Nature Reports Stem Cells
Published online: 13 August 2009 | doi:10.1038/stemcells.2009.107
The new president of the ISSCR says that to move forward, the field must think outside the box
Irving Weissman directs Stanford University's Stem Cell Biology and Regenerative Medicine Institute in California. His laboratory was the first to identify and isolate blood-forming stem cells from mice. He has developed techniques to track haematopoietic stem cells and their progeny and used both to study the development of healthy blood and immune systems as well as the progression of malignancies like leukaemia. This summer, he became the seventh president of the International Society for Stem Cell Research (ISSCR).
What do you hope to accomplish as ISSCR president?
One of the things is to look at the continuum of stem cell therapies and to decide a way to do what the American Cancer Society has done for unproven therapies: that is, we need to list unproven therapies. To do so we need to get from the practitioners of potentially unproven therapies a statement that would allow anyone to look at the peer-reviewed papers from independent investigators that give the evidence that the putative stem cell therapy should work for the disease specified. In addition, they need to provide their IRB [institutional review board] approvals for the human subjects in their trials or therapies and a similar document for their local FDA [Food and Drug Administration]-equivalent approval of their approaches, their therapeutics and their clinical trials. If they lack peer-reviewed demonstrations of the discovery behind the therapies and IRB and FDA-type approvals, I would recommend that they are put on a list of unproven therapies.
You should look at every paper as an opportunity to design an experiment.
The next goal is to make real our claim that we are an international society. I won't be the first president to do so, and I certainly won't be the last, but one mechanism we are looking at is to hold more than the annual large meeting for the field and have regional meetings that are cosponsored by ISSCR. We'd have on the order of four of those a year in Europe, South America and other sites where there are fewer stem cell scientists and clinicians. By getting into that situation we will get to know the world leaders not only in the science but also in the governments that regulate science, so this will be a two-way traffic of information.
Are you worried about being sued if you put up a list of unproven therapies?
Of course. And we do have legal counsel, but I'm not so afraid that we won't do it.
I can't tell you how many phone calls and letters I get every week that start of with "I have blank untreatable condition and I'm going to blank for stem cell therapies. Tell me it's okay.' And of course I can't tell them it's okay. It's time to have a professional body do it.
Another thing that I hope to do is to clean up the language of what is a stem cell therapy.
Currently, anybody that does a bone marrow transplant, when they publish it or they advertise it, they call it a stem cell therapy, but of course they are not pure stem cell therapies. The other cells that are in the transplant of bone marrow or mobilized blood can be dangerous. So it's very important that we get a language that says, "Here's actually what you're transplanting".
Why is it so hard to move science into medicine?
First, most scientists don't know what medicine is. They don't know what whole-body physiology or pathology [is]. So they tend to be, at least at the beginning, unrealistic in their expectations. Second, there are not many people trained to do clinical trials.
And you have to realize that things don't make it into clinical, commercial therapies without a lot of money.
What advice do you have for people entering the field?
First, get into a lab as soon as you can. There's a great difference between what you learn didactically and how knowledge is really obtained, which is through experiments.
To the people who are starting to read papers: read the title of the papers in your field ? don't look at anything else: decide what was the hypothesis they were testing, and immediately after say to yourself, how would I do it? Think about the experiments and especially the controls you'd have to do. And then look to see if they did your experiment. You should look at every paper as an opportunity to design an experiment.
In order for us to define ourselves we must go through the work of defining a graduate program in the subject. I want the ISSCR to be a sort of clearing house for best practices, not to dictate, but to provide advice.
You told me earlier you hope to see more dedicated degree programs in stem cells.
In order for us to define ourselves we must go through the work of defining a graduate program in the subject. I want the ISSCR to be a sort of clearing house for best practices, not to dictate, but to provide advice. This is really saying to the stem cell community [that] this is a field. It is not a branch of developmental biology; it's not a branch of plastic surgery; it's not a branch of genetics.
What's the biggest obstacle that the stem cell community has overcome in the last 50 years?
Fifty years ago, there was essentially no direct evidence that any cell existed as a stem cell. There was a hint that you could explain haematopoiesis by donor-derived cells, but it was not clear that the cell was a stem cell. Forty years ago, the work of Till and McCulloch1 pointed the way, but it wasn't the isolation of the cells.
So in the past 50 years it is the ability to isolate stem cells prospectively from tissues and organs.
And then there was the demonstration in mice by Gail Martin2 and independently by Martin Evans3 and others that you could make pluripotent stem cell lines from the inner cell mass of preimplantation blastocysts. Others followed to show one could genetically modify them and do many, many types of studies that could not be done before. That's the path. It became a field, and Yamanaka's incredible experiment [genetic engineering to make adult somatic cells reprogrammed to pluripotency] caps off that that phase of the field.
What technical barriers must the stem cell field overcome?
The technology is at the center of being able to do stem cell biology. If you think about it, stem cells are rare cells. When we first isolated blood-forming cells, we only could do it because Stanford [University] was the place that developed fluorescent-activated cell sorters. So that was one part of the technology. If you want to know what's different biochemically between stem cells and daughter progenitors, you're working with thousands of cells, at most tens of thousands of cells, trying to apply biochemical techniques that usually need a minimum of tens of millions of cells. That means you need bioengineers and physicists to miniaturize the biochemistry so that it can be valid and reproducible and meaningful using only small numbers of cells. There needs to be more and more interactions between engineering, physical sciences, computing science, imaging sciences and of course within the stem cell community itself.
We need to have people who understand the field not only from the view of developmental genetics or classical clinical practice, but who understand development and regeneration from the view of stem cell biology.
What nontechnical barriers must the stem cell field overcome?
We need to have people who understand the field not only from the view of developmental genetics or classical clinical practice, but who understand development and regeneration from the view of stem cell biology. So I think scientifically, we have to be able to get people out of the box of thinking of development and regeneration in the way they have classically done so before.
For going from labs to commercial and clinical products, we need to understand how it could be a commercially viable business. Stem cells, unlike drugs or proteins, self-renew and differentiate in a fashion regulated by the body; they regenerate systems for life from a single therapy. If you're going to deliver stem cells for lifetime therapy, the cost of goods and reasonable profit has to be priced with the knowledge it replaces daily therapies like insulin or blood transfusions.
One of the greatest experiments I know of is being done in California. The California Institute of Regenerative Medicine [CIRM] sent out last year an RFA [request for applications] for disease teams to take stem cells and/or therapies derived from them through preclinical right up to the filing of the first IND [investigational new drug application] with the FDA. That's an area that was formerly funded only by companies. Now universities and other nonprofit institutions need to learn what companies do, including rigorous manufacturing practices [GMP] and FDA-compliant regulatory documents.
How do you feel about the new National Institutes of Health (NIH) guidelines?
I think it's also my own responsibility to get clarification from President Obama and his advisors [on] what he really meant when he said that politics and ideology will not provide the basis for scientific policy decisions. And that's because the very first test of his March speech lifting the Bush-era stem cell research funding bans, and his subsequent declaration before the assembled members of the National Academy of Sciences, was the NIH guidelines, which banned funding [of] pluripotent stem cells derived from somatic cell nuclear transfer [SCNT], even if SCNT cell derivation was done safely, feasibly, and gave human pluripotent stem cell lines derived from the tissues of patients with genetic diseases that accurately replicated the pathogenesis of the diseases. The iPS [induced pluripotent stem cell] method of Yamanaka is promising as a way of doing this, but as yet does not have the demonstrations that the reprogrammed cells are as good at reproducing the diseases using mice as donors and recipients as does the SCNT method. As an MD, I sure don't want to gamble the future of this field and the health of future patients that one way or another will be the best.
One issue is that everyone points their fingers elsewhere. If you get through to someone in the Obama administration, they say, "We didn't tell NIH to do the ban". If you get to people in the NIH, they say, "It's above my pay scale". It is in the interest of the entire government-funded scientific establishment, not just the stem cell science subset, that experimental precedents and reason, not political or religious or fixed ideology, determines our science policy and funding. So if Obama could clarify his intentions when he said, to paraphrase, "I'm not going to put politics and ideology in front of scientific policy", it would be important.
So my goal personally is not to let up until they leave open the possibility that if useful lines are derived under SCNT and made under ethical and legal methods that they should be fundable just as well.
You're implying that there has been politics keeping SCNT and parthenotes away from funding?
Well of course there is. Even the head of the NIH, Dr Kington, when he was asked why funding of SCNT was banned, said that the people aren't ready for it. That's not science. It could be that the American people are not ready for it, but he had no thorough or scientific way of testing that opinion.
How did you become a scientist?
I was born and brought up in Great Falls, Montana. My father and grandfather were fur traders and junk dealers. I was about to be the first in those generations to get an education. When I was ten years old I read a book called Microbe Hunters, which was about the lives of people like Robert Koch and Louis Pasteur. It was incredibly exciting to me.
The greatest pleasure is being the scientist who is doing the science, not looking over your shoulder to see if you can make it go faster.
I really looked for a way to do research after that. I should say I was never a straight A student. When I was about 16, I met Ernst Eichwald at the local hospital. Ernst was German, his father was Jewish. During the beginnings of WWII Ernst belonged to a student group against the Nazis; somebody in his group was arrested, and without going home he crossed the border. He came to Harvard, he was on faculty there; he came to Utah, was on faculty there for awhile. He got sick of academic politics and decided to run the pathology service at the Montana Deaconess Hospital. Very early he handed me a paper [George Snell's paper on histocompatibility genes] as if I could read it, and I told him that I didn't understand the first word! He spent a whole Saturday with me, and we covered just that one paper.
I realized that the language of science substitutes Greek and Latin terms for plain English, that it was a way to keep people out of the field. He didn't need to say histocompatibility. He could say "tissue-transplantation compatibility", but I also realized I could understand it. Thanks to the freedom Dr Eichwald gave me, I began designing my own experiments at 16.
What's the best advice you've ever received as a scientist?
Probably the best advice came from the late Donald Michie; he was both an immunologist and one of the founders of the field of artificial intelligence. He told me in 1962 that when he began a project, he quit reading the literature. He'd work at his project until it was done, and then he'd read the literature so he could write up what he was doing. What that meant to me was that the greatest pleasure is being the scientist who is doing the science, not looking over your shoulder to see if you can make it go faster.
The best example of a scientist was Sir James Gowan, who taught me that really purifying the cell could change immunology from something that was largely phenomenological to something that was quantitative and understandable.
A third was Harry Kaplan, who said it should be you the scientist who pushes to translate your discoveries to the clinic. Find a way to do it; don't wait for someone else to pick it up.
1. Till, J.E., McCulloch, E.A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213?222 (1961). | Article | PubMed | ISI | ChemPort |
2. Martin. G. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634?7638 (1981). | Article | PubMed | ChemPort |
3. Evans. M. & Kaufman, M. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154?156 (1981). | Article | PubMed | ISI | ChemPort |
1. Monya Baker is editor of Nature Reports Stem Cells.
Published online: 13 August 2009 | doi:10.1038/stemcells.2009.107
The new president of the ISSCR says that to move forward, the field must think outside the box
Irving Weissman directs Stanford University's Stem Cell Biology and Regenerative Medicine Institute in California. His laboratory was the first to identify and isolate blood-forming stem cells from mice. He has developed techniques to track haematopoietic stem cells and their progeny and used both to study the development of healthy blood and immune systems as well as the progression of malignancies like leukaemia. This summer, he became the seventh president of the International Society for Stem Cell Research (ISSCR).
What do you hope to accomplish as ISSCR president?
One of the things is to look at the continuum of stem cell therapies and to decide a way to do what the American Cancer Society has done for unproven therapies: that is, we need to list unproven therapies. To do so we need to get from the practitioners of potentially unproven therapies a statement that would allow anyone to look at the peer-reviewed papers from independent investigators that give the evidence that the putative stem cell therapy should work for the disease specified. In addition, they need to provide their IRB [institutional review board] approvals for the human subjects in their trials or therapies and a similar document for their local FDA [Food and Drug Administration]-equivalent approval of their approaches, their therapeutics and their clinical trials. If they lack peer-reviewed demonstrations of the discovery behind the therapies and IRB and FDA-type approvals, I would recommend that they are put on a list of unproven therapies.
You should look at every paper as an opportunity to design an experiment.
The next goal is to make real our claim that we are an international society. I won't be the first president to do so, and I certainly won't be the last, but one mechanism we are looking at is to hold more than the annual large meeting for the field and have regional meetings that are cosponsored by ISSCR. We'd have on the order of four of those a year in Europe, South America and other sites where there are fewer stem cell scientists and clinicians. By getting into that situation we will get to know the world leaders not only in the science but also in the governments that regulate science, so this will be a two-way traffic of information.
Are you worried about being sued if you put up a list of unproven therapies?
Of course. And we do have legal counsel, but I'm not so afraid that we won't do it.
I can't tell you how many phone calls and letters I get every week that start of with "I have blank untreatable condition and I'm going to blank for stem cell therapies. Tell me it's okay.' And of course I can't tell them it's okay. It's time to have a professional body do it.
Another thing that I hope to do is to clean up the language of what is a stem cell therapy.
Currently, anybody that does a bone marrow transplant, when they publish it or they advertise it, they call it a stem cell therapy, but of course they are not pure stem cell therapies. The other cells that are in the transplant of bone marrow or mobilized blood can be dangerous. So it's very important that we get a language that says, "Here's actually what you're transplanting".
Why is it so hard to move science into medicine?
First, most scientists don't know what medicine is. They don't know what whole-body physiology or pathology [is]. So they tend to be, at least at the beginning, unrealistic in their expectations. Second, there are not many people trained to do clinical trials.
And you have to realize that things don't make it into clinical, commercial therapies without a lot of money.
What advice do you have for people entering the field?
First, get into a lab as soon as you can. There's a great difference between what you learn didactically and how knowledge is really obtained, which is through experiments.
To the people who are starting to read papers: read the title of the papers in your field ? don't look at anything else: decide what was the hypothesis they were testing, and immediately after say to yourself, how would I do it? Think about the experiments and especially the controls you'd have to do. And then look to see if they did your experiment. You should look at every paper as an opportunity to design an experiment.
In order for us to define ourselves we must go through the work of defining a graduate program in the subject. I want the ISSCR to be a sort of clearing house for best practices, not to dictate, but to provide advice.
You told me earlier you hope to see more dedicated degree programs in stem cells.
In order for us to define ourselves we must go through the work of defining a graduate program in the subject. I want the ISSCR to be a sort of clearing house for best practices, not to dictate, but to provide advice. This is really saying to the stem cell community [that] this is a field. It is not a branch of developmental biology; it's not a branch of plastic surgery; it's not a branch of genetics.
What's the biggest obstacle that the stem cell community has overcome in the last 50 years?
Fifty years ago, there was essentially no direct evidence that any cell existed as a stem cell. There was a hint that you could explain haematopoiesis by donor-derived cells, but it was not clear that the cell was a stem cell. Forty years ago, the work of Till and McCulloch1 pointed the way, but it wasn't the isolation of the cells.
So in the past 50 years it is the ability to isolate stem cells prospectively from tissues and organs.
And then there was the demonstration in mice by Gail Martin2 and independently by Martin Evans3 and others that you could make pluripotent stem cell lines from the inner cell mass of preimplantation blastocysts. Others followed to show one could genetically modify them and do many, many types of studies that could not be done before. That's the path. It became a field, and Yamanaka's incredible experiment [genetic engineering to make adult somatic cells reprogrammed to pluripotency] caps off that that phase of the field.
What technical barriers must the stem cell field overcome?
The technology is at the center of being able to do stem cell biology. If you think about it, stem cells are rare cells. When we first isolated blood-forming cells, we only could do it because Stanford [University] was the place that developed fluorescent-activated cell sorters. So that was one part of the technology. If you want to know what's different biochemically between stem cells and daughter progenitors, you're working with thousands of cells, at most tens of thousands of cells, trying to apply biochemical techniques that usually need a minimum of tens of millions of cells. That means you need bioengineers and physicists to miniaturize the biochemistry so that it can be valid and reproducible and meaningful using only small numbers of cells. There needs to be more and more interactions between engineering, physical sciences, computing science, imaging sciences and of course within the stem cell community itself.
We need to have people who understand the field not only from the view of developmental genetics or classical clinical practice, but who understand development and regeneration from the view of stem cell biology.
What nontechnical barriers must the stem cell field overcome?
We need to have people who understand the field not only from the view of developmental genetics or classical clinical practice, but who understand development and regeneration from the view of stem cell biology. So I think scientifically, we have to be able to get people out of the box of thinking of development and regeneration in the way they have classically done so before.
For going from labs to commercial and clinical products, we need to understand how it could be a commercially viable business. Stem cells, unlike drugs or proteins, self-renew and differentiate in a fashion regulated by the body; they regenerate systems for life from a single therapy. If you're going to deliver stem cells for lifetime therapy, the cost of goods and reasonable profit has to be priced with the knowledge it replaces daily therapies like insulin or blood transfusions.
One of the greatest experiments I know of is being done in California. The California Institute of Regenerative Medicine [CIRM] sent out last year an RFA [request for applications] for disease teams to take stem cells and/or therapies derived from them through preclinical right up to the filing of the first IND [investigational new drug application] with the FDA. That's an area that was formerly funded only by companies. Now universities and other nonprofit institutions need to learn what companies do, including rigorous manufacturing practices [GMP] and FDA-compliant regulatory documents.
How do you feel about the new National Institutes of Health (NIH) guidelines?
I think it's also my own responsibility to get clarification from President Obama and his advisors [on] what he really meant when he said that politics and ideology will not provide the basis for scientific policy decisions. And that's because the very first test of his March speech lifting the Bush-era stem cell research funding bans, and his subsequent declaration before the assembled members of the National Academy of Sciences, was the NIH guidelines, which banned funding [of] pluripotent stem cells derived from somatic cell nuclear transfer [SCNT], even if SCNT cell derivation was done safely, feasibly, and gave human pluripotent stem cell lines derived from the tissues of patients with genetic diseases that accurately replicated the pathogenesis of the diseases. The iPS [induced pluripotent stem cell] method of Yamanaka is promising as a way of doing this, but as yet does not have the demonstrations that the reprogrammed cells are as good at reproducing the diseases using mice as donors and recipients as does the SCNT method. As an MD, I sure don't want to gamble the future of this field and the health of future patients that one way or another will be the best.
One issue is that everyone points their fingers elsewhere. If you get through to someone in the Obama administration, they say, "We didn't tell NIH to do the ban". If you get to people in the NIH, they say, "It's above my pay scale". It is in the interest of the entire government-funded scientific establishment, not just the stem cell science subset, that experimental precedents and reason, not political or religious or fixed ideology, determines our science policy and funding. So if Obama could clarify his intentions when he said, to paraphrase, "I'm not going to put politics and ideology in front of scientific policy", it would be important.
So my goal personally is not to let up until they leave open the possibility that if useful lines are derived under SCNT and made under ethical and legal methods that they should be fundable just as well.
You're implying that there has been politics keeping SCNT and parthenotes away from funding?
Well of course there is. Even the head of the NIH, Dr Kington, when he was asked why funding of SCNT was banned, said that the people aren't ready for it. That's not science. It could be that the American people are not ready for it, but he had no thorough or scientific way of testing that opinion.
How did you become a scientist?
I was born and brought up in Great Falls, Montana. My father and grandfather were fur traders and junk dealers. I was about to be the first in those generations to get an education. When I was ten years old I read a book called Microbe Hunters, which was about the lives of people like Robert Koch and Louis Pasteur. It was incredibly exciting to me.
The greatest pleasure is being the scientist who is doing the science, not looking over your shoulder to see if you can make it go faster.
I really looked for a way to do research after that. I should say I was never a straight A student. When I was about 16, I met Ernst Eichwald at the local hospital. Ernst was German, his father was Jewish. During the beginnings of WWII Ernst belonged to a student group against the Nazis; somebody in his group was arrested, and without going home he crossed the border. He came to Harvard, he was on faculty there; he came to Utah, was on faculty there for awhile. He got sick of academic politics and decided to run the pathology service at the Montana Deaconess Hospital. Very early he handed me a paper [George Snell's paper on histocompatibility genes] as if I could read it, and I told him that I didn't understand the first word! He spent a whole Saturday with me, and we covered just that one paper.
I realized that the language of science substitutes Greek and Latin terms for plain English, that it was a way to keep people out of the field. He didn't need to say histocompatibility. He could say "tissue-transplantation compatibility", but I also realized I could understand it. Thanks to the freedom Dr Eichwald gave me, I began designing my own experiments at 16.
What's the best advice you've ever received as a scientist?
Probably the best advice came from the late Donald Michie; he was both an immunologist and one of the founders of the field of artificial intelligence. He told me in 1962 that when he began a project, he quit reading the literature. He'd work at his project until it was done, and then he'd read the literature so he could write up what he was doing. What that meant to me was that the greatest pleasure is being the scientist who is doing the science, not looking over your shoulder to see if you can make it go faster.
The best example of a scientist was Sir James Gowan, who taught me that really purifying the cell could change immunology from something that was largely phenomenological to something that was quantitative and understandable.
A third was Harry Kaplan, who said it should be you the scientist who pushes to translate your discoveries to the clinic. Find a way to do it; don't wait for someone else to pick it up.
1. Till, J.E., McCulloch, E.A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213?222 (1961). | Article | PubMed | ISI | ChemPort |
2. Martin. G. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634?7638 (1981). | Article | PubMed | ChemPort |
3. Evans. M. & Kaufman, M. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154?156 (1981). | Article | PubMed | ISI | ChemPort |
1. Monya Baker is editor of Nature Reports Stem Cells.