Stanford University Home

Stanford News Archive

Stanford Report, January 22, 2003

Vision statement for the Institute of Cancer/Stem Cell Biology and Medicine at Stanford

By IRVING WEISSMAN, MD

CANCER
Cancer is a cellular disease; the unit of cancer development is a cell that proliferates indefinitely and beyond the controls that normally limit growth of cells in its native tissue or organ. Cancer cells can be defined as cells that through genetic alterations have 1) acquired the capacity of high level self-renewal, 2) usually limited their ability to differentiate, 3) developed mechanisms to avoid programmed cell death due to intrinsic signals as well as external cues, 4) developed mechanisms to evade the intrinsic lifespan mechanisms that their normal counterparts have, and 5) often acquired high intrinsic rates of mutation.

Usually the process to generate a cancer cell from a normal cell involves a number of changes in the genes that regulate these characteristics, and because each of these events are rare, only one cancer cell at a time emerges; thus most cancers are clones of self-renewing cells derived from the original cancer cell. Many of these characteristics are shared with normal tissue-specific stem cells, which for the most part are the only cells within a tissue that retain high rates of self-renewal. Because in normal tissues only stem cells self-renew, for many, if not all cancers, the rare genetic alterations that are part of the cancer progression occur first in normal stem cells, and only later do cancer stem cells emerge that are largely independent of the normal and premalignant clones around them. Since these cancer stem cells often have differentiating daughter cells as well as self-renewed daughter cancer cells as their clonal progeny, and these differentiated daughter cells do not self-renew or proliferate extensively, it is the properties of the cancer stem cells that determine the properties of invasion, metastasis, and selected drug resistance that limit or allow successful cancer therapies. For these reasons, a Cancer/Stem Cell Institute focused on the basic molecular and cellular features of the normal homeostatic mechanisms of stem cell growth control and their perturbations in cancers is an essential for the medical center’s future.

When cancer stem cells have not spread from their site of origin, ablative therapies such as surgery and local radiotherapy can be curative. When cancer stem cells have spread beyond their sites of origin unpredictably, almost always when they invade the bloodstream, systemic therapies are required. The scientific basis of such therapies derives from the pioneering work of the bacterial and phage geneticists of the 40’s and 50’s, including Luria at MIT, Delbruck at Caltech, and Lederberg at Wisconsin and Stanford, who showed that genetic variants to any antibiotic pre-exist within the population, and are not induced. Because each variant is rare, the probability that a single cell or phage existed that was randomly resistant to several antibiotics is nearly zero. While there are now known to be multidrug resistance genes for antibiotics in bacteria, and anti cancer agents in cancers, for the most part systemic cancer therapies, championed by Frei and Freireich in the early 60’s for children with acute leukemias, are based on multiple drugs given simultaneously targeting different genes or processes in cancer cells, but that have independent toxicities for normal cells.

Modern cancer therapies with curative intent depend on practicing these scientific principles. Local disease or cancer that has spread predictably via lymphatic drainage to local lymph nodes are treated by surgery or high dose local radiotherapy (a field whose inception occurred largely at Stanford by the late Henry Kaplan) now aided by advanced imaging methods. Metastatic disease is usually treated with combinations of chemotherapy agents so that the amount of tumor at diagnosis, usually 10e11 or 10e 12 cells, do not likely have variant cells simultaneously resistant to all agents. This strategy is compromised, however, if access to the tumor by such agents is limited, or the tumor cells possess multidrug resistance properties such as those contributed by transport molecules that generally carry hydrophobic entities out of the cell.

The natural targets of chemotherapeutic agents were originally DNA itself, so that the dividing cancer stem cell would die before the damage could be repaired. Increasingly new targets are found by the discovery of cancer genes, genes that were altered in their sequence or expression levels as part of the cancer progression. The most important molecular targets for chemotherapy or immunotherapy would be the molecules on the surface or inside of cells that are essential for cancer stem cell behaviors. In the recent past the principle avenues of discovering cancer genes are by 1) fundamental research finding genes incorporated into or activated by oncogenic viruses in animal models, or 2) characterizing cancer specific chromosomal translocations, amplifications, inversions, etc. Stanford has participated well in these kinds of studies. Most recently Brown, Botstein and their colleagues at Stanford have adapted a new technology called expressed gene microarrays to find and characterize genes selectively expressed in defined cell subpopulations, and this has proved to be powerful as a method of gene discovery in whole tumors. It needs to be applied to cancer stem cells. Cancer genes found by any of these methods are always genes used also by normal cells, often by tissue specific stem cells, and are parts of cellular signal transduction and transcription, and even post-transcriptionally regulated pathways involving upstream and downstream gene products. As these pathways become elucidated, it is expected that new targets for molecular and immunotherapies shall emerge.

As will be discussed in more detail later, the field of bone marrow, and now hematopoietic stem cell (HSC), transplantation was invented to allow multi-drug protocols that kill cancer cells, but also endogenous HSC and blood-forming progenitors; the transplanted hematopoietic cells rescue the patient that received an otherwise lethal dose of therapy. Similar tissue specific stem cells, not yet found, could be required for rescue when other organs such as liver, lung, and gut are damaged by anti-cancer therapies.

A natural defense against cancers that has been brought into the therapeutic realm is the patient’s immune system. Both the antibody and the cellular (T cells, natural killer cells, activated macrophages, etc) parts of the immune system can bind to cancer cells (ideally cancer stem cells) and either wall them off or kill them. These too are limited by the possibility of variation naturally present in rare clones of cancer cells, and so these too will likely transition to cures only when multiple independent molecular targets on the surface of cancer stem cells can be identified and targeted.

Virtually all chemotherapies and immunotherapies now available have come from translational research that may have started at academic institutions, but were then developed by commercial entities. This has introduced a problem for developing therapies with a curative intent. As described above, only multi-therapies are successful with widespread cancers, but commercial entities are lucky if they can develop a single useful agent or approach. Thus integration of efforts really only happens at clinical research medical institutions, and usually as organized multi-institutional efforts. If Stanford hopes to play a role in treating cancers with curative intent it has to develop a whole infrastructure to do so. It must start with physician-scientists and scientific clinical trialists who perceive what might be an important protocol, but to be successful must also include clinical trial nurses, biostatisticians, dedicated hospital wards or outpatient units with medical and administrative support staff, etc. There must be close interactions between those that study cancer at a fundamental level and those that have access to fresh clinical samples such as cancer cells and normal tissues so that discovery research is facilitated. In addition, skilled scientists and clinical trialists must establish research and educational programs to train the next generation of medical students, graduate students, residents, and post-graduate fellows. Thus developing a cancer center that intends to span discovery to therapy in an educational institution, even for a selected subset of cancers, will require authority and organization that does not now exist at Stanford.

STEM CELL BIOLOGY

Within any tissue stem cells are a very rare subset, and their isolation requires a combination of scientific, immunological, biological, and transplantation studies. While most of our body cells turn over and die or are resident for long periods of time while they function, their ultimate regeneration can only come from stem cells. Because stem cells are the only cells capable of self-renewal they are critical for the maintenance of tissues. Inasmuch as stem cells can self-renew, it is an important property for the maintenance of tissues, but it is also a dangerous property. As described above, cancers can be defined as having their core cancer stem cells that undergo unregulated self-renewal, and it is the properties of cancer stem cells that determine the properties of invasion, metastases, and drug resistance.

The field of stem cell biology began at Stanford with the first isolation of a stem cell-the mouse HSC. This is the only cell that is functional in a bone marrow transplant, the procedure described above. At Stanford we pioneered the isolation of stem cells using the high speed cell sorters that were developed at Stanford, the biology of stem cells were worked out by physician scientists, and clinicians in the BMT unit were first to test their uses in breast cancer The Stanford group was the first to isolate human HSC’s at a company on the Stanford Industrial Park campus. At least three biotechnology companies were spun out of these efforts. Human brain stem cells were isolated by Stanford consultants and ex-trainees at one of these companies, and rodent peripheral nervous system stem cells were isolated by a former Stanford trainee at Caltech. But these are the only kinds of stem cells that have to date been isolated from adults. There are many tissues and organs that undergo degeneration that likely could be reversed by tissue or organ specific regenerative stem cells; these include liver, heart, blood vessels, muscle, skin, insulin-producing cells of the pancreas, bones, and in fact perhaps every tissue in the body.

There are two principal justifications for marrying stem cell biology with cancer biology and treatment. One is developing a comparative understanding of cancer stem cells and their normal tissue counterparts, and the other is the promise of stem cell-based therapy of a variety of cancers. As an example of the latter, prospectively isolated HSC’s from patients with metastatic breast cancer, from patients with a class of non Hodgkin’s lymphomas, and from patients with multiple myeloma are largely if not totally free of the cancers cells that contaminate bone marrow or mobilized peripheral blood, the usual source of transplantable tissues from these patients. Five years after a phase I/II clinical trial with stage IV widely metastatic breast cancer led by the Stanford Bone Marrow Transplant team, very promising results both in terms of freedom from cancer recurrence and overall survival were obtained (and need to be verified in large, phase III/IV trials). Thus stem cell biology and regenerative medicine have been from the beginning true translational research and medicine at Stanford.

One goal for the establishment of an Institute of Cancer/Stem Cell Biology is to take the lead in identifying and prospectively isolating some of these stem cells. In the isolation of human HSC and of human brain stem cells it was found that each of these stem cells when transplanted into the cognate organ in genetically immunodeficient mice, often newborns, could give rise to site appropriate engraftment, self-renewal, migration, and differentiation, so that the hematopoietic and brain tissues contained the appropriate human cells side by side with their mouse counterparts. This opens the possibility for stem cell biology to provide new tools for biologists and pre-clinical scientists to study the development, function, and repair of these organs and tissues. The same should be true with other prospectively isolated stem cells from other tissues and organs. The elucidation of developmental choices that stem cells take to make more of themselves by self renewal, or of defined daughter cells (blood cells of all types from HSC, brain cells of all types from neural stem cells), especially with microarrays, should open up new principles as to how genetic programs shift to stop the cells from being stem cells or progenitor cells to become functional cells in an organ or tissue. The full understanding of these important developmental steps should allow the discovery of master genes used normally for developmental processes. Application of these same methodologies to cancer stem cells vs their differentiated progeny that make up the majority of the tumor mass, and/or the normal or premalignant tissue stem cells from the primary tumor should be important in defining targets for drug therapies and for immune attack.

EMBRYONIC STEM CELLS AND THEIR POTENTIAL FOR STANFORD MEDICAL SCHOOL

At a very early stage of development the pre-implantation blastocyst contains a class of stem cells that have not committed to any particular developmental pathway. These are called pluripotent embryonic stem (ES) cells, and they can be cultured at that stage to produce ES cell lines from mouse or man. It shall be important to use human ES cells to understand the developmental processes by which they give rise to tissue committed stem and progenitor cells. Currently, the only human ES cells available come from excess blastocysts at in vitro fertilization clinics. But these cells represent only a tiny fraction of human genetic diversity. In mouse models the transfer of an adult body cell nucleus from a mouse that has a genetically inherited disease into a mouse egg that had its own nucleus removed gives rise to ES cells which recapitulate the development of the disease that had been inherited in the first mouse-the nucleus donor. This is true of the differentiating cells that can be produced in tissue culture, and even if the daughter tissue stem cells are transplanted into suitable mouse hosts. Genetically inherited diseases probably represent close to a majority of diseases we treat, and unfortunately the pathogeneses of these diseases* are still unclear. If nuclear transfer of human cells into human eggs to produce ES cell lines is allowed, this will provide powerful new tools to study directly human disease development using the methods described above.

All cancers are cells that have undergone a number of genetic alterations that were involved in the progression from normal cell to cancer cell. If a cancer stem cell nucleus works to produce ES cell lines, then the genetic changes that resulted in that rare cancer stem cell might do so in ES lines derived from them in vitro and in transplants of their tissue stem cells into immunodeficient mice. Research in mouse models and, if allowed, at several levels in early experiments with human cells, would be appropriate for the Stanford Institute of Cancer/Stem Cell Biology. In California nuclear transfer to produce human ES lines is not only allowed, but could be funded from state and private sources. The Institute plans to produce lines for Stanford community biomedical researchers. These could fuel much of our translational medical research for decades to come.

* Genetically inherited diseases include most heart and blood vessel diseases, both adult and juvenile (type 1) diabetes, most neurodegenerative diseases such as ALS (Lou Gehrig’s Disease), all autoimmune and allergic diseases, all congenital immunodeficiencies, the muscular dystrophies, and a host of other, largely common diseases.


STEPS TO ESTABLISH THE INSTITUTE AT STANFORD


We envision the Institute to be a geographically contiguous small unit initially that evolves into a free-standing Comprehensive Cancer/ Stem Cell Center over 3-5 years of preparation. The Institute will be the administrative unit that takes responsibility to establish and govern a NCI Comprehensive Cancer Center, and as such must have control of slots and space, reporting directly to the Medical School Dean. Although these will be Institute appointments, all faculty in the Institute will have appointments in departments of the medical school, and will be the result of co-recruitment efforts between the Institute and the relevant departments. Funding of the Institute will be via a combination of private fundraising and research grants. The Institute and the departments will share research grants indirect costs based on a formula established by the Medical School Dean, and the Institute will share in tuition fees again on a formula established by the Dean. Appointments to the Institute are not permanent, and shall be 5 years with renewal potential. Not all members of the Institute will have space in the Institute, although many investigators will have access to some bench space for collaborative research, the so-called hotel space (see below).

The Director of the Institute will be a decanal appointment, presumably for a 4 or 5 year term. There will also be 2 Deputy Directors, one for Scientific Affairs, the other for Clinical Investigation. A primary responsibility of the Clinical Investigation Director will be to chair a group to develop a plan and the grant application for the NCI Comprehensive Cancer Center at Stanford. Several administrative personnel will be required to serve this Directorate, and will be part of hard funding from the Medical School. The initial Directorate will be Irving Weissman as Director of the Institute, Karl Blume as Clinical Investigation Director, and we will establish a search to find the Director of Scientific Affairs. That director should be a nationally recognized Cancer or Stem Cell scientist of the highest reputation as a scientist and an administrator.

In addition to the Directorate, there will be an Executive Committee that shall advise and report to the Directorate. I propose that committee will include Judy Swain (Medicine), Ron Levy (Medical Oncology), Mike Cleary (Director of Cancer Research at the LPCH), Pat Brown (HHMI and Biochemistry), Ruel Nusse (HHMI and Developmental Biology), Joe Lipsick (Chair of the Program in Cancer Biology), Steve Galli (Chair of Pathology and Director of the Stanford Tissue Bank), Mike Clarke (new head of the Cancer Program at PAMRF), the to be named Clinical Director of the Cancer Center, and the senior recruit in Stem Cell Biology. The Executive Committee will meet to coordinate Institute efforts on a schedule of at least every other week.

The Executive Committee, likely working through the Cancer Biology Program, will establish a Cancer Research and Training track for Stanford Medical Students who choose that option; it will be coordinated into a 5 year MD option. Similar programs will be developed for Stem Cell Research and Training for MD students. The Institute will carry out fundraising to supplement MD/Ph.D. program slots for students in the Institute. The Institute will also be the home of the Cancer Biology Ph.D. and Postdoctoral programs, and will help establish Clinical Trials and Translation programs for selected MD residents and fellows.

SPACE ALLOTMENTS TO THE INSTITUTE


From the beginning there will be a core of internal investigators in the Institute who will have all or a majority of their benches in the Institute. These will include the Director (25 benches), the Deputy Director for Scientific Affairs (18-22 benches), a senior recruit in Stem Cell Biology (20 benches), and eventually at least 4-6 junior faculty level recruits total in cancer biology, stem cell biology, and cancer immunology, each of whom will have 10-15 benches. The timing of these recruitments will be phased with availability of space, funds, etc. If the Institute initially includes part of the 2nd floor of the Beckman Center and eventually an adjacent wing in CCSR, then Associates of the Institute at HHMI would include at least Nusse, Davis and Brown. Recruits could be internal candidates as well as external candidates, both of whom must be actual or potential leaders in their research areas.

In addition to the internal investigator core there will be reserved for UTL and MCL translational investigators initially 10, but eventually 20 benches with 2 desks per bench. The investigatorships will be granted for 2 years and awarded by the Executive Committee from applicants whose own research is collaborative with or complementary to the internal investigators. Potential applicants could include both translational and basic researchers in cancer biology and stem cell biology.

The eventual total size of the Institute could reach about 170 benches, and so space planning should include lab-specific benches, associated facilities for tissue culture, microscopy, arrays, etc. on a lab-specific basis, as well as general facilities including FACS, Imaging, Research Microscopy, Microarray Development, and perhaps GLP/GMP space. (The actual size of the Institute and its location will be developed over time, but one should consider the above estimate as an ideal to be achieved. Reality may intervene.) Of course, outside of the Institute floor there will have to be adequate mouse facilities, facilities for the preparation of transgenic animals, core facilities for protein and nucleic acid synthesis and sequencing, etc. There will need to be a major effort including logistical support for establishing relevant tissue/tumor banks, presumably in Pathology space. I favor research offices in research labs, but the Directorate will need additional administrative space, especially for the office of the Deputy Director for Clinical Investigation. Because there will be in addition to individual lab meetings a weekly floor meeting for scientific and clinical presentations, there will need to be access to conference facilities of a larger size (like Munzer) as well as smaller rooms on the floor. Of course, the ultimate goal is for the Institute to occupy a floor in a building, most likely the next increment at Stanford Medical School adjacent to the existing medical research facilities.

I believe the Institute will need an external advisory committee that meets either annually or every other year to advise the Dean and the Directorate of the quality of their efforts. Ideally it will be a small committee that could include a few non-Stanford members and 1 or 2 Stanford members.

I am concerned about Stanford-industrial collaborations, and will require access to a conflict of interest oversight group to guide the Institute and its membership when appropriate. I do not see the Institute as a testing ground for any therapies not initiated by Institute faculty research discoveries or interest. The oversight group will need to pay close attention to interactions between faculty and faculty-associated companies. I am not in favor of seeking extensive funding from commercial entities that require quid pro quo agreements or efforts.

I believe that the Institute of Cancer/Stem Cell Biology and Medicine represents a coherent and innovative effort that should be attractive to donors with interests in these areas. I expect that the Directorate and initial faculty will spend significant time with potential donors, as the establishment of a real and functional Institute first in reorganized space, and then in separate space could cost on the order of many tens of million dollars, and perhaps in excess of 100 million dollars. I do expect that these will be mainly enabling funds, as the Institute will eventually generate grant and royalty funds to cover much of its operations. However, it is essential that the Medical School and Center establish a line item budget from the University/Medical School to cover core salaries and expenses. The budget should include the required packages for recruitment of incremental faculty. The planning of the growth of the Institute will be phased, and in the first phase should provide for a minimum of 3 new recruitments, the 2 senior positions in cancer biology and embryonic stem cell biology, plus a junior recruit in either.

No Institute that will evolve a Comprehensive Cancer Center can do so without much more extensive interactions, collaborations, and clinical trials with a much larger group of medical school and university faculty, including medical care, epidemiology, biostatistics, etc. Certainly all clinical departments with cancer patients or that consult on cancer patients must be an integral part of that effort. It will be a major goal and milestone for the Institute to lay the groundwork for such a major effort in the first 3 years.