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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.
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