According to the FDA your body is a drug and we get to regulate it

The Food and Drug Agency (FDA) serves a very necessary purpose. If you remember history at all, you will recall the Massengill Corporation and their elixir of sulfanilamide that was spiked with diethylene glycol that killed over one hundred people, most of whom were children. Were it not for the herculean efforts of FDA field agents who collected the containers of sulfanilamide elixir, far more people would have died. Also, were it not for an error made in the labeling of the elixir, FDA fields agents would have had no authority to confiscate the poisonous containers. This tragedy led to resolutions in the US House and Senate in November of 1937 to ask Secretary of Agriculture Henry A. Wallace to report on the Elixir Sulfanilamide deaths. Wallace’s report, the content of which became widely publicized, was submitted to the Secretary of the Senate, Edwin A. Halsey, on Thanksgiving morning, November 25, 1937,

Wallace’s report revealed the extent of known elixir-related casualties in the United States, and the chronology of events that led to them. It cataloged the elixir recipe, the lack of testing before marketing, the wide distribution of elixir shipments, the evasive words of Massengill’s first recall telegrams, and the FDA’s yeoman efforts to confiscate the poisonous medicine—often in the face of considerable obstruction. This led to the passage of the 1938 Food, Drug and Cosmetic Act, which empowered the FDA to determine if patented drugs were safe for consumption before they were marketed.   The 1938 Food, Drug, and Cosmetic Act also shored up many of the shortcomings of the Pure Food and Drug Act of 1906.  For example, the old law did not provide for the government regulation of cosmetics, since all language relevant to such regulation was dropped from the proposed law in 1900.  Secondly, the 1906 law did not adequately cover the regulation of patented medicines, since the definition of dangerous drugs was outdated, given the pharmaceutical innovations of the early 20th century.  Third, language concerning the definition of food adulteration was vague and ambiguous; and the law also provided no control over false advertising.

However, the FDA has presently become too highly enamored of itself and has tried to grab power simply for the sake of power.  For example, in November, 2011 the FDA rejected attempts by Genentech to gain approval for its anti-cancer drug Avastin (bevacizumab) for breast cancer.  Avastin had already bee approved for colorectal, lung, brain and kidney cancers.  With respect to breast cancer, Avastin was first approved on the basis of progression-free survival, or PFS, the time women live without their disease spreading or worsening.  In 2009 Genentech applied to upgrade the approval status of Avastin to full approval.  They had some new studies that showed PFS improvements, but they were less statistically robust than the initial trials.  The FDA withdrew Avastin’s breast cancer approval last year—leading to Genentech’s unprecedented appeal and a two-day trial in June, 2011.  In her decision denying that appeal, FDA Commissioner Margaret Hamburg conceded that there are groups of “super responders” who experience dramatic improvements when treated with Avastin.  However, she then made the extraordinary claim that such patients don’t count because “it is not possible to determine if there is some subset of patients within the population as a whole that may have had a meaningful benefit.” Dr. Hamburg also conceded that Avastin may produce better results when used with different chemotherapies, but that those prospects haven’t been sufficiently tested.  The denial is about FDA reasserting its political culture of delay and control, rigging the re-review against Avastin and emphasizing safety risks.  Mind you, the risks of Avastin are real.  However they are also well-understood and manageable, especially during end-stage oncology where there are no good options.  The FDA’s real goal was to send a warning to the rest of the drug industry about who is in charge of drug development.

If you need further evidence of the FDA’s political power grab, take a look at the Regenexx-C treatment.  This protocol uses bone marrow mesenchymal stem cells (BM-MSCs) that have aspirated from the top of the pelvis and cultured for about 6 weeks, and are precisely applied to the areas of need in joints, bones, tendons and ligaments.  Because the BM-MSCs are cultured and then reintroduced into the patient’s body, the FDA claims that they are a drug and should be subjected to the FDA’s political culture of delay and control (read about 12 years of bureaucratic nonsense and millions of dollars).  Regenexx replied that our body is ours to regulate, and the question should end there.  However, according to the FDA, in court documents has now said that since it regulates chemical drugs, and since all living things produce chemicals, then all living things fall under FDA jurisdiction.  No you read that right, these people actually believe that.  There is a very good summary of the legal issues here.

This nut-ball statement by FDA came in recent court filings in response to a judge’s order slapped on the agency in the Regenexx case.   The judge pointed out that Congress only authorized FDA to consider chemicals which had “chemical action” as a drug.  The judge also asked the obvious question: “How do you get from chemicals=drugs to cells=drugs?  She gave the FDA 30 days to respond and denied their motions.

The FDA’s response is a remarkable example of political hubris, and every American should find this troubling.  According to the FDA’s own internal expert: “When living cells interact with their environment to mediate repair of and/or regenerate damaged tissue, they do so by chemical action.”

So here’s the FDA’s “logic:  1) Congress said that chemicals are drugs; 2) Cells produce chemicals and are made of chemicals; 3) Therefore, cell are drugs.

To which all God’s people said, “huh?”  If you are confused, join the party.  We know what drugs are.  They are compounds that interact with bodily processes to achieve a particular physiological outcome.  That outcome could be bringing some physiological read outs back within normal ranges (blood pressure medicines, heart medicines, diuretics, etc.), relieving pain, killing invading microorganisms, and so on.  However, cells taken from your body and expanded and re-introduced you body are not drugs, unless they are derivatized so that they not longer resemble their original state.  Increasing the numbers of those cells does not make them a drug.  All the legal hand-waving in the world does not change that.  The FDA’s argument is radical at best and asinine at worse.

The real danger in all this is that the FDA is completely serious about their views.  Look at the note from the FDA here.  Fat-based stem cells are a drug according to the FDA.  It doesn’t matter that they came from your body and were only isolated, expanded and reintroduced into your body.  The FDA wants to regulate it even though they do not regulate in vitro fertilization.  Certainly human eggs and “minimally manipulated” when they are fertilized, but the FDA does not regulate them.  Why not?  Nether should they regulate fat-based stem cells.

In order to balance this, I should add that there are non-drug things that the FDA regulates and should regulate.  For example medical software that delivers medical imagery and radiation dosage information are regulated.  If these devices were not properly regulated, we might have another Therac-25 incident.  Therac-25 was a radiation therapy machine and it was involved in at least six accidents between 1985 and 1987 that consisted of patients receiving massive overdoses of radiation (approximately 100 times the intended dose).  Also autotransfusion of blood is regulated by the FDA even though one’s own blood is used.  In this case the blood is pre-donated before a those procedures that cause large blood loss (aneurysm, total joint replacements and spinal surgeries).  Blood is collected by a device commonly known as the Cell Saver.  Since the blood is collected by a specialized device and then reintroduced during surgery, it makes sense to regulate autotransfusion.  Likewise, normal hormones that are given for menopause are regulated by the FDA and they should be.  However, regulation of your own cells is ridiculous and FDA should know better.  The agency is still working within a regulatory mindset that is appropriate to the 1960s.  It’s time to upgrade the FDA and stop this vast encroachment of government over own bodies.

Co-culturing Immune Cells with Umbilical Cord Stem Cells Reverses Type 1 Diabetes in a Small Study

Type 1 diabetes results from an inability to make sufficient quantities of insulin. Insulin is made by specific cells in the pancreatic islets (also known as the islet of Langerhans). Most type 1 diabetics have suffered destruction of their pancreatic beta cells. Beta cell destruction can result from physical trauma to the pancreas, which causes the digestive enzymes of the pancreas to destroy the beta cells. For example, pancreatitis, pancreatic surgery, or certain industrial chemicals can cause diabetes. Also, particular drugs can also cause temporary diabetes, such as corticosteroids, beta blockers, and phenytoin. Rare genetic disorders (Klinefelter syndrome, Huntington’s chorea, Wolfram syndrome, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes, and others) and hormonal disorders (acromegaly, Cushing syndrome, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma) also increase the risk for diabetes.

Additionally, viral infections of pancreas can cause the immune response to destroy pancreatic cells, and this wipes out enough beta cells to cause the onset of type 1 diabetes. The coxsackievirus family of viruses is a family of enteric viruses that are cause infections that are sometimes associated with the onset of type 1 diabetes, as are mumps and congenital rubella. In most cases, genetic factors cause the immune system to view the pancreatic beta cells as foreign invaders, and the beta cells are attacked and destroyed. Researchers have found at least 18 genetic loci that are designated IDDM1 – IDDM18 that are related to type 1 diabetes. The IDDM1 region contains the “HLA genes” that encode proteins called “major histocompatibility complex”. HLA genes encode cell-surface proteins that act as “bar codes” for the immune system. When cells have the proper bar codes on their cell surfaces, the immune system recognizes those cells as being a part of the body in which they reside, and the immune system leaves them alone. Any cells that do not have the right bar codes are attacked and destroyed, which is known as the “graft versus host response.” Therefore, it is fair to say that HLA genes affect the immune response. New advances in genetic research are identifying other genetic components of type 1 diabetes. Other chromosomes and genes continue to be identified.

A recent paper attempts to cure type 1 diabetes by using umbilical cord stem cells. Umbilical cord stem cells (UCSCs) have the ability to greatly calm down the immune system. UCSCs secrete a wide variety of molecules that prevent immune cells from reacting to and destroying other cells, and also have many cell surface proteins that bind to the surfaces of immune cells and put them to sleep (see Abdi et al., Diabetes 2008;57:1759-67 & Aguayo-Mazzucato C. and Bonner-Weir S, Nature Reviews Endocrinology 2010;6:726-36).

Animal experiments have shown that co-culturing UCSCs with circulating immune cells alters the immune response against pancreatic beta cells and greatly increases the ability of the animal to regulate blood glucose levels (Zhao et al., PLoS ONE 2009;4:e4226). The UCSCs seem to “re-educate” the immune cells so that they do not recognize the pancreatic islets are foreign anymore. Therefore, Yong Zhao and his colleagues in Theodore Mazzone’s laboratory at the University of Chicago, IL, and collaborators at the General Hospital of Jinan Military Command, Shandong, China, used human UCSCs to re-educate immune cells in human type 1 diabetic patients.  See here for this paper.

To do this, they circulated the blood of each patient through a close-loop system that separated the immune cells (lymphocytes) from whole blood. Thee lymphocytes were then co-cultured with UCSCs for 2-3 hours and then returned to the patients.

The results were remarkable. Six patients in group A, who all had some residual beta cell function showed successively improved insulin production 12-24 weeks after treatment. They also showed a reduced need for insulin shots, and overall improvement of their fasting blood glucose levels. Six patients in group B, who had no residual beta cell function, showed increased production of insulin production 12 week after treatment. This is an incredible finding because those without beta cells essentially grew new ones that were not attacked by the immune system. The group B group also saw successively reduced requirements for injected insulin. The patients in the control, whose immune cells did not undergo re-education by UCSCs showed no improvement.

Furthermore, the patients whose immune cells were re-educated by the UCSCs, did not experience any adverse effects. This procedure seems to be quite safe and feasible.

There is a word of caution here. These patients must be followed over several years to establish that the re-education of the lymphocytes is maintained over time. Also, this study is quite small and despite the amazing results, a larger study is needed. All the same, this is an incredible result that reverses type 1 diabetes, and even though caution is needed, embryonic stem cells were not required to do this.

Direct Conversion of Skin Cells into Neural Precursor Cells

Cell reprogramming involves the use of genetic engineering techniques to push cells into a new cell type WITHOUT passing those cells through the embryonic stage. Several different studies have shown that transferring particular genes into specific cell types or removing distinct genes from them can drive them to become other cell types. There are several published examples of transdifferentiation:
1) In 1989, Weintraub and colleagues overexpressed a gene called MyoD in cultured fibroblasts to convert them into muscle cells. Unfortunately, this conversion was incomplete and required continuous expression of MyoD (Weintraub H et al., Proc. Natl. Acad. Sci. USA 1989;86:5434-8).
2) Tachibana and colleagues overexpressed a gene called MITF to transdifferentiate fibroblasts into pigment-synthesizing melanocytes (Tachibana et al., Nature Genetics 1996;14:50-4).
3) Xie and others overexpressed genes that encode two transcription factors (C/EBP and PU.1) in B cells, T cells, and fibroblasts into transdifferentiated them into cells that looked like macrophages (Xie et al., Cell 2004;117:663-76).
4) Deletion of a gene called Pax5 can transdifferentiate antibody-secreting B lymphocytes into common lymphoid progenitors, macrophages and antigen-presenting T cells (Cobaleda C, Jochum W, and Busslinger M. Nature 2007;449:473-7).
5) Doug Melton’s laboratory at Harvard University transferred a specific combination of three transcription factor genes (Ngn3, which is also known as Neurog3, Pdx1 and Mafa), into pancreatic exocrine cells (those cells that produce and secrete digestive enzymes).  This reprogrammed the cells into insulin-secreting beta cells (Qiao Zhou et a., In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 2008;455, 627-632).
6) Deletion of a gene that encodes a transcription factor called Foxl2 converts granulosa and thecal cells (found in the ovary) into Sertoli and Leydig cells, which are found in the testes (Uhlenhaut et al., Cell 2009;139:1130-42).
7) Thomas Vierbuchen and colleagues in the laboratory of Marius Wernig at Sanford University School of Medicine used a combination of three genes (Asc1, Brn2 and Myt1l) to convert fibroblasts into functional neurons (Vierbuchen et al., Nature 2010;463:1035-42).
8) In 2010, Ieda and co-workers in the laboratory of Deepak Srivastava have used ectopic expression of three genes (GATA4, MEF2C, and TBX5) to directly convert heart-based fibroblasts into heart muscle cells. These reprogrammed cells did not require expression of the introduced transgenes (Ieda et al., Cell 2010;142:375-86).

A recent study has extended these results even further. In an earlier study, Marius Wernig’s lab at Stanford University School of Medicine showed that skin fibroblasts can be transdifferentiated into functional neurons. Wernig’s lab has followed up in a paper that was published online on Jan. 30, 2012 in the Proceedings of the National Academy of Sciences.

In this study, Wernig’s lab used mouse skin cells and directly transdifferentiated them into the three main parts of the nervous system. These transdifferentiation experiments show that pluripotency (a term that describes the ability of stem cells to become nearly any cell in the body) is NOT necessary for a cell to transform from one cell type to another. Together, these results raise the possibility that embryonic stem cell research and induced pluripotency could be superseded by a more direct way of generating specific types of cells for therapy or research.

In the new study, Wernig and his colleagues converted fibroblasts in to neural precursor cells (NPCs). NPCs have the capacity to differentiate into neurons, but they can also become the two other main cell types in the nervous system: astrocytes and oligodendrocytes. In addition to their greater versatility, newly derived NPCs offer another advantage over neurons because they can be cultivated to large numbers in the laboratory — a feature critical for their long-term usefulness in transplantation or drug screening..

The switch from skin cells to NPCs occurred with high efficiency and only took about three weeks after the addition of just three transcription factors. Wernig’s research group used a different combination of three transcription factors than those used to generate mature neurons (Brn2, Sox2 and FoxG1) than was used to generate mature neurons. This combination of transcription factors drove the fibroblasts to transdifferentiate into “tripotent” NPCs that have the ability to form neurons and astrocytes but also into oligodendrocyte. The finding implies that it may one day be possible to generate a variety of neural-system cells for transplantation that would perfectly match a human patient.

The lab’s previous success with transdifferentiation experiments led Wernig to wonder if his lab could convert skin-based fibroblasts into the more-versatile NPCs. To do so, Wernig’s research group infected embryonic mouse skin cells — a commonly used laboratory cell line — with a virus that encoded 11 transcription factors known to be expressed at high levels in NPCs. Just over three weeks later, about 10 percent of the cells began to look and act like NPCs.

They then winnowed down the original panel of 11 transcription factors to just three that still converted fibroblasts to NPCs. Three of these genes (Brn2, Sox2 and FoxG1; in contrast, the conversion of skin cells directly to functional neurons requires the transcription factors Brn2, Ascl1 and Myt1l.) drove fibroblasts to differentiate into NPCs that were “tripotential” – that is, the NPCs could differentiate into not just neurons and astrocytes, but also oligodendrocytes, which make myelin that insulates nerve fibers and allows them to effectively transmit nerve impulses. Wernig’s lab workers dubbed the newly converted population “induced neural precursor cells,” or iNPCs.

In vitro experiments showed that the astrocytes, neurons and oligodendrocytes made from iNPCs expressed the same genes and morphologically resembled that they resembled astrocytes, neurons and oligodendrocytes found in living organisms. However, Wernig’s lab wanted to know how iNPCs would react when transplanted into an animal. Therefore, they injected them into the brains of newborn laboratory mice that were bred to lack the ability to myelinate neurons. After 10 weeks, they found that the injected cells had differentiated into oligodendroytes and had begun to coat the animals’ neurons with myelin.

Marius Wernig, MD, assistant professor of pathology and a member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, said: “We are thrilled about the prospects for potential medical use of these cells. We’ve shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons. This is important because the mouse model we used mimics that of a human genetic brain disease. However, more work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy.”

Pediatric cardiologist Deepak Srivastava, MD, who was not involved in these studies noted, “Dr. Wernig’s demonstration that fibroblasts can be converted into functional nerve cells opens the door to consider new ways to regenerate damaged neurons using cells surrounding the area of injury. It also suggests that we may be able to transdifferentiate cells into other cell types.” Srivastava is the director of cardiovascular research at the Gladstone Institutes at the University of California-San Francisco. In 2010, Srivastava’s lab transdifferentiated mouse heart fibroblasts into beating heart muscle cells.

The first author of this article, Ernesto Lujan, added: “Direct conversion has a number of advantages. It occurs with relatively high efficiency and it generates a fairly homogenous population of cells. In contrast, cells derived from iPS cells must be carefully screened to eliminate any remaining pluripotent cells or cells that can differentiate into different lineages.” Pluripotent cells can cause cancers when transplanted into animals or humans.

“Not only do these cells appear functional in the laboratory, they also seem to be able to integrate appropriately in an in vivo animal model,” said Lujan.

Wernig’s group is now working to replicate the work with skin-based fibroblasts from adult mice and humans, but Lujan emphasized that more research is needed before any human transplantation experiments could be conducted. Until that time, the ability to quickly and efficiently generate NPCs that can be grown in the laboratory to mass quantities and maintained over time will be valuable in disease and drug-targeting studies.

“In addition to direct therapeutic application, these cells may be very useful to study human diseases in a laboratory dish or even following transplantation into a developing rodent brain,” said Wernig.

SCIPIO Clinical Trial Shows Remarkable Promise

Scipio Africanus is the name given to a very competent Roman general who defeated that wily Carthaginian general Hannibal at the Second Punic War. SCIPIO, therefore, is a fitting name for a remarkable clinical trial that goes by the longer title: Cardiac Stem Cell Infusion in Patients with Ischemic Cardiomyopathy.  This clinical trial is the brainchild of researchers at the University of Louisville and Brigham and Women’s Hospital, and is the first clinical trial to test the safety and efficacy of heart-based stem cells as treatments for heart attack patients.

SCIPIO researchers isolated and expanded cardiac stem cells (CSCs) from approximately one gram of atrial tissue.  This tissue was taken from heart attack patients during coronary bypass surgery.  CSCs were initially discovered and cultured by scientists in the laboratory of Piero Anversa at Brigham and Women’s Hospital in Boston (see Frati C, et al., Resident cardiac stem cells. Current Pharmaceutical Design. 2011 17(30):3252-7).  CSCs have the capacity to express several heart-specific genes and, in animal studies, can repair the heart after a heart attack.  Anversa’s lab was quite careful to establish that the isolated cardiac stem cells expressed a gene called “c-kit,” which is a marker for these stem cells, and that these cells had good growth potential and were largely uncommitted.  In this case Anversa was quite sure that the cells given to the patients were able to grow, differentiate, and integrate into the heart.

Between three to four months after coronary artery bypass surgery, around one million CSCs were transplanted into the heart of each heart attack patient.  This feature of the clinical trial is known as an  “autologous” stem cell treatment, since each patient received stem cells taken from their own body.  Autologous stem cells treatments minimize the risk of rejection by the patient’s immune system.

Throughout the following year after the stem cell treatment, participating patient’s left ventricles were viewed and their heart function was assessed with echocardiography and magnetic resonance imaging.   To say that the results were encouraging is an understatement.  Before the stem cell treatment, each patient was experiencing a stable decrease in left ventricular function.  There was no change in left ventricular function and functional status in the seven control patients who underwent coronary bypass surgery but did not undergo CSC transplantations.  However, 14 of the 16 patients who received CSCs transplants showed an 8.2% average increase in ejection fraction and a 24% decrease in infarct size.  In eight patients studied one year after the CSC treatments, these benefits not only were sustained, actually increased.  Even more encouraging is the absence of adverse effects, which confirms the overall safety of the CSC treatment.

SCIPIO study author, Dr. John Loughran, said this about the current status of the SCIPIO study: “We have enrolled 20 CSC-treated patients, all of whom have been treated with CSC infusion. The trial is currently closed to enrollment.  All patients are followed at serial time points for 2 years. We are working diligently on the creation of an IND application to the FDA for a Phase 2 clinical trial. We hope for this next investigation to be underway within 2 years.”

Dr. Loughran also noted that the isolation of CSCs from the heart is safe and feasible.  This will allow physicians to also treat heart patients who do not depend on surgery, which turns out to be the majority of heart patients.  A simple heart biopsy could probably provide enough tissue for CSC isolation and expansion in the laboratory.

Roberto Bolli, M.D., Director, Institute for Molecular Cardiology at the University of Louisville, echoed these sentiments:  “Harvesting, culturing and infusing CSCs are not particularly expensive and could be repeated multiple times in the same patient. We have preliminary data suggesting that CSCs can be isolated and expanded from minuscule fragments of cardiac tissue obtained during endomyocardial biopsy, which would make this procedure widely applicable in patients with heart failure.”

There are also possibilities that CSCs can be tested for use as a treatment for other heart-based diseases.