Dr. Theresa Deisher and Lawyer Samuel B. Casey

Plaintiff and Stem Cell Researcher Theresea Deisher Discusses the “Sherley vs Sebelius” Court Case

Wadman, M., 2011. The Crusader. “Theresa Deisher once shunned religion for science. Now, with renewed faith, she is fighting human-embryonic-stem-cell research in court.” Nature 470. P156-159.

Casey, S.B. 2011. A legal history of the federal funding ban on destructive human embryo research 1995 to the present. Jubilee Campaign, Law of Life Project. (provided by Mr. Samuel Casey).


TRANSCRIPT

00:00 Alright, well. Let me officially welcome you to my stem cell seminar course. These are all my students behind me. Thank you so much for taking this valuable time out of your schedules to join us. As you both know, my students read through a whole long list of many articles and related resources to learn a lot about your research, Dr. Deisher, and the court related stuff, that both of you were involved in. So, to get us going, I was wondering if you can both sort of tell us little bit about yourselves, the career path over the years. Ultimately, Dr. Deisher, what led you to getting involved in biotech, and using adult stem cells for your research. And then also, with the aid of Mr. Casey here, if you could describe a little bit the lawsuit that you brought against the federal government for funding embryonic stem cell research. Okay, so thank you very much again for your time.

01:10 So I think I’ll let Sam start with a little bit of his background, because mine will probably take us directly into the lawsuit, and then we might miss Sam’s background. So I’ll let you start briefly, Sam.

01:22 Well, like Dr. Deisher, I attended Stanford as an undergraduate. I went to the University of San Francisco law school. After law school I worked at the California Supreme Court. Then I went to work for an international law firm in San Francisco, ultimately becoming a partner in that firm. During a part of that time while I was an associate attorney, I took some time off and for about two years I was an assistant district attorney for the City and County of San Francisco. After my apprenticeship at Orrick Herrington ended, I became a law school dean, where I taught legal ethics, among other things. And then, in 1994 I became the Executive Director of the General Counsel of the Christian Legal Society. It was right during that period of time that the American Bar Association decided rather than being, that they would be in favor of abortion, and our society decided that we would be in favor of life. And so from 1994 until now, I’ve concerned myself with one of the central ethical questions this class has to address, and that is, when does a life begin, when do we become a human being? This case presents this matter in a very central way. And that’s, the kind of background I think, right now, and I’ll turn it back over to you, Theresa.

03:08 Alright, thank you Sam. Well as Sam mentioned, I did my undergraduate work at Stanford University, studying human biology and I did an honors thesis on thermoregulation while I was there. I had always been interested in science, particularly clinical science, although I did not want to be a physician and actually treat patients. So I went to graduate school at Stanford University as well and attained my PhD in Molecular and Cellular Physiology. Most of my work, or a large portion of my work as a student, found developing the use of beta blockers for heart failure, which is a very interesting and challenging topic because at that time, beta blockers were considered contraindicated by scientific dogma for use in heart failure. And it wasn’t until the mid to late 1990s that the use of beta blockers for heart failure was approved at which time it very rapidly became standard therapy, standard in care, for patients with heart failure. And it was actually fascinating to me in 2001, when I was working at Immunex a colleague of mine pointed out that some medical textbooks continue to list beta blockers as contraindicated for use in heart failure patients. So my graduate work focused on heart failure, and with my interest in developing clinical therapeutics to treat human disease, I chose to spend my career in commercial biotechnology. I worked at places like Genentech, Repligen, ZymoGenetics, Immunex and Amgen. And then in 2008 I formed AVM Biotechnology which is my own company, and we are dedicated to producing vaccines alternative to those vaccines that are currently produced using aborted fetal cells and are also focused on developing biological delivery agent for stem cell therapy. One of the hurdles in stem cell therapy, with any kind of stem cell, is the observation within humans and animals, that stem cells do not like to go to or stay in the target organ. And so our focus is on getting those stem cells to damaged organs and keeping them there, so that we can have the full effect of stem cell therapies that we are interested in. With that I think I’ll segue a little bit into the second part of the question, which is, I’m gonna read it. What led Dr. Sherley and I, with the aid of Mr. Casey, to file a lawsuit against the federal government for funding human embryonic stem cell research. Starting in about 2006 I actually had begun to publicly in local forums, Washington State, about the science and the economics of stem cell therapies, comparing various types of stem cell therapies including adult stem cells from bone marrow and pluripotency, which is embryonic stem cells or spermatogonial stem cells, or the types of stem cells we now call IPS. And the safety and economics issue that those cells have always had me concerned, as they had most if not all pharmaceutical and biotech scientists. So the pharmaceutical biotechnology industry was not, and largely still is not, working on these cells because of these issues. The dangers inherent to use of pluripotent stem cells and the economics associated with them. And a woman in the audience who had adopted a frozen embryo, she’s what’s called a snowflake mom, knew Sam from previous experience, and when this lawsuit was first contemplated, I actually gave Sam my name as an adult stem cell scientist who was opposed to embryonic stem cell research, and that’s how Sam and I got.

– Alright, fantastic.

– Sam.

07:50 No, that’s great, does anyone have any follow-up questions related to her career path or Mr. Casey’s career path? So to set the stage, for the rest of our discussion and all the student-generated questions, which were very specific on certain points, I thought it would be very nice to hear from you to sort of describe for us your legal argument against the NIH for really charging it to stop the funding of human embryonic stem cells. And I think that would just be a great way to lead in to all the student-generated questions. So thanks.

08:29 Well let me answer that question. The arguments are really quite simple. The first argument is, the plain meaning of the federal statute called the Dickey-Wicker Amendment which has been the law in the United States for the last 15 years, says that you cannot use federal funds to pay for research with embryos in which they are destroyed, discarded or knowingly subjected to risk of injury or death. And our second argument is, even if it was permissible to do this kind of federal funding, which the plain meaning of the law prohibits, you did not adopt the regulation that we now are using to fund embryonic stem cell research in a procedurally proper way. You violated the Administrative Procedures Act by virtue of the fact that you said that your mind was already made up before you even took public comment, and that the public comments that were received, over half a million comments, you ignored intentionally without even reading them, because you took a position that those were not the comments you wanted and therefore you don’t have to look at them. So those were our two basic legal arguments.

– Do you have any comments on that, Dr. Deisher?

10:15 No, the only comment I would add is just to clarify when Sam uses the word you, he’s referring to the NIH and Health and Human Services, not you as in students sitting in the class.

– I was worried there for a second. Does anyone have any followup–

– No obligation, you sitting in that class, have no obligation to read those 60-plus thousand comments. But the NIH and the HHS do.

– Okay, any quick follow ups there? Alright, we’re gonna proceed with our first student who is Nadine. So Nadine, if you could go right up here. Right in front of the computer so she can hear you well.

– I think he just–

– You think so? Are you okay with that? Alright, so Nadine is fine with your quick assessment and description of the Dickey-Wicker Amendment. Sam, did you want to elaborate more on that, or?

11:12 Well I think, I would like to elaborate a little bit because it’s important that the students understand, particularly Nadine, when she said in her question, how are you and doctors Deisher and Sherley interpreting the amendment? We are not actually doing any interpretation here. We’re doing simply reading it for its plain meaning and I just, because that is our argument I thought I would read it to you and then explain to you more importantly the two provisions that are referred to at the end that you otherwise wouldn’t know about, okay?

– Sounds good.

– So the law itself, which has been in the law since 1995, says as follows: none of the funds made available by this act may be used for research in which a human embryo or embryos are discarded, destroyed or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under 45 CFR 46.204and 498 of the Public Health Services Act. I just wanted to tell the students that these coded provisions that are referred to at the end are really very important from an ethical point of view. Because you see, it’s not Dr. Deisher or myself that are making a normative judgment here. The normative judgment was made my congress in defining the legal and ethical boundaries of research involving human subjects. And this was done, not just recently, but a long time ago. This is not something that originated with the Bush administration. It originated with the administration’s, it was the persistence actually, back in the ’70s, with senators Walter Mondale and a democrat from Minnesota, and Edward Kennedy, from your own state there, that resulted in the 1974 legislation, establishing what was called then the National Commission for Protection of the Subject. And this is really the big things this is about. This case is about how we’re going to treat all human subjects going forward. And what we’re trying to prevent is falling down a slippery slope where the very hard-won human subject regulations that came to us, not just in 1974, because of a lot of abuses that had occurred to African Americans and had occurred to disabled children in a hospital at Long Island. Go all the way back to World War II. Now as you students of history know that a number of governments, including the German Government, have experimented on human subjects against their will. So this led to a number of treaties, the Nuremberg treaty, the Helsinki treaty, and eventually arrived with this law in 1974 on human subjects, which led to the adoption of the federal regulations on human subjects, and I just wanted to read to you the provision that we’re most concerned about, Section 36.204. It says, human embryos may be involved in research if all of the following conditions are met. And the one condition is, the risk to the human embryo is caused solely by interventions or procedures that hold out the prospect of direct benefit for that human embryo. Or, if there is no such prospect of benefit, the risk to the embryo is not greater than minimal and the purpose of the research is the development of important biomedical research which cannot be obtained by other means. The other provision that I cited has pretty much the same thing. It basically says we should not treat embryos in research any differently than we treat an embryo we expect to be brought to full term in a pregnancy. Okay? So that’s the law that frames this entire law suit and it’s not a law that recently came up. It is a law that has been applied to many human subjects, including human embryos and just at this time what we have for the first time is an administration did not want to follow the law, and did not want to change the law. They just wanted to ignore the law. And since we didn’t want them to ignore the law, we commenced the litigation.

16:41 The only comment I would add is just to clarify when Sam uses the word you, he’s referring to the NIH and Health and Human Services, not you as in students sitting in the class, right.

– I was worried there for a second.

Question: Though PSCs-derived cells may have certain problematic aspects, from a purely scientific standpoint, do you think any unique benefits lie in the use of hPSCs research? Kim Chi Ngo

– You had no obligation, you sitting in that class had no obligation to read those 60-plus thousand comments. But the NIH and the HHS did, yes. 17:10 So Kim, your question is basically from a purely scientific point of view, do I find anything unique in our ability to work with pluripotent stem cells, and in that pluripotent stem cell category, we can include embryonic stem cells, reprogrammed stem cells or say spermatogonial stem cells. And, you know, actually if you take a look at it from a purely scientific point of view, and we look at a technology that we have which is called tetraploid complementation, scientifically, there are actually things that are very, let’s say cutting edge and cool, that we can do with pluripotent stem cells that we cannot do with other cells. And that really rests in the area of reproductive cloning. So what we can do is we can take two embryos and we use an electrical current to fuse them together and we form what’s called a tetraploid embryo. So two embryos now become one, so we have four sets of chromosomes, and that tetraploid embryo cannot give rise to an organism. So, it couldn’t make a baby mouse, couldn’t make a baby rat. But what it can do is it can make the placenta and once we’ve made that tetraploid embryo if we take a pluripotent cell, like an embryonic stem cell, or a reprogrammed cell, for instance we could take a cell from your skin, and reprogram it, and we mix it with that tetraploid embryo, we can give rise to an organism formed solely from that pluripotent cell. So for instance, if we were to use a reprogrammed stem cell, that would be a true genetic clone. And from a scientific point of view, I guess that’s actually very cool, exciting. We cannot do that with any other type of stem cell. We couldn’t take an adult cell and mix it, an adult stem cell, and mix it with that tetraploid embryo and generate a true genetic clone. So in that respect, this is very unique to those pluripotent cells. But that’s in relationship to reproductive cloning and not into treating human diseases with stem cell or regenerative medicine therapy. A couple of other things that we’ve been able to do with these technologies, which are exciting, cutting edge, is to take, we’ve been able to create mice that are genetically from two mothers and one father. So that’s two moms and one dad, and we’ve created baby mice. And we’ve also been able to take two fathers and create offspring from those fathers using these kinds of techniques. So two dads, no moms, right. And that’s again, scientifically pretty cool but that’s not helping patients. That’s not advancing the interests of human disease, and that area of reproduction is what truly is unique with these pluripotent stem cells. Now, not only is that not helping patients but that’s not the mandate of the NIH and those studies were funded by NIH funds. And if you just go on to the NIH website and read their mission statement, which I actually pulled up and I am gonna read parts of it, while the NIH mandate absolutely will require some underlying basic science, all of that science is to be geared towards advancing human health, right. So the goals of the agency are to foster fundamental creative discoveries, innovative research strategies and their applications as a basis for ultimately protecting and improving health. And if you go on and you read the rest of their mission statement their mission is all geared towards human health, not towards basic science purely for the sake of basic science, and certainly not for advancing purely reproductive types of technology. So I do thing scientifically that’s very cool but that’s not going to help patients who are waiting for treatments.

– So the pluripotent stem cells, regardless of how you get them, whether they’re from a reprogrammed stem cell or an embryo or a spermatogonial stem cell, do not differentiate in cell culture towards adult stem cells. They differentiate towards primitive fetal type cells at best. So for instance, when we want to look at studying oxygen carrying, right, and you look at driving cells towards a cell type that carries hemoglobin, you don’t want to be working with a pluripotent cell because fetal hemoglobin does not carry oxygen. You want to be working with cells that can be differentiated to cells that make adult-type hemoglobin. The same for the heart. The types of muscle cells that we have in our heart as an adult, the myosin is very different than the fetal myosin and the fetal myosin is not useful as far as functioning in an adult. So if you look at ALS, Lou Gehrig’s Syndrome, right, and we differentiate these cells towards nerve cells they’re not adult nerve cells, and the patients that we would be treating would be born patients. And so the research would not be directly applicable. And as a matter of fact, not only is there a problem that those cells don’t differentiate all the way down the pathway to the mature types of cells that we want, but when we study embryonic or fetal development, the science, the knowledge that we gain is rarely, if ever, applicable to the adult state. So for instance, during fetal development the liver is the major site of hematopoiesis. And so if we study fetal liver, we might learn something about fetal liver hematopoiesis, but in a born human, a born animal, post-natal, the liver does not do hematopoiesis, it’s a metabolic organ. So that’s not going to give us information about how to treat a born person. There are other examples of that. If we study heart development in mice, and we look at the TGF family, it’s a growth factor family, and we knock out that family, those mice have very small hearts. We call them hypoplastic hearts. And so we thought, as we were studying this in mice, and then if we give mice, during embryonic development, this same growth factor, they get really big hearts with lots of heart muscle, okay. So we thought, well, let’s use this growth factor in adults, to treat adults who’ve had a heart attack, have lost heart tissue, and need replacement heart muscle. And when we did that, in adult mice, instead of causing more heart cells to be generated or to grow, that growth factor actually caused scarring. So its actions in an adult were the opposite of its actions during embryonic and fetal development.

Question: What is your opinion on using technology to drive pluripotent stem cells down different differentiation pathways? Christina Wright

– 25:10 So the hopes from the researchers who have done that work and published that work, clearly are that we’ll be able to bypass the reprogramming and directly convert from one lineage to another. And the reason for that is that when we reprogram all the way back towards the embryonic state, the pluripotent state, we actually don’t get those cells to differentiate into the types of cells that we want to be working with. For a clinical point of view, when you look at treating a patient the less invasive a therapy that we can use, that’s always best for the patient, right. So if you tear your tendon and you can go through physical therapy and take anti-inflammatories and repair that tendon, that’s almost always preferable than going to surgery. So the less invasive we can be, the better that is for the patient. What I think will probably be most valuable as scientists work on this direct conversion, direct lineage conversion, might be to identify growth factors that can trigger that kind of conversion in situ in a patient. However, if you think about this from, let’s just say a sort of a common sense, logical approach and take the coolness of the direct conversion out, because that’s also very cool. It’s a fascinating, cutting edge technology. In all of our bodies, in all of our organs, we have resident stem cells and progenitor cells that are there in the right place, in the right location, so that they can be triggered when we need them to repair our tissue and exact a regenerative process. And this goes on, on a daily basis. Now, as we age, the viability and the number of those stem cells decline as part of the natural process of aging. What happens when we have a patient who’s had, say, a massive heart attack, is that the damage to their heart is so great that that natural process is not sufficient to restore the damaged area of their heart. And looking at this from a patient perspective, the best way to do that for the patient would be, if we could identify growth factors that would mobilize their endogenous stem cells and get them to divide more efficiently and bring about an endogenous repair. So for instance, when we were talking about treating cancer patients with radiation and chemotherapy, what we try to do is give them growth factors whenever we can that stimulate their resident hematopoietic stem cells to repair their blood system, before we would go and give them a transplant. The transplant is a second line when we have to give such intensive chemotherapy or radiation in the cases of, say, blood cancers, and we want to kill off all of their stem cells. But other than that, we try to use what are call chemokines. Drugs like Neupogen or Neulasta or Epogen. That’s a preferred way, and so when I think about taking this to the clinic, to patients, I would think first about, well let’s go after those growth factors that mobilize and work on the endogenous stem cells. And for those patients whom that’s not sufficient, let’s take the next step and let’s see if we can isolate stem cells from their own body, expand them in culture, and give them back to them. For patients where that doesn’t work, then we may need to go to the next step, which might be identifying factors that cause direct conversion. But that’s a little bit down in the process, I think, to think of it right now as the primary way to go in and treat a patient.

29:36 You were talking about conversion here as opposed to the, convert the cells and then to direct conversion to whatever cell type you need.

– 29:49 We don’t know very much about this direct conversion and we just learned from papers that have come out, there’s a question on this, that pluripotent cells, the reprogrammed stem cells, and also including embryonic stem cells, we’ve actually known this for a while, have chromosomal abnormalities. There are deletions, there are insertions, there are altered copy numbers of certain genes. So we don’t yet know what this direct conversion process would do to a cell when we are taking, basically a genetic retroviral type approach for direct conversion. What it might allow us to do is identify growth factors that would bring about that type of conversion, that wouldn’t cause genetic abnormalities in the cells.

Question: The article you gave us describes direct conversion from fibroblasts to hematopoietic cells. How significant do you anticipate direct conversion will be in the future (particularly in the case of cell types that are not closely related in terms of lineage)? Do you think we will one day be able to use this technique to bypass reprogramming to IPSC first? Christina Wright

– 30:48 I don’t think that there’s any evidence that has accumulated that shows that people treated with hematopoietic growth factors have marrow failure at a higher rate than the rest of the population. And certainly, not at any higher rate than someone who’s had a transplant. So that kind of brings into another area of ethics in the stem cell area. And when we talk about getting stem cells to treat patients, so let’s say we have a patient who’s 85 and they don’t have a lot of stem cells anymore and their stem cells are not as viable as they were when they were 10, one option that people are talking about is to take young children, up until the age of 10, they have very high numbers of stem cells circulating in their blood. And the suggestion is that we put these children under general anesthesia, and collect blood from them through a process called apheresis that would take about four to five hours, and collect these very multi-potent stem cells that have some interesting immune properties, in that they’re immune tolerant. They don’t illicit the immune rejections of some stem cells that we would think about using. And treating these patient with them. So when you talk about doing something like that, I think you are talking about putting that donor, that child at risk for marrow failure by taking too many of their stem cells. That’s certainly a risk that’s addressed when you have a sibling having stem cells taken from them so that they can be donated to a sick sibling. The donor sibling is put at risk of having marrow failure, and that’s from the extraction of their stem cells. Now, human ethics guidelines allow siblings to do that because of the great emotional benefit that their family derives. So there’s no medical benefit directly to them. It’s very difficult to imagine what kind of benefit would derive from a child or an unrelated child or young person donating stem cells to an older person. When we talk about giving patients endogenous chemokines or cytokines or giving them biologics to trigger this endogenous regenerative process, we actually don’t see that rate of risk of subsequent marrow failure. Now, we might not see it because these are patients who are sick. They might not have the normal lifespan that a person who doesn’t have cancer and doesn’t have to undergo these types of treatment has. But in general, no, that has not been a problem with using biologics to trigger endogenous processes. Certainly you could over-trigger a process if you did not give a safe dose. Those are things that we very carefully work out in animals before we get to treating humans, to treating a patient.

Question: In your “State of US stem cell field January 2011” presentation, you state that the US “leads the way as far as new therapies and medical treatments EXCEPT for adult stem cells outside of the cancer indications”. Could you describe some of the non-cancer related adult stem cell research going on internationally? How is it that they are pulling ahead of the United States? Do they have superior funding, or is it something else that is helping them to be so much more successful? Sean McGill

– 34:14 Stem cells, I actually pulled out a list of diseases that are in clinical trials. And predominantly outside of the US. We have osteopetrosis, we are looking at that in the US, a company Osiris is. Sickle-cell anemia, Type 1 diabetes, stroke, limb ischemia, heart attack, heart failure, lupus, multiple sclerosis, spinal cord injury, paralysis, Type 2 diabetes, Parkinson’s disease, non-healing bone fractures, Crohn’s disease, Sjogren’s disease, retinitis and blindness, epilepsy, cirrhosis, nephropathy, that’s kidney disease, myasthenia gravis, lipodystrophy, and cartilage repairs. So for instance, knee repairs. Rather than doing surgery, stem cell treatments and being investigated. Now, when you look at interventional clinical trials, and these are trials that are designed to treat or improve a patient’s outcome, not observational trials, and you search the NIH’s website, so the NIH maintains this website and worldwide people can register clinical trials on there as well. If anything it’s an under-representation of clinical trials outside of the US. Of all clinical trials, 52% are done in the United States, and in contrast, when we look at stem cell trials, not embryonic, only 26% are done in the United States. If we look at stem cell trials for cancer, the conventional stem cell indications, the discrepancy is even greater, where 72% of those clinical trials are done in the US, as opposed to 26% for stem cells for non-conventional indications. So why is that? The US is actually now just starting to do some clinical trials. We are eight to 10 years behind the rest of the world. For instance, in the fall of 2010 the first phase one completion of a bone marrow clinical trial for heart attack was announced, and in Germany they’re well underway on their phase three trials. They’re actually nearing completion of those phase three trials. Why the discrepancy? I think there are several reasons and it differs from country to country. So for instance, in Germany embryonic stem cell research is outlawed, banned, except under very few exceptions. In the US, embryonic stem cell research is not illegal. Embryonic stem cell research can be done. The legalities of this case relate only to NIH funding of the embryonic stem cell research. But in Germany, embryonic stem cell research is banned and so they have moved forward with adult stem cell therapies, which, whenever possible, would always and logically be the best treatment for the patient. And they’ve moved those forward. Germany has truly led the way and for many German scientists, who might want to do research on embryonic stem cells, they can’t, and so they’ve had to take I think the more difficult path forward, working with cells in the lab that are more difficult to grow. The end result though is that patients have benefited because those are the cells that benefit patients. In the UK, the story is different than the US but also very interesting. The UK really has not gotten caught up in the polarizing debates that we have in the United States. And the UK has gone forward with both adult stem cell research and clinical trials to treat patients, as well as the research using pluripotent, such as the embryonic stem cells that scientists consider pretty cool. So they make hybrid, they’ve approved making human-animal hybrids using pluripotent stem cell technology. And they never got caught up in these paralyzing debates that be became caught up with in the United States. Unfortunately, what happened in the United States, and I tell you this from hindsight, because while it was happening I really didn’t understand what was going on, and I certainly had no moral objection to embryonic stem cell research at that time. But what happened was, people objected morally to the use of embryonic stem cells. To the destruction of embryos for research. And so what scientists did, who wanted to go ahead and do embryonic stem cell research, was convince the public, convince our elected officials, and they were very effective in their arguments, that embryonic stem cells were the only way to move forward and to treat patients. So the focus in the United States, not just under the current administration, but under the Bush administration, has not been on adult stem cells. It has been on pluripotent stem cells because the embryonic stem cell proponents absolutely insisted that they had to have pluripotent cells to treat patients. Incidentally, it’s the worst kind of cell you would want to use to treat a patient, because they’re tumor-forming. People bought into it, and so focus in the US has been, well, let’s do it morally. Let’s get pluripotent cells that are morally gotten, so that we won’t have these moral issues. And unfortunately, it doesn’t matter whether a pluripotent cell is morally derived or not. It’s tumor-forming, it’s not safe to use in patients, and the economics of those stem cells are absolutely horrendous. We’re talking probably $500,000 price tags per patient. So the US has been paralyzed because of this effective publicity campaign that convinced everyone that we absolutely required pluripotency, which just is not the case. I might ask Sam to comment a little bit here on this issue as well, and for me, ethics, I think it is wrong to destroy a human embryo for research. And that’s, for me, unambiguous. But I think that there are ethics to human treatment that are also critically important, for instance price tag. So if taxpayer dollars are going to be used to develop therapies, they should be used to develop therapies that require taxpayer dollars. Bone marrow and other adult stem cells cannot be patented. So they will not get to patients if the federal government doesn’t fund them, and they will be affordable so that all of us could hope to use them. Pluripotent stem cells will not be like that, and we know that from price tag quotes from the makers of embryonic stem cells, Geron. You can also do a Cost-of-Good analysis and arrive at the same conclusion. So affordability, I think is a very important ethical consideration when we consider developing treatments.

– 42:10 Pluripotent cells, besides the embryonic stem cells, can be used to differentiate into these myriad of stem cells in the culture. So we have an alternative to the human embryonic stem cells and part of the ethical guidelines that Sam read earlier said that we could only do human subjects research when there was no alternative. Particularly when that research presents the danger of harm to the human subject, and in this case with the embryo, the embryo is destroyed. So that’s a clear danger of harm. So we have alternatives to study this process of cell culture differentiation. But the process of cell culture differentiation is a very artifactual process, and does not recapitulate the process of embryology or development that goes on in utero. And we cannot model that process, even if we try to construct scaffolds and three-dimensional structures, because we do not have a complete understanding of what goes on in utero. What we can do, with the techniques that we have, is we can label specific cells during embryogenesis, say in a mouse, and we can follow the fate of those cells as the mouse goes through embryogenesis and then into fetal development, and so we can understand what germinal layer, for instance, a cardiac stem cell, originally came from. Because we can go to the born mouse and we can isolate cardiac stem cells and if we labeled the mesodermal layer green, with a green fluorescent protein, then those cells will be green. And actually that has been done and we know that stem cells that reside in your heart originally came from the mesodermal layer. So we have the tools, the techniques, and the potential to study this in developing mice which will provide useful information about embryological development. The study of cells in a test tube is not going to provide additional information and certainly is not going to recapitulate the developmental process that goes on in a womb, in a uterus.

Question: Setting aside their potential for therapeutic applications, human embryonic stem cells can also help in the study of basic science. For example, how can a single cell develop into a hundreds of different cell types? How cancer or other disease states arise? Human embryonic stem cells represent the first real model of human developmental biology. What is your stand on the need to understand basic science, since in some cases, this research may also lead to a better understanding of adult stem cells are first generated? Gwen Nguyen Huynh

– 44:54 So what you’re suggesting is that by studying pluripotent cells differentiating in cell culture and studying the signal transduction pathways, we will gain an understanding of how that happens in situ, right, of how the embryonic stem cells travel through the developing embryo and fetus to their ultimate target organ, and the lineage commitment signals that they undergo. So we can’t do that in cell culture. We actually can with 2D confocal laser microscopy, follow the fate of labeled stem cells as they move through an animal during development. So we can follow those pathways. Can we follow signal transduction pathways? Well we can look at various knockout and other transgenic models and determine if that ultimate stem cell fate is impacted and learn about signal transduction. We can extract those cells at any time in that process and do high throughput screening, if we’re trying to identify small molecules that turn on certain kinases and whatnot. So we do actually have that capacity. We can study things in cell culture, as I mentioned, through using reprogrammed pluripotent cells and causing them to re-differentiate as far as they well. But again, that would be an artifactual process. I do not see any utility in studying human embryonic stem cells for their differentiation capacity as far as gaining insight or discovering new drugs that will help human patients, and as a matter of fact, our study of embryonic stem cells starting in 1980, has not identified any drug or any therapy that is actually helping patients by this type of discovery.

Question: Coming from a Catholic family myself, I am very familiar with specific church doctrine. Your argument against embryonic stem cell research seems to be one based on moral objections grounded in church teachings, which also oppose other forms of the embryo creation such as IVF. What is your stance on IVF? If embryonic stem cell research isn’t moral, wouldn’t that also extend to the source of the blastocysts creation in an IVF clinic? Should the leftover embryos from IVF be destroyed instead of being used for research? Rachael Stein

– 47:18 So I think you’ve raised a topic that the United States dove into this area of IVF without giving a lot of thought and without considering the potential end results. That we would have all of these embryos frozen and leftover and that’s because we took the approach that we would create 40 embryos at once for the convenience of the couple, freeze them, and if the technique didn’t work then you can go back to the freezer, you can pull out more of these embryos. It’s interesting, there are countries, particularly in Europe, who have laws about the number of embryos that can be created. So for instance only three can be created and they all have to be implanted. We did not grapple with this issue in the United States. So when we approached IVF, I think most people approached it from the point of view of great empathy towards people who did not have children when they wanted to have children. I know I have friends who’ve done IVF. I have a cousin who has done IVF. And they did not think about that issue or grapple with that issue, until they’d already had the procedure, and now they’re forced to think about this question. What do we do with those frozen embryos? So, what do we do with them as a society? A couple of things I think that need to be pointed out. One, those embryos do not belong to me, they do not belong to you, and they do not belong to the scientists who want to do embryonic stem cell research. They belong to the people who made the embryos. That’s something that we as a public and particularly scientists who want to do embryonic stem cell research seem to have forgotten. The next issue is that most of those people who have those embryos do not want to donate them for research. So I hear commonly people claiming, well, there’s 400,000 or 500,000 frozen embryos. They’ll all donate them for research. The actuality is that only approximately 11% of those embryos are available for donation, okay. Very few couples want to donate those embryos. What do we do with the rest of the 450,000 frozen embryos? Well first, I think as a nation, we need to think about regulating the IVF industry. We just had Octomom and that’s raised a lot of issues about the numbers that should be generated, the numbers that should be implanted. Embryo adoption is one alternative. I know people who’ve done that. I’m not sure exactly where I stand on the morals or ethics of that. I know for instance the church has not taken a stand on that, although they’re not encouraging it. And I think that that’s a question, there are some grave ethics with doing that. I’ve heard people suggest that they thaw them and allow the embryos to die naturally. That’s a natural death, that’s not actively killing or destroying the embryos. I don’t know, that’s not the first solution that comes to my mind. I think this is something that we need to turn our attention as a nation and we need to have some rules and regulations put in place going forward from now on so that we don’t have the continuing exasperation of this problem. And we need to have some discussion about what do we do with those embryos? How do we solve this dilemma that’s been created? I can’t give you an answer and I think it’s something that is gonna require a lot of careful and thoughtful discussions and we need to look around the world and see how other countries are solving these issues.

Question: We talked to a lot of researches who have devoted countless years to stem cell research, both embryonic and adult. Everyone who worked with adult stem cells said that while overall NIH funding has decreased for both fields, they do not believe that embryonic stem cell research has taken away from their funding. When looking at the NIH website, I see that out the total amount of stem cell funding from 2007-2012, 10% goes to human embryonic stem cell research, while 27% goes to human adult stem cell research, and an even larger 45% has gone to nonhuman, nonembryonic stem cell research. Do you think that this 10% of funding of human embryonic stem cell research truly represents a threat to the available funding for adult stem cells? More of a threat then that posed by nonhuman, nonembryonic stem cell research? Rachael Stein

– 51:31 So a couple of points to the question. You quoted adult stem cell scientists who had come and spoken to you and had said that both embryonic and adult stem cell funding has been declining. So my first comment is in looking at these numbers, I’m not sure why anyone would say that because funding in neither areas has declined, it’s actually gone up, and you’ll see that as you look at the statistics, particularly in the American Recovery and Reinvestment Act. We’ve had 187 million in 2009 and 112 million in 2010 added to stem cell research. So a couple of questions that we have with those numbers. Non-embryonic research also includes pluripotent stem cells and we have not been able to get a breakdown from the NIH on how the non-embryonic, whether human or non-human, is actually allocated to pluripotent stem cell research or adult stem cell research. So if you take out the non-embryonic, non-human, which is absolutely basic research, and you look only at non-embryonic human. So in 2010, we had 388 million that was spent in that area. We don’t know how much of that was pluripotent. I think we could take a good estimate with the widespread research into that area and say that probably the same amount that was allocated to embryonic human was allocated to pluripotent. And so what you find out is that you probably have $200 million really for adult human stem cell research, and how much of that is going to clinical trials? When we talk about these indication, there are 22 indications that are being helped worldwide using adult stem cells. To get those cells through clinical trials in the US requires up to $100 million in indication. $200 million is a drop in the bucket when we’re talking a need for 1-2 billion plus to get these treatments that are not patentable through clinical trials and to helping patients. Now embryonic and pluripotent stem cells are patentable and they’re heavily patented. If they were a good, clinical idea they would be funded by industry. Adult stem cells from the bone marrow, from blood, and from all endogenous sources are not patentable. They’re not going to be developed by industry and we absolutely require federal dollars to get these treatments to our loved ones. And less than 348 million, and it’s probably closer to 200 million if not less than that, we cannot get the breakdown from the NIH, is absolutely not sufficient to do that. And what’s more alarming is that the NIH, which is the organization who should be driving adult stem cells into clinics, setting the tone, leading the way, is not doing this, and when asked in a 2010, a September 2010 senate hearing, the director of the NIH said that they’re not supporting adult stem cell research because adult stem cells are not standard of care. Adult stem cells cannot become standard of care in the United States until the NIH supports them. So that’s the most ridiculous statement one could possibly make. It’s NIH support. They actually drive the programs. They are supposed to be showing leadership and without that leadership, without that support and without that funding, we are not gonna see these treatments for our loved ones.

55:35 Just one other comment, Rachel, it’s a very good question. We’re not really talking about a threat here, in the law. What we’re talking about simply is this. In order for a person to be allowed to go into federal court they must show that they have some injury. And in this case is was not Dr. Deisher or myself but it was the federal district court that said that adult stem cell researchers like Dr. Deisher and Dr. Sherley are being injured because they are experiencing more competition, more competition. We’re not talking about a threat, we’re talking about more competition and that’s all we’re talking about.

56:21 Well and I think Sam, that’s also an issue many people don’t understand. Is the difference between the standing and the suit. So, that gives a standing to sue. The lawsuit is not about that at all.

56:36 Right. People think that we have to prove in the lawsuit that there’s some threat to Dr. Deisher or Dr. Sherley’s research. That’s not what the lawsuit is about. The lawsuit is simply about whether federal law bans or does not ban the federal funding of research on human embryonic stem cells.

– 56:59 So the adult stem cell clinical trials that are furthest along and that are showing the greatest efficacy in humans, are using stem cells that are found in a fraction of cells from people’s bone marrow or blood that we call the mononuclear cell fraction. That fraction has been used for transplant for over 50 years. So it’s public knowledge, one cannot patent that. And within that fraction are multiple types of stem cells. We’re not purifying a certain type of stem cell. We’re not using any new or novel process to get the mononuclear cell fraction. It’s a well established, publicly available process. So no one can patent that. For instance, if a a company went and funded clinical trials to use the mononuclear cell fraction, that fraction looks like it’s best for the patients. It’s working best in patients. And they spent $100 million to get through all the hurdles at the FDA, they could never charge for that therapy. Any doctor can get it, take a bone marrow aspirate, get the mononuclear cell fraction and inject it. They’re not gonna call up the company and say hey, I just injected my patient with some bone marrow mononuclear cells for liver regeneration, how much should I send you? That’s why I say they’re not patentable. Embryonic stem cells are patented and the University of Wisconsin holds some very valuable patents. Actually, people are suing now to have those patents invalidated. Geron is the one who licensed those patents. So Geron owns the embryonic stem cells that they’re developing. There are many other groups that have patents on embryonic stem cells. Pluripotent stem cells are patented. Various derivatives of these embryonic stem cells and pluripotent stem cells are patented. And what that means is that they can refuse to allow other people to use those cells for therapy if they don’t pay a price for them. So actually they’ll develop a product. One cannot do that with the mononuclear cell fraction because it’s in the public domain. There are patents on adult stem cells. They are isolated, purified, selected adult stem cells. The adult stem cells in the mononuclear cell fraction which have gone furthest along in clinic, and which are showing the greatest results and promise, cannot be patented. The mononuclear cell fraction from your bone marrow cannot be patented. Stem cells used to treat paralysis and spinal cord injury, what they do is they take a scraping from your olfactory passage, from your nasal passage, and they isolate nerve stem cells that are contained there and inject them into the spinal cord of the paralyzed patient. The results are absolutely fantastic. You cannot patent that. Anyone can go in and take a nasal scraping and isolate the stem cells in the mononuclear cell fraction from that scraping, does that make sense?

– 1:00:29 Embryonic stem cells were first developed in a lab and before publicized that was patented. So it was not in the public domain. And they reduced that to practice by actually making the embryonic stem cells. So a patent is a novel discovery that’s not in the public domain, and embryonic stem cells were not. Now, if someone comes up with a new method to make embryonic stem cells they could patent that. If someone came up with a brand new method to patent how you get mononuclear cell fractions that could patent that. But since everyone knows how to do it, it’s unlikely anyone would spend the money for that. Does that make sense? There are people trying to come up with special devices to clean up the mononuclear cell fraction. This is one way they’re trying to fund the clinical trials in Germany, because these fraction are not patentable. And they’re trying to get private investors to come in and fund this, and they’ve considered a part of the procedure proprietary. There are attempts to get around this because it’s so problematic to get funding if you can’t get government or federal funding. People are trying to be creative. How can we get the mononuclear cell fraction to patients? How can we get that funding?

Question: A poll by Charlton Research Company in 2005 asking whether Americans support embryonic stem cell research states that 58% of the population either strongly favor or somewhat favor stem cell research while only 29% strongly or somewhat oppose it. The court stated that “a stop order was consistent with the public interest” however how can this be true when there seems to be a majority in support of embryonic stem cell research? Sylvie Bae

– 1:01:53 33% are in favor of federal funding, 57% were opposed. So the other thing I want to add that is interesting about these polls, and it’s fascinating to me when I see this stem cell issue presented by the media. When the media presents stem cell stories, like some of these touching animal stories, military dogs treated with stem cells walking again. They drop the word adult. Whenever they do cover stem cell advances early in the US, or maybe some of the advances from other countries, they drop the word adult. And none of these studies ever ask people if they know about adult stem cells, if they know that there’s a difference between adult and embryonic stem cells, and I have found most people do not know that there is an alternative to embryonic stem cells. When they think stem cell, they think embryonic. And so, when you think of this in that light, that poll is even more surprising. That so few people support embryonic stem cell research when they think that’s the only thing available for them. If they knew about adult stem cell research, fewer people would be in support of this. And I think as Americans wake up, we have waiting lists. 50,000 US citizens waiting, to get into the German trials for heart attack, using adult stem cells. When the taxpayers find out how their money’s been used, what we cannot get, what our dogs can get, but we cannot get, I think they’re gonna be a little bit upset at how the stem cell issue has been presented to them. They haven’t been given full disclosure. And so those numbers are very suspect until a poll actually comes out with full disclosure. So if you said to an American, hey, would you rather have embryonic stem cell treatment that is gonna form tumors. It’s gonna be hundreds of thousands of dollars. You’re gonna have issues of immune rejection and you’re gonna have to take immune suppressants for your entire lifetime, which puts you at risk of osteoporosis, Type 1 diabetes and hypertension. Or would you like adult stem cell treatments where we use your own stem cells. It’s affordable. There’s no issues of immune rejection. And there’s no morals involved. What do you think people would choose? The numbers would be overwhelmingly in favor of adult stem cells. No one’s ever done that poll.

Question: To end our discussion today can you please comment on how you might proceed should your law suit be successful, should the court side with the federal government in favor of hESC research, or should congress pass legislation that would supersede your case? Michael Barresi

– 1:04:52 Regardless of the outcome of the case, whether it’s in favor or against us, I will continue to do what I do, which is to work to educate people. Educate leaders, community leaders. Educate legislators, on the utility of adult stem cells and the absolute need for federal funding in order to advance these treatments into clinical trials. And I will continue to do what I’ve done, which is, hope that by that education I can help America become a country where we’re thinking about patients again, and not an obsession with pluripotent stem cells. And that’s a problem from both sides, right. Pro-life and the other side. This obsession with pluripotency which has given us embryonic stem cells and reprogrammed stem cells, has not given us something to treat our patients. And so my focus will stay the same, regardless of the outcome of the court case. Is to let people know and educate legislators so that they can make these funds available so that we can help our family and our friends who have diseases.

1:06:10 Incidentally, there is a bill in congress, as there was in the last congress, to get beyond the debate and just provide more funding for this research that is so necessary for patient care. So everybody, no matter where they are in the debate, ought to support the Adult Stem Cell Enhancement Act. The wheels of justice grind very slowly, Michael, and I do not doubt we will still have a case next year. Congratulations to all your students for getting into this so deeply. You did a very good job.