Message from the Outgoing (Gone) Director
Just a few days ago, the mantle of Director of the Institute for Stem Cell Biology and Regenerative Medicine officially passed from me to Ravi Majeti, who is in my view a superb choice by the Dean and Search Committee. So I thought I’d use this space to look back to when the institute began, to let you know about some projects I hoped to do using stem cells, and as the title of this piece indicates, tell you why some of these are the unfinished business that I concluded would not go forward if I stayed on as director.
In 2002, I accepted the suggestion from Dean Phil Pizzo that it was time to help bring stem cell biology into the fore, and to see whether we could use what we learned to understand cancer and adult-onset diseases better, as well as to test whether adult tissue stem cells—primarily blood-forming stem cells (HSC)—could be used more generally as therapeutics. At the same time, Koichi Akashi and I isolated human acute myelogenous leukemia stem cells and showed that they were distinct from human HSC, and so there was a chance we could target the leukemia without targeting normal blood formation by HSC.
In the 1990s SyStemix, a company I co-founded, discovered that our method to prospectively isolate HSC from women with metastatic breast cancer massively depleted breast cancer cells that contaminated the bone marrow and mobilized peripheral blood. Even in the earliest days, we were able to use cancer-free these blood stem cells (HSC) to rescue the blood forming system of women with metastatic breast cancer following near-lethal, high-dose combination chemotherapy. The HSC rapidly regenerated their blood cells, and their progression-free survival was much better than patients with metastatic breast cancer in general, or those rescued with their own unpurified mobilized peripheral blood. We had already shown, in mice, that purified HSC, lacking contaminating T cells, could also regenerate the blood systems of lethally irradiated mice not only of the same strain, but also completely unrelated strains without causing graft vs host disease from mature T cells present in bone marrow or blood. The recipients had both donor and recipient blood cells, and were specifically tolerant of tissue grafts such as skin or heart from either donor or recipient strain, but not of tissue from those unrelated to the HSC donor or irradiated recipient.
So we were starting the institute with knowledge that HSC could be not only therapeutic, but also could be a platform for regenerative medicine and transplantation tolerance of HSC donor organs, tissues, and tissue stem cells. At that time, as head of a US National Academies of Science, Engineering, and Medicine panel, I had proposed in a journal article that embryonic stem (ES) cells, or similar induced pluripotent, ES-like cells called iPS cells, could be used to study tissue and organ development. In addition, I proposed that ES cells and iPS cells from patients with heritable genetic diseases could be used to test (in laboratories) how the variant genes caused their disease. Finally, perhaps HSC and tissue stem cells could be derived from these pluripotent cell lines for regenerative medicine.
Given this background, Dean Pizzo appointed me to be director of both the Stanford Cancer Center and the ISCBRM. He and I agreed that all new faculty would be jointly recruited with relevant departments, and that this could help cross-fertilize basic science disciplines, and also be the focal point for developing clinical translations from stem cells with clinical departments. We would establish a program to share the cancer and stem cell fields across the university far beyond the number of billets we had been allotted.
But at the same time, an executive order by President George W. Bush led to deep restrictions on US government funding of research on embryonic and fetal tissue stem cells, and a ban on producing new pluripotent stem cell lines. California parents of children with type 1 diabetes and children of patients with senile dementias turned to many of us in the stem cell field for help. I joined with Robert Klein and others to help establish California Proposition 71 as an initiative. Klein would fashion a legal and political path forward, and I would explain the science that would be lost without NIH support of this new science, as well as propose that the agency could fund research through early translation to avoid the “valley of death” that kills so many promising therapies. The initiative passed in 2004, and was cleared of judicial challenges to begin funding stem cell science by late 2006. The Stanford ISCBRM had a chance to compete for funds available for construction, for faculty research support, and to establish graduate programs in the stem cell and regenerative medicine fields.
Earlier in my career, I was able to take advantage of the then-mandated, 5-year curriculum at Stanford Medical School to work with Jim Gowans at the Dunn School of Pathology at Oxford University, financially supported by my other mentor, Henry Kaplan. When Gowans stepped down from his research group to become the head of the UK Medical Research Council (their NIH), he was asked how he would direct UK medical research by funding, and he told reporters and members of the House of Commons that he wouldn’t dictate direction, but instead would hold a mirror up to UK scientists and tell them to seek their directions from themselves. I took that advice seriously, and with some of the early recruits to our cancer and stem cell faculties—Mike Longaker, Renee Reijo Pera, Mike Clarke—helped write a successful building grant to the California Institute of Regenerative Medicine established by Proposition 71. And with President John Hennessey and Dean Pizzo, as well as the Office of Development, we helped raise nearly 3x matching funds from Lorry Lokey, Anonymous Donors, John Scully and others to fund SIM1, the Lorry I. Lokey Stem Cell Research Building. Karl Blume and I had applied for and received an NCI Cancer Center grant, and I also became director of the Ludwig Center for Cancer Stem Cell Research.
We were ready to hire faculty of unquestioned accomplishments in the stem cell fields, and to show them and junior recruits a mirror.
We were established in 2002 and began our labs at a facility off Arastradero Road until the Lokey building was ready. In my view, the ISCBRM has succeeded in opening many new fields by stem cell related discovery science, and unquestionably has also succeeded in several arenas of translation of these discoveries. All investigators, whether billeted or voted into the faculty, in my view have risen to, or were already recognized for, their eminence in their field.
But the translation of purified HSC for transplantation into metastatic breast cancer patients and as a platform for regenerative medicine has not moved as fast as I had envisioned. The company that purchased SyStemix pivoted several years later to emphasize other properties they had acquired, reminding me that the primary function of a company—any company—is to make a profit, not to cure disease or ease suffering. While my part of writing Proposition 71 was to enable CIRM to fund the discovery phase of stem cell research to and through the clinical proof of principle---the valley of death—at academic and research institutions in California, HSC somehow got lumped into the usual practice of bone marrow transplantation, and although gene editing of blood forming cells was funded, purified HSC were not.
When my own team discovered that cancer cells expressed upregulated levels of cell surface ‘don’t eat me’ signals such as CD47, we were funded by CIRM to take our mouse antibodies that block CD47 to and through phase I clinical trials. Our CIRM grant covered all preclinical developmental phases up to filing with the FDA (and the UK equivalent) an Initial New Drug application. To do so, Ravi Majeti and I assembled a team at Stanford, including a clinical research organization, without pressure to raise venture capital. We produced, identified and humanized a CD47-blocking antibody. Giving that blocking antibody to immune-deficient mice transplanted with primary human leukemias or lymphomas activated mouse ‘eating’ cells called macrophages to remove the tumors. At that point, Stanford decided to put up the intellectual property for licensing, and we competed for the license for part of our discoveries. We formed a biotech that advanced the trials to show benefit in early stage (phase 1/2) clinical trials, and it was acquired by a large pharmaceutical company. So our idea that a nonprofit funding agency could allow the discoverers of a field to lead it into early phase successful clinical trials was proven.
But what about women with metastatic breast cancer, and patients with inherited or acquired blood disorders and autoimmune-prone blood forming systems, both of whom we showed decades ago could benefit from pure rather than cancer- or T cell-contaminated HSC transplants? That was completely unfinished business. I decided that licensing the HSC field exclusively to a company prematurely led to barriers that, against expectations, actually blocked clinical translation. Over the past few years, I’ve been able to retrieve the hybridomas that make the antibodies we used to purify HSC from all blood and bone marrow contaminating cells, and I insisted that we’d carry out trials in a not-for-profit setting. The time I spent to do so, while managing several bureaucracies (albeit inefficiently), has helped persuade me that I cannot pursue these trials and also be director of an institute, at least at my age.
Even more profound barriers have arisen to block the HSC rescue of metastatic breast cancer patients after high-dose chemotherapy as we did in the 1990s: While SyStemix was doing this trial, the bone marrow transplant units were allowed by medical journals to call their transplants stem cell transplants, while continuing to use unpurified mobilized blood. As I approached experts in these units, they were unaware of our published long-term results from the SyStemix early phase trial, in which metastatic breast cancer patients with widespread cancer spread (rescued with their own cancer-free HSC) had a median survival time of ten years vs. the two years provided by the then standard of care. This two-year median survival is now only marginally better for some breast cancer subtypes. Equally importantly, in that trial, 33% of the women rescued from high dose chemotherapy with cancer free HSC are still alive today, a quarter of a century later. None of the women with metastatic breast cancer who were rescued with mobilized blood or treated with the standard of care at the time survived. When I approached experts in BMT or breast cancer oncology, or even some of the MDs I trained, the universal response was that 1) HSC transplants don’t improve survival of metastatic breast cancer patients, and 2) much better therapies are now available or are in trials for the metastatic breast cancer patients. Neither is true to the extent that they get even close to the survival levels we achieved.
The field of purified, T cell-free (not just reduced) HSC allotransplants to avoid graft vs. host disease in the attempt to replace defective or absent blood systems with healthy HSC has not advanced to the point of using purified HSC anywhere, even here. And moving that into induction of tolerance to HSC donor organ, tissue, or tissue (e.g., brain) stem cell transplants also has not advanced as I had planned and hoped. In every stage of my efforts to carry out the vision I proposed over 30 years ago, there are entrenched groups that are opposed, and bureaucracies that seem designed to block what should be their mission. So when I last messaged that “I ain’t done yet,” when I said that to complete this transition I had to step down as director, you now know my reasons. I am resolute in moving these translations forward.
I am confident that the ISCBRM will continue to advance stem cell science and medicine with Ravi Majeti in the leadership. To friends of the institute and our faculty and students, you are in good hands.