.
The diseases under investigation are not exclusive to the Bedouins nor to Israel, but it is almost impossible to study the genes responsible for them elsewhere, as very few other populations around the world constitute a "genetically isolated" group that allows the use of special methods for gene mapping.
This research is a collaborative effort conducted with a group headed by Dr. Val Sheffield from the University of Iowa, an official site of the Human Genome Project. This collaboration has broadened with time to include investigation of the genetics behind multifactorial syndromes. These are syndromes caused by multiple factors, some genetic and others environmental; moreover, the genetic influence is polygenic, i.e. more than one gene is involved. Examples of such syndromes include diabetes, hypertension, obesity and celiac disease.
One strategy utilized to decipher the mechanism behind a multifactorial syndrome is to go to a known monogenic disease, i.e. one caused by a single gene mutation, whose physical expression or phenotype includes that of the multifactoral syndrome. Let us take obesity as an example. It is thought that obesity is influenced by a number of genes. If there is a syndrome determined by the mutation of a single recessive gene that includes obesity in its manifestations, then it is highly probable that that gene plays a role in obesity. The Beer Sheba group have found three separate genes that independently cause a disease known as Bardet Biedel. Part of Bardet Biedel's diverse phenotype is obesity. This suggests that the three genes are generic genes for obesity. It is not clear yet how these genes interact together or how many other genes are involved, but the evidence is that somehow they do. At this stage the researchers know the gene's relative position on the chromosome and are working on characterizing the gene. The next step will be to confirm the connection by checking for the mutation in the genes of obese patients.
This strategy of examining the genetics of Mendelian disease with a phenotype related to a larger syndrome such as diabetes, cancer or mental disease is becoming an increasingly popular and useful tool. Carmi takes it one step further and emphasizes the concept of generic genes — genes involved in several diseases that hold the keys to certain syndromes. She believes that there is great, untapped potential in carriers' genes, and that a lot more could be learned from them. Although according to strict genetic theory, a carrier simply passes on the disease gene and is outwardly physically healthy and symptomless, like carriers of the cystic fibrosis gene, this is not always the case. Thirty percent of carriers of a gene for dwarfism are notably shorter than average, indicating that the recessive gene is exerting some effect. Carmi asserts that the study of recessive genes may well lead us to an understanding of multi-factorial diseases and traits.
One of the Institute's outstanding features is its dedication to the population it is studying. The Institute's philosophy is that clinical research must give back to the community that enabled its research. For every family that helps them to find a gene, researchers intend to offer a diagnostic tool. As soon as the gene has been mapped, it is possible to develop prenatal screening tests for the family that provided the opportunity for research. Thus in the case of fetuses bearing severe hereditary diseases, families can be offered the option of early termination of pregnancy.
Presenting the families with a prenatal test is not enough, however. For a community whose cultural beliefs and values are often different from standard western thought, one cannot just announce the development of a diagnostic tool and a prenatal test and expect the population to participate. To many families the concept of an early pregnancy termination is unacceptable. It is also entirely unrealistic and unreasonable to expect to dispense with the custom of interfamilial marriages. Carmi quickly realized that if the group really wanted to make an impact on the prevalence of lethal hereditary diseases in the Bedouin community, they would need to invest in understanding the community. Thus, for the past three years, the Institute has been running a community project together with the Ministry of Health to raise awareness within the population of available services and increase their use of these services, through public outreach employing peer educators. By training members of the community to discuss the issues with peers, custom and health needs are slowly being reconciled. For example, early termination may now be sanctioned if it is done at an early enough stage.
Together with the Faculty of Health Sciences of the Ben Gurion University, a multi-disciplinary study is under way to investigate the little researched issues of how a traditional community perceives the concepts of genetic diseases, carriers, stigmatization of carriers and so on.
Alongside the development of prenatal tests, the Institute has also begun a project for carrier detection. There are known to be over two thousand carriers of the deafness gene mutation within the Bedouin population. The aim is to introduce the concept of carrier testing to the community, to increase utilization of testing services and to encourage matchmakers to adopt carrier status as a criteria for arranged marriages — still very popular within the community. If the health status of prospective partners can be checked ahead of time by the matchmaker, the possibility of disease occurring in a couple's children can be prevented from the very outset. As with the prenatal screening program, the carrier detection program also required a well thought-out strategy to gain acceptance. This experience is now being documented as a doctoral thesis.
The provision of genetic services within traditional populations whose socioeconomic and educational levels are lower than the national norm, has been little researched; carrier screening within such populations has been studied even less.
The Institute's overall philosophy is part of an emerging trend. Increasingly, the question being asked is how isolated communities can help map genes and shed light on the mysteries behind many mono and polygenic syndromes. The real challenge, as Professor Carmi views it, is to see the potential of each gene to lead to the understanding of still other diseases. Carmi contends that we need to start looking not only at diseases' genes codes but also at other diseases with which they may be connected. For example, the gene for a malignant bone disease that causes unwanted bone cell growth may hold the secret behind bone metabolism and be relevant to osteoporosis, even though the two conditions display opposite effects. Carmi believes that clinicians have a distinct advantage over laboratory researchers because their day-to-day experience with real cases gives them a sharper eye for spotting related syndromes. She contends that many start-up companies looking for genes have yet to grasp the importance of clinician input.
If the aim is to find the potential within the genes for the understanding of related diseases, there is little question that the Beersheba group has great potential for teaching us about a variety of issues related to genetic diseases.
Fertile Knowledge in the Fertility Field
Israeli fertility specialists have played a prominent role in fertility research and have been at the forefront of developments of assisted reproduction techniques since their initiation four decades ago. This commitment continues today, with every major hospital in Israel supporting clinical activities in in-vitro fertilization (IVF) and other assisted reproduction methods. These clinical activities are supported by very significant investment in the highest quality research. An illustration of their degree of commitment comes from a survey of the two leading journals in the field — Fertility and Sterility and Human Reproduction. The survey revealed that from 1990 onwards, approximately five percent of all published articles came from Israel.
Professor Eliezer Shalev of the Obstetrics and Gynecology Department at Ha'Emek Hospital in Afula asserts that Israel's experience in fertility research is so advanced that today the focus has progressed beyond researching basic methods. Instead, the main emphases of research can be loosely categorized as: (1) the refining of current techniques, (2) the prevention and treatment of iatrogenic complications and (3) the application of knowledge and experience in fertility research to related disciplines.
Beginning with the last category, we see an example of the application of knowledge and experience in interdisciplinary research taking place at Hadassah Hospital, the location of the largest concentration of investigators and research in Israel. Here experts in the fields of fertility and molecular biology are working together to develop techniques that allow genetic diagnoses of an embryo before implantation to prevent the development of lethal conditions.
Professor Nery Laufer of the IVF Unit of the Department of Obstetrics and Gynecology at Hadassah University Hospital, Mount Scopus, provides an example — the management of rhesus isoimmunization. Rhesus Factor Disease is a severe blood disorder caused by an incompatibility between the blood group of the fetus and that of the mother. Dangers arise if the mother is rhesus negative and the father rhesus positive and passes this on to the fetus. If the fetus is rhesus positive, the mother reacts to its red blood cells and produces antibodies against them. The danger is minimal in the first pregnancy, but by the second pregnancy antibody levels rise, causing mild to extreme hemolytic anemia in the fetus which can lead to severe hemolytic disease, prenatal death or both.
Until now, treatment has been through exchange transfusion via the umbilical cord immediately after birth or even while the fetus is still in the womb. Alternatively, rhesus negative women can be prevented from developing antibodies by the administration of immunoglobins. Neither of these methods are always successful. The Hadassah group has developed a pre-implantation diagnostic technique which combines molecular biology and IVF expertise.
Pre-implantation diagnosis is based on the genetic analysis of single blastomeres from 8-10 cell embryos obtained in-vitro. Diagnosis at such an early stage allows the transfer of only normal embryos to the uterus. To get enough DNA to allow a correct genetic typing to be made, an amplifying technique called polymerase chain reaction (PCR) is carried out on the cell's DNA. The fathers in this case were heterozygous and so to ensure the accuracy and efficacy of the method rhesus blood group typing was performed on single sperm cells as well as on blastomeres. This is the first time that polymerase chain reaction has been used to type the sperm before in-vitro fertilization.
Thus we have progressed beyond the stage of treating couples who cannot have children to enabling couples at risk to give birth to healthy babies. In a similar vein, Hadassah has also developed a diagnostic system to identify embryos which have one or both of the two cystic fibrosis (CF) gene mutations —
F508 and W1282. CF is the most common autosomal recessive disorder in Caucasians. It is caused by different mutations in the CF transmembrane conductance regulator (CFTR) gene.
The diagnostic method developed detects both mutations simultaneously in a single blastomere, diagnosing both affected embryos and normal carriers. The combination makes the method very useful, as while
Diagnosis at such an early stage provides an important alternative to therapeutic abortion. Pre-implantation diagnosis could be highly beneficial, as religious opposition to abortion has caused affected families to decline to participate in screening programs. Additionally, the group hopes that the PCR model for pre-implantation diagnoses will be applicable to additional disorders caused by a variety of mutations.
Along with a wealth of experience in fertility, Israel has also amassed greater understanding of the more unwelcome results of the treatment, i.e. iatrogenic complications — undesirable effects occurring as a consequence of the treatment itself. One example of this is Ovarian Hyperstimulation Syndrome (OHSS), a potentially life-threatening condition that results from the pharmacological stimulation of the ovary. Fertility specialists are working to understand the factors involved in the syndrome; the mechanisms involved in the development of the disease are still unclear.
Recently investigations have pointed to the role played by cytokines, protein intercellular mediators. It is believed that the underlying pathology of OHSS could be hyper-permeability in the peritoneal cavity of the mother's abdomen. If so, permeability-modulating factors are prime candidates for mediators of the syndrome. A group of collaborating researchers from the two Hadassah campuses and Tel Aviv's Serlin hospital decided that the best strategy to search for possible players was to look at the ascitic fluid of the mother, the fluid contained in the cavity. Key findings of their study were that in comparison with control subjects, the three cytokines IL-6, IL-8 and TNF-
were found to be present in significantly higher concentrations in the fluid of severe OHSS patients. Previous knowledge about these cytokines points at their possible roles in the pathology, specifically the hyper-permeability process. Low nitrite levels found also tie into this theory, as reduction of nitrites can result in the accumulation of superoxide radicals that in turn enhance micro-vascular permeability.
These discoveries are already influencing treatment of the OHSS syndrome, and it is anticipated that knowledge gained from the studies will be applied to develop protocols for milder ovarian stimulation, thus avoiding the syndrome altogether. As Professor Laufer explains, with the development of better tissue cultures, it is hoped that the number of ova required for implantation will be reduced, making the treatment a more friendly, healthy and cheaper process.
Finally, another assisted reproduction technique currently being refined is a treatment for male infertility. Intracytoplasmic Sperm Injection (ICSI) is one of three micro-manipulative strategies that have been developed to improve the fertilization ability of spermatozoa. Direct micro-injection of sperm nuclei into the ooplasm promises high fertilization and pregnancy rates. However, technical difficulties during development made it clear that operator skill was a key factor to high success rates. Assisted hatching techniques are definite improvements to operator skills, as they aid the implantation of the fertilized ovum. Hadassah's researchers are developing such techniques, including the use of the Excimer Laser in the process, as described in a previous section. This refinement promises to be especially beneficial as it opens up treatment possibilities for patients of an advanced age undergoing ICSI for male factor infertility.
Fertility research is particularly prominent in Israel. Laufer presents two interlinked factors for the incredible interest. First, treatment is covered by the health care system's benefits package, and thus patients are not required to pay out of pocket. Second, and possibly the reason behind the first, increasing the country's fertility rate (for Jews) is seen to be a great investment in the country's future — as Laufer puts it "an internal Aliyah" (Aliyah is the term used for immigration to Israel, and for going up to the podium to read from the Torah).
Whatever the reason, as long as this kind of investment continues, Israel can be relied on for leadership and innovation in the field of fertility.
Marrow Transplantation — Working Toward Transplants for All Who Need Them
A bone marrow transplant provides the recipient with a new set of stem cells that act as a source of healthy new red and white blood cells, platelets and immune system. Transplants are most often used as therapy for blood cell disorders or to replenish the critically low blood cell levels of cancer patients after radiation therapy.
Israel is the home of cutting-edge developments in Bone Marrow Transplantation (BMT) technology. Two groups in Israel are currently investigating key topics, such as how to improve BMT protocols to make transplants available to all patients who need them, how to utilize BMT to reduce or even eliminate radiation therapy for cancer patients, and still further, how to develop BMT as a cure in its own right for a plethora of diseases.
Progress in BMT technology has always been dependent on our ability to overcome a double barrier. First, as with all organ transplants, there is a chance of a host versus graft response, i.e. rejection of the donor cells by the host's immune system. A second complication unique to BMT where the donor's immune cells react against the patient, is known as graft versus host disease. As the bone marrow is actually part of the blood system, the tissue where progenitor blood cells begin, many lymphocytes (white blood cells) are present in the tissue. These are easily recognized as foreign by donor lymphocytes, triggering a lethal attack on the host. The attack is mediated by a special group of lymphocytes known as T-cells. It has long been known that if T-cells could be removed from a graft of donor cells , then so would host versus graft complications.
Donor bone marrow comes from several sources: an autologous source, the patient herself or an allogenic donor, a genetically-matched sibling or a matched donor from a bone marrow donor bank. A patient's chance of finding a matching is 30% for family members; in the US, a donor pool of three million adds another 30%. This is correct for the white Anglo-Saxon population only. Minority populations such as African-Americans have reduced chances of finding matching donors, due to their comparatively rare genetic makeup. Thus, the only option for more than 40% of patients is an autologous transplant, which is not ideal as it lacks the benefits that come with cells from a healthy immune system. In a country such as Israel, similar problems are encountered in finding donors for members of the various ethnic groups. Consequently, BMT research today is directed toward increasing the percentage of patients able to receive allogenic transplants by innovating technologies that allow "mismatched" allogenic donors.
Professor Yair Reisner of the Immunology Department of the Weizmann Institute has been researching the immunological aspects of transplantation and the problem of the double barrier for many years. He was directly involved in the discovery of the cure for Severe Combined Immune Deficiency (SCID) patients — a major breakthrough for graft versus host disease twenty years ago. The cure was a bone marrow graft containing only the essential stem cells and excluding the T-cells which mediate the graft versus host response. SCID patients are born without an immune system and thus have no rejection mechanism. Consequently it was thought this technique could be applied to leukemia patients whose crucially low white blood cell counts following superlethal radiotherapy treatment were thought to make them analogous to the SCID patients. Disappointment came when rejection still occurred. It became apparent that after intense radiation therapy, a small number of T cells remain. These cells are highly resilient survivors of a normal immune system which can direct major rejections of donor cells.
Returning to animal models to understand more about the immune system after radiation, two possible directions to circumvent resistance emerged from the research. The first, killing off the remaining T-cells, was judged undesirable as it essentially meant dismantling the patient's last line of defense against infection. A second more exciting and stimulating option, manipulation of the bone marrow itself to overcome rejection, was pursued by the Weizmann group.
One simple yet effective approach to bone marrow manipulation emanated from the several possibilities investigated in the animal studies. This was to increase the stem cell dose. The more donor cells given to mice, the less likely they were to be rejected. The next step was to find a way to harvest enough cells. Whereas in mice one can pool ten identical donors, in humans one is limited to 1 liter of bone marrow, an insufficient dose. It was not until 1993, four years after the first paper was published suggesting that cell dose was the key, that the breakthrough came. Inspiration came from studies on autologous transplants which revealed that cytokines administered to patient-donors boosted production, resulting in the collection of huge numbers of white blood cells, including a high proportion of essential CD34 stem cells. Cytokines are non-antibody proteins that act as intercellular mediators. Reisner's group found that certain cytokines had the same effect on allogeneic donors and used them to collect tenfold more stem cells for transplantation. Cell dose was evidently the key. More than one hundred patients have now been treated with this procedure in Italy, Germany and Israel.
Now that a solution has been found for donor difficulties for leukemia patients, and graft rejection rates are down from 80% to below 20%, the group aims to take this basic solution of increased cell dose and apply it to other conditions. Studies in mice have shown that if transplants are carried out with high enough cell volumes, levels of radiation therapy can be reduced to sublethal doses. This ability to lower necessary levels of radiation and reduce the toxicity of the protocol opens up opportunities to treat populations other than leukemia patients. There are many patients suffering from non-malignant disorders who could benefit from bone marrow transplants but cannot cope with the radiation treatment.
Various applications of megadose stem cell therapy are being explored, including:
1. Blood disorders — Patients suffering from conditions like Sickle Cell Anemia and Thalassemia would benefit from a bone marrow transplant that would introduce normal stem cells capable of building a healthy immune system. The high radiation leukemia BMT protocol puts patients at grave risk from infections; therefore, transplants can only be considered if a less aggressive protocol is developed.
2. Enzyme deficiencies — Conditions such as Gaucher's disease are caused by an enzyme defect. Donor blood cells transplanted could produce the missing enzyme. BMT in these cases would result in "mixed chaemerism," where the patient's immune system contains both host and donor blood cells. Again, BMT was not considered appropriate for such patients as long as the procedure involved high radiation therapy, due to the gravity of the side effects and the fact that the patients themselves were not in immediate danger of death.
3. Organ Transplants — Cells from the donor graft are used to create a new immune system, with the sole aim of familiarizing the patient's body with the donor cells in preparation for the transplant. This would eliminate the need for immunosuppressive drugs.
4. Cell Therapy- As will be discussed further below, immune cells affect tumors independent of radiation, and this anti-cancer effect can be exploited in treatment. The only obstacle is the need to find a method to introduce these "fighter" donor cells into the host without upsetting the host immune system. Reisner's megadose stem cell therapy is one way of doing this under mild, non-drastic conditions, i.e., not by radiation. As for organ transplants, the transplant "sets the stage" for the anti-cancer treatment. In theory, certain viruses such as HIV, could also be treated by donor cells, which could recognize and eliminate the virus.
The application of cell therapy clearly demonstrates that donor cells have the ability to do what the host's cells failed to do for themselves — fight back. This pertains as long as they are introduced to the host effectively. Reisner recognizes the potential and sees the key to progress in the resolution of host T-cell resistance. He believes the answer lies in fine-tuning volumes of stem cells for transplantation, understanding the specific role of stem cells. Efforts are now focused on developing reasonable protocols and methods of achieving tolerance under mild conditions.
A second group in Israel investigating tolerance mechanisms in relation to cell therapy is based at the Hadassah University Hospital. Professor Shimon Slavin heads the BMT Department of the Cancer Immunotherapy and Immunobiology Research Center. The Department specializes in cell therapies not only for disorders where chemotherapy is inappropriate, such as those listed above, but also in a revolutionary new direction: for cancers as an alternative to radiation therapy. The elimination of the need for radiation is the ultimate goal, as even when successful, the treatment can have many unpleasant side effects such as sterility, endocrine disorders and stunted growth.
As Professor Slavin explains, up until now, enhancements to BMT procedures have always focused on how to cope with the radiation dose limiting factor of marrow toxicity. The trend has been to find ways to give as much radiation therapy as possible, despite this limiting factor, and a cure has been seen as a function of treatment intensity. The normal protocol of intense chemotherapy to kill the leukemia, followed by the "rescue" of the patient's immune system by a bone marrow graft, implies that most of the anti-cancer effect is from the radiation. However, Slavin claims that the effect is mostly due to the donor T-cells injected into the patient rather than to radiation.
Slavin came to this conclusion after observing that patients with grafts from siblings had far higher success rates of recovery than patients who received grafts from an identical twin. It seemed that donor cells from an identical twin are indeed so identical that they are impotent against the cancer, being as they are equivalent to the patients' own immune cells — those that originally failed. In contrast, grafts from siblings are sufficiently different to be able to fight the patient's cancer cells.
Slavin believes that the adverse response of the graft versus host reaction can be exploited in a graft versus leukemia reaction. T-cells in the donor's marrow which attack the host can be deployed to attack cancer cells. The theory that the blood system alone could cure leukemia was first proposed when mice with BCL1 leukemia were cured following lymphocyte transfer from healthy donor mice.
Proceeding with clinical patients after the success of these animal studies, the Hadassah group began with terminal leukemia patients in relapse who had little hope of survival following several unsuccessful rounds of chemotherapy. The procedure known as donor lymphocyte infusion was first performed in a patient over a period of six weeks on an outpatient basis. Within this time the patient's tumor disappeared entirely and this patient has now been cured for over ten years.
Like Reisner's group, the Hadassah group also learned from their experiences with cytokines in autologous transplants. They are combining this knowledge with their experience with terminal patients to develop and perfect donor lymphocyte infusion treatment protocols for relapse patients. The donor lymphocyte infusion procedure is enhanced by various steps to maximize success rates. These include the addition of the cytokine interleukin-2, activation of cells with the cytokine in vitro before transplantation, and treatment administration in graded increments. The rationale behind this last step is that as resistance increases with time after the transplant, so should the treatment.
Following successes with relapse patients, it was felt that if donor lymphocyte infusion could be used in relapse patients and in others for whom all kinds of chemotherapy had failed, why could it not be harnessed to work prophylactically to prevent relapse entirely and possibly replace radiation therapy — thus avoiding the unwanted outcomes of radiation. The success also opens up treatment possibilities for populations such as the elderly who are not eligible for BMT with radiation therapy.
This will be accomplished by first "setting the platform" for cell therapy by adding the step of non-myeloblative stem cell transplantation (conditioning that does not kill off bone marrow cells) to their protocol. Similar to Reisner's idea of inducing tolerance for organ transplants, Slavin believes this educates the patient's body to accept the donor, allowing the subsequent donor lymphocyte infusion to do the work of eliminating the tumor.
Thus BMT technology in Israel includes two different research groups, one in a basic research institute and the other based in a University hospital working toward the same goal. Their ideas and aspirations converge as they both express similar aims: looking for ways to introduce stem cells through non-invasive and non-aggressive treatment, developing cell therapies as a cure and understanding more about the induction of tolerance as the prelude to donor T-cell addition. At the same time they work in independent fashions developing their own methods to answer these essential questions.
Speaking about his megadose stem cell approach, Reisner acknowledges that many groups around the world are exploring various answers to the same issues. The most important thing, he believes, is that in the end all the answers will contribute to the ultimate solution. The final answer will be a synergy of the ideas and concepts being developed today. If this is the case, a significant number of these ideas and concepts will undoutedly have their roots in Israel.
Cardiology — Bypassing the Bypass
Worldwide, cardiology is known as a device-driven field, and this is no less the case in Israel. In fact, a combination of all-Israeli clinical and engineering expertise is what has produced one of the most important cardiological devices of recent years, the "NIR®" stent, a device that could radically reduce the need for coronary bypass surgery.
Coronary angioplasty is a surgical procedure that effectively reconstructs blood vessels surrounding the heart, normally dilating strictures in these vessels. It is facilitated today by techniques such as balloon angioplasty and bypass grafts, whose development has allowed an increasing number of patients to undergo this procedure and benefit from it.. Due to improvements in operator technique and equipment in recent years, possibilities of coronary artery surgery have opened up for patients whose conditions were formerly thought to be too complicated to operate on. Despite the greatly improved success rates, however, these patients are still more at risk for acute complications.
More recently, a new device, the "stent," has emerged, offering new hope and an alternative to established methods of angioplasty. A stent is a rod or tiny metal net, shaped like a tube, which is placed in the lumen of tubular structures to provide support either during or after anastimosis — the surgical union of two hollow or tubular structures. Coronary stents are surgically implanted to prevent coronary artery collapse after angioplasty. They have been shown to be an effective method for reducing both the incidence of restenosis (recurrent vessel strictures following surgery) and clinical adverse effects.
Over the last decade, utilization of stents in coronary arteries has been shown to be increasingly effective, and now a second generation of stents has come through to deal with the difficulties encountered by their predecessors. The Israeli NIR® stent is a leading design in this new generation. The original stents' most prominent drawback was their rigidity, making it difficult to insert them into tortuous or distal vessels. Long lesions often required overlapping stents — if they could be treated at all. The NIR® stent has been designed specifically to provide greater longitudinal flexibility.
According to Dr. Yaron Alamagor of the Cardiac Catherterization Laboratory of Sha'are Zedek Medical Center in Jerusalem, it is the NIR® 's unique design, a blend of geometric properties, which represents the greatest innovation. Made of stainless steel sheets, micrometers thick, etched into a geometric pattern and then rolled and welded into a tubular configuration, it provides the rigidity and radial support required while at the same time offering maximum flexibility. With features of high longitudinal flexibility (length of up to 32 millimeters) before expansion and high radial support and minimal recoil and shortening afterwards, it provides a "best of both worlds" solution. For these reasons, the NIR® is especially useful in patients with complications and is suitable for implantation in complex and difficult-to-reach lesions.
Dr. Almagor is responsible for the clinical application of the stent and has been involved in clinical trials of the NIR®, which took place as part of a multicenter international registry. In a recent report of the FINESS study, an international collaboration to determine the feasibility, safety and efficacy of the NIR® stent, the stent was shown to be highly efficacious and highly promising. Further prospective, randomized trials comparing it to other currently available stents are currently in progress.
From an Israeli perspective, the NIR® has an additional feature of being entirely home grown or "blue and white," highlighting Israel's excellence in several fields. As Dr. Almagor explains, it is a fine example of cooperation between the medical and engineering sectors in Israel. The engineering expertise behind the NIR®'s creation came from the Israeli manufacturing company Medinol Ltd, recently acquired by Boston Scientific Corporation. Now as clinical trials are being performed in twelve top medical research centers in seven different countries. production and marketing remains locally based at Medinol Ltd. in Tel Aviv. Even the stent's name reveals Israeli spirit. Although the acronym NIR stands for "new intravascular rigid flex" stent, surgeons also chose to name the stent NIR in memory of Officer Nir Poraz, a soldier who gave his life in a military attempt to rescue kidnapped soldier Nachson Waxman in 1994.
Thus this product represents a blend of Israeli excellence and extensive interaction and cooperation with the international medical community. And for the Cardiac Catherterization Laboratory of Sha'are Zedek Medical Center, the international collaboration on the development of cardiological technique has not ended with the development of the NIR®. The laboratory now uses ISDN communication technology to transmit real-time pictures of surgery to and from experts worldwide to facilitate consultations to enhance treatment for their patients.
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