British Hospital Refuses to Hydrate a Dehydrated Patient: Hospital Administrators Hide and the Patient Died

I lived in Great Britain for three years (1994-1997) and have first-hand experience with the National Health Service. Needless to say, I was not impressed. They do fine with child-birth and then abandon older people to their own fate. Nationalized health care is rationed health and do not let anyone tell you differently. When you become old enough, the health service you spent your whole life paying into abandons you in your time of greatest need. Now we have a stark example of this.

Wesley Smith has a blog entry on this. It will make you sick. According to the British newspaper, The Daily Mail, a desperate hospital patient died after he was denied hydration by the hospital. To get hydration, he called the police and begged them to bring him a drink. The patient, Kane Gorny, 22, needed drugs to regulate his hormone levels after successfully beating brain cancer months earlier. However, during a further hospital stay nurses forgot to give him his medication and he became so delirious he was forced to call 999 (the UK equivalent of 911) to ask for help. The police officers went to St George’s Hospital in Tooting, south London, but were turned away by staff who insisted that Mr Gorny was fine. Gorny had been admitted in May 2009 to undergo hip replacement surgery after his bones became brittle. This was a side-effect of his prescribed steroids. Kane’s mother, Rita Cronin, said she spent hours trying to convince hospital staff that Kane needed urgent attention but was repeatedly “told he was alright.” See for the article.

An inquiry into the matter has been initiated by the Crown Prosecution Service at the behest of Gorny’s parents.  Kane Gorny had surgery on his pituitary gland, and he had problems regulating his levels of salt and water in his system.  Pituitary surgery commonly damages that back part of the pituitary gland and this prevents the release of antidiuretic hormone (ADH, also known as vasopressin).  Without ADH, patients have a condition called diabetes insipidus, and they need to take exogenous ADH.  Without exogenous ADH, the patient will urinated themselves to death.  The nurses failed to give him his medicine, and dismissed his concerns and the concerns of his mother.  Because he was so dehydrated, Kane called the police to get some fluid, but the nurses at the hospital dismissed them.  He died from dehydration and abnormally sodium levels.  His death was almost certainly a painful one.

The inquiry will probably result in some nurses being sacked (British for fired), but the status quo will probably be maintained.  This kind of abuse is more routine in the British Health System than they would probably admit.  Doctors have even started to prescribe water to elderly patients to prevent them from dying from dehydration.  Is this what we want for the US?

Blood Cell-Making Stem Cells from Umbilical Cord Blood

The process by which bone marrow stem cells make blood cells is called “hematopoiesis.” All blood cells arise from one multipotent stem cells known as the “hematopoietic stem cell” or HSC. HSCs are found in bone marrow and they are the basis of bone marrow transplants.

The first bone marrow transplant was done in 1957 by Donnall Thomas. Unfortunately, this patient died as a result of “graft versus host disease,” in which the immune cells from the transplanted bone marrow attack the tissues of the recipient. With the advent of tissue typing, the first successful bone marrow transplant was done in 1968, and since that time, bone marrow transplants have been used to treat leukemia, aplastic anemia, lymphomas such as Hodgkin’s disease, multiple myeloma, immune deficiency disorders and some solid tumors such as breast and ovarian cancer. Because treatments can wipe out hematopoietic stem cells, bone marrow transplants can replace them.

Fortunately, bone marrow is not the only source of HSCs, Umbilical cord blood from new-born babies also has a robust HSC population. The disadvantage of using cord blood HSCs is that the volume of cord blood in the umbilical cord is quite small compared to the material available from a bone marrow aspiration. However, umbilical cord HSCs are capable of higher rates of cell division, since they are more immature than their bone marrow counterparts. During development, HSCs divide and increase in numbers in the fetal liver. The HSCs reside there until shortly after birth. After birth, the HSCs begin to mature but still show increased growth capabilities that are greater than those from bone marrow HSCs.

HSCs form hematopoietic progenitor cells (HPCs), which have a lower capacity to divide and differentiate. The ability of HPCs to form blood cells is determined by means of a “colony forming cells assay” or CFC. In this test, the HPCs are placed on a plastic culture dish filled with a semi-solid medium that is laced with particular growth factors that are known to stimulate the formation of blood cells (cytokines). HSCs are usually assayed in a living animal, but a laboratory test does exist for HSCs called the long-term culture-initiating cell (LTC-IC) assay. This test, and others, do a pretty passable job of determining the health and effectiveness of a batch of HSCs to reconstitute the bone marrow of an organism, at least in mice, but how well these tests work for human cells is not as clear-cut as they are for the mouse.

One successful assay for human HSCs involves reconstitution of the bone marrow of laboratory animals that have been exposed to lethal doses of ionizing radiation. The blood-making capacities of these animals can be completely reconstituted by infusing human HSCs into them. Sheep are one of the large animals of choice, but mice are equally as valuable even though the mouse model may not completely accurately predict the behavior of HSCs in larger animals.

Mice that carry a mutation called the Prkdc mutation can have their bone marrows completely reconstituted by human HSCs after lethal irradiation, and such mice now have a blood cell-making system that is completely human in nature. Introduction of other mutations can make the immune systems of these mice even more human-like, and such mice are models for the study of a variety of immune system diseases.

How does one identify a HSC in bone marrow or umbilical cord blood? It has a protein on its surface called CD133.  There is also an enzyme that is found in HSCs that isn’t found in other blood cell types (aldehyde dehydrogenase).  HSCs also have the ability to exclude a toxic dye called Hoechst33342, which also distinguishes them from other cells.

Umbilical cord blood HSCs grow much faster than HSCs from adult bone marrow, and therfore, 20-fold fewer cells are required to reconstitute the bone marrow if umbilical cord HSCs are used.  However, when given to a recipient, donated HSCs must home to the bone marrow in order to take up residence there.  Unfortunately, umbilical cord HSCs do not home as well as those from bone marrow.  They do not express some of the genes necessary for homing at high levels, and this impedes them from finding their way to the bone marrow.  Experiments with engineered umbilical cord HSCs that express some of the genes required for homing at higher levels have proven successful in animals.  Also, introducing such cells directly into the bone marrow can also deposit the umbilical cord HSCs where they need to be.

Umbilical cord HSCs are a potent source of HSCs for clinical work, and with the banking of umbilical cord blood, more and more of these cells are available for clinical use.  While they are not a perfect source of treatment for various maladies, they offer a possible treatment where, in the past, no such treatment possibility existed.  The graft versus host response is a genuine possibility when umbilical cord blood is used.  However, umbilical cord-based treatments are becoming more and more important in the treatment of many maladies and the importance of these cells has only just begun to be realized.

Obamacare: The Aftermath

Since many have asked my what I think about Obamacare and the recent Supreme Court ruling, I thought that I might provide my views on the topic.

In the first place, the law is obviously unconstitutional. The federal government cannot compel you to buy something. There is simply no universe in which someone can read our Constitution and come to the conclusion that the Constitution gives the government that power over its citizens.

Secondly, if Obamacare is a tax, then the lawsuit before the Supreme Court would have been dismissed, because according to the Anti-Injunction Act Donald Verrilli argued before the Supreme Court that the individual mandate is NOT a tax. However, in order to find the bill constitutional, Roberts had to treat it as though it was a tax. But wait a minute. The Anti-Injunction Act says that you cannot contest a tax bill until the tax is paid. Therefore, if Obamacare was a tax, then the case should have been dismissed til the tax was collected. Thus for the sake constitutionality, Obamacare is a tax, but for the sake of litigating it, it is not a tax. Roberts tried to have it both ways, but he can’t. This is the reason why legal pundits all over the US are troubled by Robert’s garbled, self-contradictory opinion. If this was a principled ruling then why did it make no internal sense.

Third, Obamacare is unworkable. In the words of Holman Jenkins of the Wall Street Journal, Obamacare is “upheld and doomed.” The problems with Obamacare are four-fold and they are :

1. Taxes

Besides being a massive federal power grab, Obamacare contains one of the largest tax increases ever imposed on the American economy. These tax increases come at a time when job growth should be the nation’s number one priority.. The tax sections of Obamacare begins with an increase in the Medicare payroll tax of 0.9 percent for individuals with incomes above $200,000 ($250,000 for couples) in 2013. Needless to say, this tax will depress the demand for labor at a time when job creation is critical in order to for jump-start the economy. Some might think that this tax will not hit the middle class because of the relatively high initial income thresholds, but they are wrong. These income thresholds were purposely not indexed to inflation. Therefore, as the years pass, more and more middle-income families will cross the thresholds because of normal wage growth.

Obamacare also includes an additional 3.8 percent tax on investment income; a new 2.3 percent excise tax on medical devices that will reduce the size of the industry. It also includes taxes on the drug and insurance industry that will be passed on to consumers in the form of higher premiums; and a tax on high-premium insurance plans that will also be passed on to consumers.

2. Deficits and Debt

Obamacare will exacerbate our nation’s already alarming entitlement spending and debt crises. The dramatic rise in spending on Medicare and Medicaid already is pushing the federal budget to the breaking point. Obamacare makes the problem much worse since it adds two new additional entitlement programs in the form of a massive Medicaid expansion and a new premium credit entitlement for households with incomes between 138 percent and 400 percent of the federal poverty level. These two entitlement expansions are expected to add a minimum of 35 million Americans to the entitlement rolls when phased in, at an expense of more than $200 billion annually by the end of the decade (CBO, Letter to House Speaker Nancy Pelosi, March 20, 2010, Table 4.).

Obamacare was sold by means of offsetting cuts in Medicare that supposedly would pay for it. Unfortunately, the Medicare cuts have been exposed as unrealistic because they would result in Medicare paying even less for medical services than Medicaid does today. (John D. Shatto and M. Kent Clemens, “Projected Medicare Expenditures Under Illustrative Scenarios with Alternative Payment Updates to Medicare Providers,” Office of the Actuary, Centers for Medicare and Medicaid Services, May 18, 201). This would severely jeopardize seniors’ access to care. Even worse, the offsetting cuts were made, the savings are double-counted under Obamacare, and are used once to pay for future Medicare commitments that are today counted as unfunded governmental liabilities, and then a second time to supposedly cover the costs of Obamacare’s entitlement expansions (Charles Blahous, “The Fiscal Consequences of the Affordable Care Act,” The Mercatus Center of George Mason University, 2012). Since money cannot be used twice, Obamacare will add hundreds of billions of dollars in new debts this decade, and trillions over the longer term (James C. Capretta, “The Medicare Trustees’ Report and the $8.1 Trillion Double-Count,” The Weekly Standard Blog, April 24, 2012).

3. Individual Mandate

The individual mandate hands immense regulatory power to the Department of Health and Human Services (HHS). According to Obamacare, HHS controls just about every aspect of the nation’s health system. In January 2012, the Administration announced that it planned to use that power to impose new benefit requirements on all employer-sponsored insurance in the name of “preventive health services” (now frequently termed the “HHS mandate”).

Additionally, the regulations issued by the Administration in this regard would require all employers, including religious employers such as Catholic hospitals and universities, to cover abortifacient products, contraceptives, and sterilization procedures in the health plans they offer to workers. By requiring all employers to offer these products and services in their health insurance policies, they would directly violate the religious liberty rights of thousands of religious institutions around the country.

4. The Bureaucratic Micromanagement of American Health Care

The bulk of Obamacare is based on the theory that the federal government has the capacity and know-how to micromanage American health care. This is the basis for the provisions that establish an unaccountable and unelected board—the Independent Payment Advisory Board (IPAB)—to oversee all aspects of how Medicare is run. It is also the theory behind Accountable Care Organizations (ACOs), which are authorized in Obamacare to give the federal government a new role in influencing how doctors and hospitals are organized to deliver care to seniors.

Unfortunately and contrary to socialistic preconceptions, the government is NOT adept at micromanaging how health care or any other aspect of people’s lives. When the government is given this much authority and discretion, it does not result in higher-quality care for patients. Instead, it leads to price controls and one-size-fits-all regulations that misallocate resources and lead to access problems. Obamacare compounds the problem since it creates massive new and costly bureaucracies at the federal and state levels of government that will become permanent and unresponsive centers of power. The IRS and HHS will grow. A new agency in HHS is slated to spend $10 billion supposedly testing new ideas, but already there is indication that the money is being wasted on projects driven more by politics than substance.

Obamacare is also pours hundreds of millions of dollars into the states to coax them into building the “exchanges” that will become the foundation of the Obamacare edifice. These exchanges, far from fulfilling the supposed mission of fostering a dynamic marketplace, will be the means by which the federal government will extend its reach to every corner of the health sector. Every American who does not obtain his or her insurance through an employer will have little choice but to go through Obamacare’s exchanges.   It will only be a matter of time before the federal government uses its new powers to impose even more top-down cost controls on the health system, to the detriment of the quality of American health care.

Obamacare is a disaster. Had the Supreme Court ruled properly, we would be out of this mess, but as it sits now, repeal – complete and total repeal – is the only answer.

The FDA is Responsible for the Drug Shortages

The Food and Drug Administration (FDA) has implemented extremely restrictive drug policies that are generating drug shortages across the nation. According to the Regenexx blog, clinicians all over the United States have been feeling the effects of this pinch for some time.

Centeno gives the following example: “we were paying about $1 a bottle for local anesthetic, now when we can find it-that same bottle is often $4 a bottle.” As you might guess, this is having a significant effect on patient care, since surgery centers cannot get their hands on certain drugs. Cancer patients have been dramatically affected, since stocks of cheap, generic drugs are drying up.

On his blog, Centeno predicted that these shortages were due to “an ascendant hyper-regulatory FDA.” As it turns out, Centeno’s instincts were dead on. A Congressional hearing has confirmed that the FDA is responsible for the drug shortages. The “new FDA” focuses on reducing the so-called “type 1 regulatory” errors. Type 1 regulatory errors occur if a dangerous drug is allowed to go through market. It is certainly a proper function of the FDA to prevent type 1 regulatory errors. However, by overly focusing on type 1 regulatory errors, the agency is guilty of type 2 errors, in which good drugs are from the market.

The number of people harmed by type 2 errors is very large indeed. One estimate puts the number at 82,000 lives a year. Forbes Magazine documented the enormous rise in Warning Letters issued by the FDA. These Warning Letters have essentially shut down the production of generic drugs. These factories were shut down not because there was an actual problem, but because of theoretical risks due to current Good Manufacturing Practice violations.

The FDA employees that issued the letters did not take into account the consequences of their actions; namely that entire factories would have to shut down. A fair number of these manufacturers may or may not be able to reopen their production lines for these cheap medications because of the increased regulatory costs. Some of these companies may even have had to build new facilities. Many companies will simply drop the production line and this means less generic drugs. Also for many of these drugs, there are no brand name alternatives anymore, and the consequences of all this is that our hyper-regulatory FDA that has chosen to focus on reducing one type of regulatory error and by being only focused in one direction, they place the public’s health at risk.

What is the solution? We need a FDA that is as concerned with type 1 errors as they are with type 2 errors. This will balance these concerns so that the public is as protected from bad drugs as much as it’s protected from delays in promising therapies or shortages of generic drugs.

Reprogrammed Amniotic Fluid Stem Cells Provide Alternatives to Embryonic Stem Cells

According to a study published in the journal Molecular Therapy has shown that stem cell found in amniotic fluid can be differentiated into a state that is similar to that of embryonic stem cells. Researchers from Imperial College London and the UCL Institute of Child Health were able to reprogram amniotic fluid cells without having to introduce any extra genes. These findings mean that stem cells derived from donated amniotic fluid could be stored in banks and potentially used for therapies and in research. This would provide a viable alternative to the limited embryonic stem cells that are currently available.

In the womb, the fetus is surrounded and nourished by amniotic fluid. Amniotic fluid can be extracted by using a small needle and a process called amniocentesis, which is sometimes used to test for genetic diseases, routinely uses such a needle to remove amniotic fluid for genetic testing. Amniotic fluid contains stem cells that come from the fetus, and these cells have the ability to develop into different cell types, like stem cells in the embryo.

Imperial College and UCL researchers used stem cells from amniotic fluid that had been donated by mothers who underwent amniocentesis during the first trimester of pregnancy. The cells were grown on a gelatinous protein mixture in the lab and reprogrammed into a more primitive state by treating them with a drug called valproic acid. An extensive set of tests found that these reprogrammed cells have characteristics that are very similar to embryonic stem cells (ESCs). ESCs are capable of developing into any cell type in the body – a property known as pluripotency.

Even after growing in culture for some time, the reprogrammed cells were able to develop into of many different types, including liver, bone and nerve cells. Furthermore, these cells were also functional. The reprogrammed amniotic stem cells also maintained their pluripotency even after being frozen and rethawed.

The results suggest that stem cells derived from amniotic fluid could be used in treatments for a wide range of diseases. Donated cells could be stored in banks and used in treatments, as well as in disease research and drug screening. A previous study estimated that cells from 150 donors would provide a match for 38% of the population.

The ethical concerns surrounding ESCs has prompted many scientists to seek alternatives them. Other scientists are also interested in alternatives to ESCs since the availability of donor embryos is poor. Other research has shown that adult cells can become pluripotent if particular genes are introduced into them (so-called induce pluripotent stem cells or iPSCs). The production of iPSCs, however, requires the introduction of extra genes into the cells, often by using viruses. Such a technique, however, does not efficiently reprogram cells and there is a risk of introducing tumor-causing mutations into the cells. This new study is the first to induce pluripotency in human cells without using foreign genetic material. Pluripotent cells derived from amniotic fluid stem cells showed some traits associated with embryonic stem cells that have not been found in induced pluripotent stem cells from other sources.

Unfortunately, amniocentesis is associated with a small risk of miscarriage (~ one in 100).

Dr Pascale Guillot, from the Department of Surgery and Cancer at Imperial, said: “Amniotic fluid stem cells are intermediate between embryonic stem cells and adult stem cells. They have some potential to develop into different cell types but they are not pluripotent. We’ve shown that they can revert to being pluripotent just by adding a chemical reagent that modifies the configuration of the DNA so that genes that are expressed in the embryo get switched back on.

“These cells have a wide range of potential applications in treatments and in research. We are particularly interested in exploring their use in genetic diseases diagnosed early in life or other diseases such as cerebral palsy.”

Dr Paolo De Coppi, from the UCL Institute of Child Health, who jointly led the study with Dr Guillot, said: “This study confirms that amniotic fluid is a good source of stem cells. The advantages of generating pluripotent cells without any genetic manipulation make them more likely to be used for therapy.

“At GOSH we have focused on building organs and tissues for the repair of congenital malformations, which are usually diagnosed during pregnancy. Finding the way of generating pluripotent cells from the fluid that surround the fetus in the womb move us one step further in the this direction”.

Dr Caroline Johnston, Research Evaluation Manager with children’s charity Action Medical Research said: “These new findings could be a step forward for treatments of a wide range of diseases that affect babies and children. We are proud of our history of funding medical breakthroughs and of our support for these researchers in their move towards life changing therapies.

UMass Stem Cell Bank to Close

Wesley Smith at his Secondhand Smoke blog has noted that the University of Massachusetts Stem Cell Bank is closing.

According to a May 9, 2007 article in the New York Times by Pam Belluck, the UMass stem cell bank was the brainchild of governor Deval Patrick. In the words of the article:  “It would also establish the first stem cell bank, a repository of all the stem cell lines created in Massachusetts laboratories, which would serve as a kind of stem cell lending library to scientists around the world.”  The article continues by quoting the Governor: ”In many ways the health of this industry and the health of our society are very closely linked,” Mr. Patrick said at an international biotechnology convention here, where he announced the plan. ”That’s why we will not rest on our laurels.”  All of this came with a price tag, and the following paragraph reveals how much all of this cost the taxpayers:  “Mr. Patrick’s plan involves $1 billion in state money over 10 years, some borrowed through bond issues, plus $250 million in matching money from private business.”  So the whole thing cost the taxpayers of Massachusetts a rather rather large sack of change.

How hopeful was everyone as they sought to defy the Bush Administration?  Again from the 2007 article:  “Brock C. Reeve, executive director of the Harvard Stem Cell Institute, said the state’s investment would help scientists who have had to delay research because of limited federal financing and would ”attract the new junior faculty, the rising stars.”

Dr. Leonard Zon, director of the stem cell program at Children’s Hospital Boston, said the stem cell bank would be ”a fantastic way of distributing the stem cell lines to the world,” and would be cost-effective because it would provide one location where stem cell lines could be monitored to ”make sure they have the correct number of chromosomes and that they’re growing correctly.”

Dr. Mello, whose research concerns a gene-blocking mechanism called RNA interference, or RNAi, called the proposal a ”substantial investment,” adding, ”There’s so much we can do; it’s really critical to keep the funding coming.”

So there was clearly a whole lot of hope when it came to the opening of this stem cell bank.  What is the case now?  From the Boston Globe, June 28, 2012:  “The stem cell bank that was a marquee piece of Governor Deval Patrick’s effort to bolster the life sciences industry will run out of funding at the end of the year and close, state and University of Massachusetts Medical School officials said Wednesday. The state invested $8.6 million in public funds to establish the bank at the medical school’s Shrewsbury campus.”

It could be me, but 8.6 million dollars is a lot of money.  You can’t blame this one on Bush, folks.  Apparently, there is not enough state, federal (as in NIH) or private money to support this thing, and it’s going down in flames.

Some scientists hitched their star to a technology that is quickly becoming passe and involves the deliberate murder of young human beings.  The sooner this ethically dubious research is shuttered the better off all of us will be.

Mesenchymal Stem Cells Are Used In Tumor-Targeted Gene Therapy

My apologies to my readers. I have been in Seattle, Washington for the past week at the Free Methodist National Bible Quizzing Tournament for this week, and I have not had a chance to blog at all. Nevertheless, I have time now. In case you are interested, my team made it to the Senior Teen Veteran Division by winning their subdivision, and then during the double elimination portion of the tournament, they were eliminated in the third round. My quizzers quizzed gallantly, but they happened to quiz the first place and second place teams at the beginning and both teams were quizzing particularly well. They did not go down without a fight, but they were simply out-jumped by the extremely talented quizzers from Winona Lake, IN and Rainer Avenue, Seattle, WA. Oh well; someone has to lose.

I have a paper in my hot little (well not so little) hands that is from C.J. Bruns’ lab at the University of Munich in Munich, Germany. In this paper, Bruns and his German and American collaborators review the use of mesenchymal stem cells (MSCs) as vehicles to specifically deliver toxic genes to tumor cells. These experiments are still preliminary, but with the proper refinements, they might lead to clinical trials for cancers that are difficult to treat with more traditional methods.

MSCs are found in many different locations throughout the body. They are most easily isolated from bone marrow and fat, and they can also be cultured and grown to larger numbers in the laboratory for limited periods of time. When isolated from bone marrow, MSCs appear as a subpopulation of cells that adhere to the plastic tissue culture dishes.

Because of the ease of their isolation and manipulation, researchers have used MSCs to introduce genes into tumor cells. There are several advantages that make MSCs a very attractive cell for such a venture. First, MCSs do not activate the immune system when they are introduced into another body. Secondly, they seem to home to tumors and provide them with a kind of scaffold upon which the tumor cells grow. Thus MSCs and tumors cells form a kind of natural partnership. This means that introduced tumor cells will readily integrate into a growing tumor. Imaging studies that implanted labeled MSCs have borne this out. For example, when implanted into mice with melanomas that have spread to the lung, the transplanted MSCs, after eight days, surrounded the lung tumors (Gao, et al., Oncogene 2010 29(19):2784-94). A similar experiment with tumors in the pancreas also showed similar results (MSCs surrounded the tumors) after three days (Beckermann et al., Br J Cancer 2008 99(4):622-31). Third, given the tendency of MSCs to home to tissue damage and heal it, introduced MSCs and endogenous MSCs tend to view the growing and invading tumor and one big wound that constantly required healing. Thus the interaction between the tumor and the MSCs gets even cozier. For all these reasons, MSCs are very good vehicles for tumor-targeted gene therapy.

One of the first experiments that utilized MSCs for tumor-targeted gene therapy (TTGT) was described by Studeny and colleagues (Studeny M, et al., Cancer Res. 2002 Jul 1;62(13):3603-8). In this paper, MSCs were engineered to express a protein called interferon-beta in order to treat melanomas in mice. Those mice that received intravenous injections of the engineered MSCs showed reduced tumor growth and increased times of survival. Interferon beta (INF-B) is a member of a large group of secreted proteins called interferons. There are three main classes of interferons and the type of receptor bound by the interferon determines which class it belongs to. Type 1 interferons (INFs) are used to treat patients with blood-based tumors (leukemias) or solid tumors. Type 1 INFs prevent tumor growth, staunch the tendencies of tumors to induce the growth of new blood vessels into the tumor mass, and also induce cell death within the cells of the tumor. Clinically, those patients who suffer from recurrent melanomas receive treatments with recombinant IFN-α2b. Thus, getting cells that express INF-B into the tumor could kill of the tumor cells and shut the tumor down.

Since Studeny’s pioneering work, several different studies have used MSCs from bone marrow (Studeny et al., J Natl Cancer Inst 2004 96(21): 1593-603; Loebinger, et al., Cancer Res 2009 69(10):4134-42; Nakamizo, et al., Cancer Res 2005 65(8): 3307-18; Hakkarainen, et al., Hum Gene Ther 2007 18(7):627-41), fat (Grisendi et al., Cancer Res 2010 70(9) 3718-29; Zolochevska et al., Stem Cells Dev 2012 21(7):1112-23), and umbilical cord (Kim, et al., Stem Cells 2010 28(12):2217-28) have been used in experiments like it. Also, several different types of genes other than INF-B have been engineered into MSCs and used to shrink tumors in laboratory animals. These engineered MSCs have also been used to treat melanomas (Studeny M, et al., Cancer Res. 2002 Jul 1;62(13):3603-8; Studeny et al., J Natl Cancer Inst 2004 96(21): 1593-603), breast cancers (Eliopoulos et al., Cancer Res 2008 68(12): 4810-8), lung cancers (Loebinger, et al., Cancer Res 2009 69(10):4134-42; Xim et al., Mol Med 2009 15(9-10):321-7), cervical (Grisendi et al., Cancer Res 2010 70(9) 3718-29) and prostate cancers (Zolochevska et al., Stem Cells Dev 2012 21(7):1112-23), soft tumors (Xiang, et al., Cytotherapy 2009 11(5):516-26), and various types of brain tumors (Gu, et al., Cancer Lett 2010 291(2): 256-62; Miletic, et al., Mol Ther 2007 15(7): Amano, et al., Int J Oncol 35(6):1265-70). The genes with which the MSCs have been engineered include TRAIL (TNF-related apoptosis-inducing ligand), which encodes a protein that causes cells to die (Studeny et al., J Natl Cancer Inst 2004 96(21): 1593-603; Grisendi et al., Cancer Res 2010 70(9) 3718-29; Kim, et al., Stem Cells 2010 28(12):2217-28), PEDF (Pigment epithelium-derived factor), a protein that prevents the growth of blood vessels (Zolochevska et al., Stem Cells Dev 2012 21(7):1112-2), IL-12, a gene that encodes a protein that makes tumors recognizable by the immune system (Eliopoulos et al., Cancer Res 2008 68(12): 4810-8), HSK-Tk, a viral gene that makes tumors susceptible to anti-viral drugs (Gu, et al., Cancer Lett 2010 291(2): 256-62; Uchibori, et al., J Gene Med 2009 11(5):373-81; Miletic, et al., Mol Ther 2007 15(7): Amano, et al., Int J Oncol 35(6):1265-70), and iNOS, a gene that encodes a protein that makes nitric oxide; a toxic molecule (Xiang, et al., Cytotherapy 2009 11(5):516-26). All of these strategies have had some successes in treating artificially induced tumors in laboratory animals.

The main focus of this paper is the use of genetically engineered MSCs to treat tumors of the digestive system. When it comes to tumors found outside the digestive system, the data seem to suggest that MSC-based gene therapies are rather successful. However, when it comes to tumors in the digestive system, the data are unclear, since the experiments show conflicting results. There are some indications that cultured rodent MSCs have the ability to form tumorous growths in extended culture (Miura, et al., Stem Cells 2006 24(4):1095-103; Li, et al., Cancer Res 2007 67(22):10889-98; Qin, et al., Cloning Stem Cells 2009 11(3):445-52). Secondly, implantation of extensively cultured rodent MSCs into the bodies of living rodents leads to the formation of soft tumors (Tolar, et al., Stem Cells 2007 25(2):371-9). Therefore, some risks might accompany MSC-based treatments. In contrast to these concerns, which largely stem from experiments in rodents, the thousands of patients who have had MSC treatments have not experienced cancers as a result of them (Le Blanc, et al., Lancet 2008 371(9624):1579-86).

Animal studies of MSC transplantations into laboratory rodents afflicted with digestive tumors have shown that MSCs stimulate tumor growth, and, in other experiments, inhibit tumor growth. The biology of tumors in the digestive tract is more complicated than other tumors, and, therefore, the results of experiments with MSCs vary from laboratory to laboratory. For example, Qiao and others gave mice with defective immune systems injections of liver cancer cells plus human MSCs that had been engineered to grow continuously in culture. The injected MSCs were able to inhibit tumor growth (Qiao, et al., Cell Res 2008 18(4):333-40). However, work from Bruns’ own lab showed that infused MSCs promoted the growth of pancreatic cancers (Zischek, et al., Ann Surg 2009 250(5):747-53; Conrad, et al., Ann Surg 2011 253(3):566-71) and liver cancers (Niess, et al., Ann Surg 2011 254(5):767-74). Li and his co-workers also showed that human MSC infusions could inhibit the invasion and metastasis of liver cancers in culture. Invasion assays in cultured usually consist of tumor cells grown on a layer of cells and the ability of the tumor cells to penetrate this layer of cells and grow on either side of them. Li and others showed that co-culturing MSCs with liver cancer cells prevented the liver cells from penetrating and invading the cell layer. However, when the same cells were infused into laboratory animals, the MSCs enhanced tumor grow (Li, et al., Cancer Sci 2010 101(12):2546-53). Li and his colleagues found very similar results with cancers of the esophagus (Tian, et al., J Cell Physiol. 2011 226(7):1860-7).

With respect to genetically engineered MSCs, the results are not as equivocal.

A scientist named You and his fellow scientists transplanted stomach cancer cells into mice with hMSCs that had been engineered with a suicide gene called cytosine deaminase (CD). These mice were then given a drug called 5-fluorouracil (5-FU), which kills cells that express CD, and this resulted in a pronounced inhibition of tumor growth (You MH, et al., 2009 J Gastroenterol Hepatol 24:1393–1400). In another experiment by Kidd and others showed that hMSCs engineered with IFN-B or without IFN-B were both found to suppress tumor growth of pancreatic cancers (Kidd S, et al., 2010 Cytotherapy 12:615–625). Additionally, Bruns’ lab also showed that infusion of MSCs in animals with pancreatic cancer strongly promoted tumor growth and increased the tendency of the tumor to spread. However, if the MSCs were engineered to express HSV-Tk, the MSCs substantially inhibited pancreatic tumor growth and prevented the spread of the tumor after the mice we treated with ganciclovir, a drug that kills cells that express HSV-Tk (Zischek C, et al., 2009 Ann Surg 250:747–753).

From all these data, it seems that there is reason to be optimistic that such a treatment strategy might work in humans. However, given the ability of MSCs to stimulate the growth of tumors in animal models is reason for concern, However, with the proper controls and safety regulations in place, anti-cancer treatments with genetically engineered MSCs could be one of the clinical trials we will see in the near future.