"Tea-bag" Adult Stem Cell Treatment for Stroke

British researchers report an amazing recovery for a 49 year old man who suffered a hemorrhagic stroke on October 15, 2008. The researchers at the company, "Biocompatibles," used adult stem cells from a healthy donor. The cells had been engineered to cause them to produce a protein that helps prevent "programmed" cell death (even after the bleeding stops and the pressure is removed) and embedded in tiny beads that had been sewn up in a cloth "tea-bag."

From the press release, published on the Medical News Today Neurology and Neuroscience website:

Stroke is one of the leading causes of death in the elderly population in the developed world. The incidence rate has been reported as 145 per 100,000. Hemorrhagic stroke is responsible for ~15 to 20% of all stroke and it is the least treatable form of stroke. It is associated with the highest morbidity and mortality rate of all stroke with only 44% of affected patients surviving the first 30 days. Only 20% of these survivors regain functional independence. The cascade of events starts with the sudden rupture of a blood vessel in the brain, causing haemorrhage and pressure inside the skull. Surgery may be used to relieve the pressure; but the haemorrhage causes a longer-term process of programmed cell death, or apoptosis, and it is this that causes the lasting neurological damage.

The CellBeads™ are delivered directly to the injury site during the surgery. They are programmed to deliver CM1, a proprietary version of a naturally occurring protein, GLP-1, which has been shown to have powerful anti-apoptotic effects. The delivery mechanism is a cluster of human adult mesenchymal stem cells obtained from a healthy donor and encapsulated in alginate beads. The cells are genetically engineered to produce the protein, which is delivered continuously, directly to the injury site. The alginate beads protect the stem cells from the body's immune system, which would otherwise destroy the foreign cells. CellBeads™ are transplanted within a retrievable mesh device and are removed completely after a treatment period of 14 days. Retrieval of the implant prevents possible long-term side effects from the transplanted cells.

The research is a "Phase I/II" trial, which means that the doctors and scientists are actually testing the safety of the treatment, and not the actual effectiveness of the treatment, itself. In other words, "does the treatment do more harm than good."

The CEO of Biocompatibles, Crispin Simon (that name is as British as tea bags), spoke to a Reuters reporter for a story published at Forbes online, stressing that the patient is young and other wise healthy, and had the standard of care for hemorrhagic strokes, surgery to relieve the pressure from the blood on the cells around the stroke. 10% to 20% of patients have similar recovery, without the Biocompatible beads.

Still, the report is a welcome source of hope for anyone who has watched and waited helplessly after a patient or a loved one had a hemorrhagic stroke.

Many Adult Stem Cell Treatments in the News

This week, we've heard about a the new "bandages" for torn knee cartilages and hope for a collagen fibers made using nanotechnology.

Animal treatments for joint disease and injury are common in horses and the treatments for dogs are now being advertised by private veterinarians in Oklahoma.

The research is ongoing in humans, too.

From the BBC, an article on the first organ regenerated from the patient's own stem cells and transplanted

Scientists in Spain have carried out the world's first tissue-engineered whole organ transplant - a windpipe - made with a patient's own stem cells.

The groundbreaking technology also means for the first time tissue transplants can be carried out without the need for anti-rejection drugs.

Five months on the patient is in perfect health, The Lancet reports.

Osiris, a company that has been developing treatments developed from adult stem cells, announced earlier this month that it is making a profit and that the rights to sell 2 treatments:

Prochymal is being evaluated in Phase III clinical trials for three indications, including acute and steroid refractory Graft versus Host Disease and also Crohn's disease, and is the only stem cell therapeutic currently designated by FDA as both an Orphan Drug and Fast Track product. Osiris also has partnered with Genzyme Corporation to develop Prochymal as a medical countermeasure to nuclear terrorism and other radiological emergencies. Furthermore, Prochymal is being developed for the repair of heart tissue following a heart attack, the protection of pancreatic islet cells in patients with type 1 diabetes, and the repair of lung tissue in patients with chronic obstructive pulmonary disease. The Company's pipeline of internally developed biologic drug candidates under evaluation also includes Chondrogen for arthritis in the knee.

(There's more on Osiris from the Washington Post, here.)


Way back in 2006, we heard about bladders grown for patients from adult stem cells and transplanted. The transplants were actually done in 1999 but the news came out about the time that Dr. Ayala was in the news for his work with Umbilical Cord stem cells.

In vitro fertilization and the beginning of life

The Los Angeles Times (a one time free registration may be required) finally notices that couples who initiate in vitro fertilization are "finding themselves ensnared in a debate about when life begins."

The proposed Colorado amendment states, "The term 'person' or 'persons' shall include any human from the time of fertilization." If it is passed, the courts would have to interpret the meaning of those words, says Kristi Burton, sponsor of the initiative and founder of Colorado for Equal Rights, which focuses on the rights of unborn children. The goal of the amendment, says Burton, a college student, "is to respect and protect all life."

Fertility advocates are skeptical that "personhood laws" wouldn't limit their choices for reproductive healthcare. In August, Resolve released a statement opposing the Colorado amendment.

"The motivation is abortion," says R. Alta Charo, a professor of law and bioethics at the University of Wisconsin at Madison. "If the Supreme Court allows states to declare embryos as personhood, you would be in a position to say immediately that all abortions have to stop."

The reproductive rights of infertile women may not be the target, says Dr. William Schlaff, director of reproductive endocrinology at the University of Colorado Health Sciences Center, "but the implications are massive depending on how this law would be used if adopted."

For instance, what happens to embryos determined to be afflicted with serious genetic diseases? "What do you do with that embryo then?" Schlaff asks.

Says Burton of the initiative's possible ramifications: "All those things would have to be dealt with later on. . . . We don't see it as preventing infertility treatment."

As for the Rathans, over the course of several weeks, the couple ruled out discarding the embryos. They discussed donating them to research but heard that option was a logistical nightmare. They pondered giving the embryos to another infertile couple.

"Before I became pregnant, I thought the decision would be easier for me," Gina Rathan says. "But when it actually happened, I realized these are three potential lives."

Finally, the couple paid for three more years of cryopreservation.

Nature nurtures debate on namesake

Josh Carter, over at the Bioethics.com blog, comments on the editorial in the April 10th issue of Nature, (subscription only. Joe quoted some but let me know if you need the full text) which uses news of a transgendered (but not transexual) pregnant and bearded woman to ask the age-old question, what is "natural" and whether "natural" is better than "un-natural."

What do you want to bet that the author prefers "natural" fibers for his clothes and "organic," when it comes to groceries? We know that the editorial board has opinions on the good and bad, since the cover of the April 3 issue in front of me has the headline, "Carbon emissions: it's worse than you thought."

Even though the question couldn't have been asked quite this way in the past, Nature asks one of the oldest philosophical questions. Unfortunately, they ask in a juvenile manner. In fact, they beg the question by stating that the approved purpose is to "enhance the human condition."

(As I commented on the Bioethics.com blog) The “natural” uses of medicine and science seek to discover and use our discoveries to encourage, enhance, and/or return to optimal what Aristotle called the “telos,” the “what it is meant to be.” For instance, a splint reduces pain and holds the limb in physiological position as it heals. Hip replacements, glasses and hearing aids aren't normally intended to give you the ability to jump higher or stronger, see with the sight of an eagle or hear a pin drop in the next county -- they are used in an attempt to return your functioning to "normal."

The most active debates in science today are actually discussions about the “nature” of the thing we are studying or manipulating. Is global climate change causing the Earth to heat up more than is “natural,” is it man-made (due to those carbon emissions), or cyclical, etc. Should there be regulation on abortions to for sex-selection or to choose for deafness? Who gets the resources to be the Six MillionTrillion Dollar Woman and why not allow men and women to demand that their limbs be cut off or that their faces be botoxed and surgeried into a human caricature that scares children?

Again, we see the problem with setting up the ethics hierarchy so that "autonomy" trumps "non-maleficence." "I want" ethics over "First, do no harm."

Is there good in the telos, or is there any standard for dividing funding and power in science and medicine? If there aren’t good and bad uses of science and medicine, then “Anything goes,” if you can get the financing, the power, or the ability to do it.

Translation of Yamanaka, Yu "induced Pluripotent Stem Cells" (Revised)

Scientists who report their findings are expected to discuss the problems as well as the outcome of their research. This is usually found in the "Discussion," "Conclusions" or "Results" section of the paper. This is the best place to figure out what the researches intended, what they did and what the report means. (Then you go back and check to see if they proved what they "discussed." And then, you wait for other labs to confirm it.)

The actual (Takahashi et al., "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors," Cell (2007).) Cell article on reprogrammed adult fibroblast skin cells, the "induced Pluripotent Stem Cells) or "iPS," is available for free, here. The Science Magazine report about similar work by James Thomson from Wisconsin (the researcher who reported the production of human embryonic stem cells in the first place) is supposed to be published November 22, 2007. (Editorial note 11/30/07 – Science published the Thompson and Yu report the same day that Tamanaka's report was published, two days ahead of schedule. See my “translation,” here.)

To the best of my understanding, here's a translation into layman's terms about what the Takahashi/Yamaka report means:

While it took a lot of cells and more time than the researchers first expected because the human iPS grew much slower than the mouse iPS,

1. The cells that grew looked and functioned like human embryonic stem cells with a few minor differences,
2. They believe they proved that their technique is responsible for all the new pluripotent cells that were found in their cultures(there weren't any cells from another culture introduced accidentally or on purpose and which would make them look more successful than they were),
3. The cells could be directed to develop nerve cells and heart cells,
4. They were able to use several types of adult specialized cells to achieve iPS, and
5. The researchers suggest several possible ways to overcome the drawbacks of the process.

The authors believe that the inefficiency or the need to begin with lots of adult cells and wait a little longer for a substantial amount of human iPS should not be a "practical" problem because the adult cells are easy to obtain and labs all over the world should be able to reproduce their results. Since the technique should be well-funded (it qualifies for US Federal funding and is ethical, since no human beings have to die), the authors believe it will be possible for lots of researchers to work on them.

If I were to predict the future, I would anticipate banks of iPS - or even specialized or intermediate forms of cells that are produced from iPS - being stored for each of us, just in case. In the very long term, we will learn more about stimulating our on bodies' stem cells from research on these cells, so that we can repair or prevent damage without transplants or waiting for cultures to grow in the lab.

The major hurdle is that the cells were produced by the Recombinant DNA technique, using retroviruses in plasmids.

The retroviruses are a class of viruses that actually insert themselves into the DNA strands of animal or plant cells to become a part of that cell’s DNA and are copied when the cell reproduces. They are manufactured in the lab in the form of plasmids in order to carry genes into the experimental cells.

Plasmids are little bits of DNA, a mini-virus in a circle. Think of a chain with pairs of magnets or interlocking puzzle pieces that connect the ends and make a loop. When open, the plasmid becomes a strand of DNA which has ends that are "sticky.” When placed in a culture with mouse or human cells, the plasmids infect the cells and then move into the nuclei of the cells. The retroviral DNA is inserted or inserts itself into the DNA of the host cell because the sticky ends of the plasmid strand match or mate to certain areas of the host DNA.

Plasmids can be manufactured to carry copies of genes that researchers want to insert into the DNA of experimental cells. The technique is common in commercial and experimental labs for at least the last 30 years. In fact, "Recombinant DNA" is used to induce strains of bacteria and yeast cells in cultures to manufacture vaccines like the flu and Hepatitis B vaccine and the insulin used by diabetics these days. The particular retroviruses used by Tamanaka are said to be "strongly silenced in humans." In other words, they don't normally get reproduced as viruses when the cell divides. Once they are taken up in the cell DNA, the viruses used in research don't break out to become infectious viruses, again. However, some of them can induce the cells to form tumors or cancers if injected in an animal or human.


One of the possible problems that the article notes is that the new iPS cells each had several copies of the retrovirus included in their DNA. There is a concern that these bits may be responsible for the tumors that were seen in the mice used in the experiments. Before iPS can be used in humans, it will be necessary to learn to remove all the viral particles or to learn to make the cells without viruses that can cause tumors. Otherwise, there is a risk of causing cancer in patients.

The researchers note that another group of scientists have already reported that it is possible to insert one of the genes without using retroviruses and that the hope is to either find a way to insert the other three genes or to remove all traces of the virus.

There's also a suggestion that what they are actually inducing to grow is a sub-set of fibroblasts with the tendency to become embryonic-like stem cells.

Non-destructive embryonic stem cells

It's all over the web (here and here, at the "news@nature.com" site,for instance), three separate labs have been able to reproduce embryonic stem cells by "reprogramming" adult cells from skin.

Much of the commentary is like Art Caplan's comments quoted in the first (Blog.bioethics.net) link above. Paraphrased, the bulk of the "mainstream remarks include, "It's only in mice, and they had to used viral vectors." Well, if you will look at all the much-hyped embryonic "break-throughs," you will see that they are "only in mice" and many of them "used viral vectors."


Caplan, who notes the coincidental timing with legislation in Washington and who chronically sees bioethics through a political lens, couldn't pass up the chance for a rant on "embryos are not people." When I was an embryo, it was close enough for me - and my Mama. I actually agree with Art Caplan's comment that ". . . ditching embryos and jumping to fund alternatives is not the right response to this fascinating news about mouse cells." The reason we won't fund embryonic stem cell research requiring the distruction of human embryos is not because we have an alternative source. It's because we won't fund research that depends on the destruction of embryonic humans.

The abstracts for two of the articles are published on the Nature advance publication online page. (I don't yet have access to the third, in Cell's Stem Cell journal.

Nature advance online publication 6 June 2007 | doi:10.1038/nature05934; Received 6 February 2007; Accepted 22 May 2007; Published online 6 June 2007

Generation of germline-competent induced pluripotent stem cells
Keisuke Okita1, Tomoko Ichisaka1,2 & Shinya Yamanaka1,2
1. Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
2. CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Correspondence to: Shinya Yamanaka1,2 Correspondence and requests for materials should be addressed to S.Y. (Email: yamanaka@frontier.kyoto-u.ac.jp).

We have previously shown that pluripotent stem cells can be induced from mouse fibroblasts by retroviral introduction of Oct3/4 (also called Pou5f1), Sox2, c-Myc and Klf4, and subsequent selection for Fbx15 (also called Fbxo15) expression. These induced pluripotent stem (iPS) cells (hereafter called Fbx15 iPS cells) are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation; however, they are different with regards to gene expression and DNA methylation patterns, and fail to produce adult chimaeras. Here we show that selection for Nanog expression results in germline-competent iPS cells with increased ES-cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The four transgenes (Oct3/4, Sox2, c-myc and Klf4) were strongly silenced in Nanog iPS cells. We obtained adult chimaeras from seven Nanog iPS cell clones, with one clone being transmitted through the germ line to the next generation. Approximately 20% of the offspring developed tumours attributable to reactivation of the c-myc transgene. Thus, iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.
Although ES cells are promising donor sources in cell transplantation therapies1, they face immune rejection after transplantation and there are ethical issues regarding the usage of human embryos. These concerns may be overcome if pluripotent stem cells can be directly derived from patients' somatic cells2. We have previously shown that iPS cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of four transcription factors (Oct3/4 (refs 3, 4), Sox2 (ref. 5), c-Myc (ref. 6) and Klf4 (ref. 7)) and by selection for Fbx15 expression8. Fbx15 iPS cells, however, have different gene expression and DNA methylation patterns compared with ES cells and do not contribute to adult chimaeras. We proposed that the incomplete reprogramming might be due to the selection for Fbx15 expression, and that by using better selection markers, we might be able to generate more ES-cell-like iPS cells. We decided to use Nanog as a candidate of such markers.
Although both Fbx15 and Nanog are targets of Oct3/4 and Sox2 (refs 9–11), Nanog is more tightly associated with pluripotency. In contrast to Fbx15-null mice and ES cells that barely show abnormal phenotypes9, disruption of Nanog in mice results in loss of the pluripotent epiblast12. Nanog-null ES cells can be established, but they tend to differentiate spontaneously12. Forced expression of Nanog renders ES cells independent of leukaemia inhibitory factor (LIF) for self-renewal12, 13 and confers increased reprogramming efficiency after fusion with somatic cells14. These results prompted us to propose that if we use Nanog as a selection marker, we might be able to obtain iPS cells displaying a greater similarity to ES cells.

and

Article Nature advance online publication 6 June 2007 | doi:10.1038/nature05944; Received 27 February 2007; Accepted 22 May 2007; Published online 6 June 2007

In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state

Marius Wernig1,6, Alexander Meissner1,6, Ruth Foreman1,2,6, Tobias Brambrink1,6, Manching Ku3,6, Konrad Hochedlinger1,7, Bradley E. Bernstein3,4,5 & Rudolf Jaenisch1,2
1. Whitehead Institute for Biomedical Research and,
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
3. Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
4. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
5. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
6. These authors contributed equally to this work.
7. Present address: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02414, USA.
Correspondence to: Rudolf Jaenisch1,2 Correspondence and requests for materials should be addressed to R.J. (Email: jaenisch@wi.mit.edu).

Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells—derived from mouse fibroblasts—can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.

Vaginal approach to gallbladder removal

Or removal of the appendix through the mouth?


I finished my residency training in 1993, and was privileged to witness some of the first "laparoscopic" gallbladder removals on one of my rotations with some private surgeons. After 5 years or so of observing and assisting with the old technique that required a 7 to 10 inch incision at the right upper abdomen and months of recovery, I was used to patients lying very still and needing encouragement to breathe after the surgery. I nearly fell apart myself when, just an hour after we removed her gallbladder, one of my patients sat up in bed. I've never moved faster than I did that time, trying to catch her before she tore her wound or fell out of bed when the pain hit!

My first reaction to this story was one of alarm about possible harm due to trying a new, risky maneuver, just because it's surgically possible.

I wasn't sure how much of my distaste was a woman's reaction to invasion through the vagina. After I read the description of the appendectomy through the mouth, I decided that it's a true caution about the risk of such a route.


The biggest problem with recovery from surgery is the trauma to the tissues surrounding the surgical site, especially the muscles that are cut and sewn.

I finished my residency training in 1993, and was privileged to witness some of the first "laparoscopic" gallbladder removals on one of my rotations with some private surgeons. After 5 years or so of observing and assisting with the old technique that required a 7 to 10 inch incision at the right upper abdomen and months of recovery, I was used to patients lying very still and needing encouragement to breathe after the surgery. I nearly fell apart myself when, just an hour after we removed her gallbladder, one of my patients sat up in bed. I've never moved faster than I did that time, trying to catch her before she tore her wound!

The new technique allowed for us to remove the gallbladder - and later, the appendix (and other stuff) - by making 3 or 4 cuts, all less than an inch and using instruments and a camera that allowed remote or video-guided surgery. Without all that cut skin and all those layers of muscle, patients got better, faster.

It's almost routine to perform hysterectomies through the vagina these days. But let's face it, in this case, everything's right there. The surgeon just has to watch for the blood vessels, the bladder and the rectum, and virtually no muscles have to be cut, at all.

Either of these operations would require muscles and "surface" tissues to be cut, and each require that the surgeons' instruments pass other organs. There's also the problem of making the surgical field sterile and maintaining infection control.

With removal of the gallbladder, there is also the risk to the liver, and especially, the common bile duct from the liver to the intestines. For that matter, an oral approach to the appendix would require reaching past the lungs, the diaphragm, the liver and the intestines, unless the instruments can be passed through the esophagus and stomach. (How would you intubate this patient, protect her lungs, or handle the leaks of acid from the stomach into the abdominal cavity?

The surgeons quoted in the New York Times article are proponents of "no scar" surgery.

I'm a little concerned about the way they "read":

Dr. Bessler said his patient agreed to the procedure (two others had declined) because he told her he thought it would have advantages for her, and she accepted his judgment. She was the first in a study that is to include 100 women who need gallbladder surgery, appendectomies or biopsies taken from inside the abdomen. All the procedures will be done through the vagina.

Dr. Dennis Fowler, another surgeon who participated in the operation, said the team began experimenting on women because “incisions in the vagina have been used for a variety of procedures for decades, and proved safe with no long-term consequences.”
. . .
The operation took about three hours, twice as long as the usual laparoscopic surgery, but it was the team’s first operation on a human, and the time should decrease with practice, Dr. Bessler said. Also because it was the first time, to be on the safe side, the doctors did make three small openings in the abdomen for surgical tools. But their ultimate goal is to perform the operation entirely through the vagina.

Leigh's Disease (Long post on end of life and baby Emilio Gonzales)

The mitochondria are the power plants of the cells. They take the sugar and turn it into the power that runs all the processes of the body. Leigh's disease is a defect in the genes of these mitochondria or of the body’s ability to make a protein or an enzyme that is used in the mitochondria, like pyruvate dehydrogenase.

The prognosis for individuals with Leigh's disease is poor. Individuals who lack mitochondrial complex IV activity and those with pyruvate dehydrogenase deficiency tend to have the worst prognosis and die within a few years. Those with partial deficiencies have a better prognosis, and may live to be 6 or 7 years of age. Some have survived to their mid-teenage years.

The defect can be nearly complete or it can be very mild depending on which of the many genes that can be involved are involved. The cells may be able to make energy but only very slowly - or very, very slowly. Or some cells may be able to make some power, but others can't. Some functions of the body need constant energy, others do not.

Pro-Life Blogs and other blogs carry posts about the very sad case of little Emilio Gonzales, who has been diagnosed with "Leigh's Disease." Unfortunately, they are full of implications that doctors (and even the Bishop of the diocese of Austin) are planning to "murder" the baby boy.

We do not have good tests to determine where the genes went wrong and they can go wrong in several places causing different symptoms and even different symptoms in the same child at different times. So this is a “syndrome” or a diagnosis given when we see a pattern of symptoms. AIDS is a syndrome that has only one cause -- infection with a virus instead of many different gene defects -- but it still develops differently in different people and can mimic different diseases in the early stages.

Sometimes Leigh’s disease does respond to thiamine – but only if the defect is in certain genes. Not in the vast majority of cases.

Another name for the syndrome is “Subacute Necrotising Encephalitis,” because in the late stages, areas of the brain die and break down. This little boy's nerve cells all over his body, including large areas in his brain, have died. This can be seen on his MRI.

It’s also supported by the findings on his EEG – that shows that he is having seizures one third to one half of the time. The seizures cause more cells to die.


However, the pain nerves still live: the report says he still reacts to painful stimuli as though he is in pain. He isn't able to process the pain.

Other organ systems fail as the lactic acid builds in his blood and tissues – cooking the proteins that make up the muscles, enzymes, and most structures of the body. If you’ve ever been sore the day after exercise, you know what lactic acid build up in one spot feels like and how long it takes to go away.

And, of course, growing and healing takes energy. The fastest growing cells for most of us line the intestines and make up the liver where food is processed - they die first, but can grow back sometimes - so the symptoms seem to come and go. When they are dead, it hurts the patient to give him tube feedings that must be absorbed by the gut or to give IV feedings that contain anything that must be processed by the liver.

Even the kidneys use energy. And the sphincters of the bowel and bladder do, too. If there is an imbalance between nerves, the sphincters spasm shut - so Emilio needs a catheter in his bladder.

The lungs stiffen with prolonged ventilator use. The stiff lungs and muscles mean that the pressure from the ventilator needs to be so high in order to give him enough oxygen that he is having leaks appear in his lungs as some of the airways break. The baby's lungs are repeatedly collapsing and having to be re-inflated. This means that over and over, he has a “pneumothorax.”The air goes into the sac around his lungs, squeezing the lung tissue itself down. The pressure outside the lungs is even higher than the pressure the ventilator is making inside the lungs -- each push from the ventilator pushes more air through the leak.

The docs then have to place a chest tube or chest tubes – possibly in a baby, they would use the temporary insertion of large bore needles - to release the air around the lungs, and allow the lung itself to inflate.

Some of the air moves between the tissues of his body, coming to the surface in little pockets – causing “subcutaneous emphysema.” Patients tell me that the pneumothorax and the subcutaneous emphysema hurt. The chest tube does not take away the air in the tissues – that takes days or weeks to be reabsorbed.

What would I do? I would suggest that the mother and the docs adopt a strategy of "this much and no more." Give Emilio droppers of fluids by mouth, to keep his mouth moist. Hold him as much as possible. Continue the ventilator, but stop placing the chest tubes and stop changing the ventilator settings. Do not add new medicines and do not resuscitate when the heart stops.

The Ethics Committee Report has been published at the North Country Gazette.

Medical Update Since Last Ethics Committee Meeting on 2/19/07:

Dr. Alexandra Wilson, the patient’s current attending physician, states that Emilio is unable to move his arms and legs and only has abnormal posturing movements with stimulation. He rarely opens his eyes, does not gag, cannot cough and cannot breathe without use of the ventilator; his pupils are not normally responsive to light. In addition, he can not empty his bladder and has to have a catheter. He does appear to experience pain, as he grimaces in response to deep stimulation, and is now receiving pain medications. He also bites his tongue, which causes bleeding, making it necessary to place a device in his mouth to prevent further injury to his tongue. In addition, he has experienced repeated full and partial collapses of his lungs, and his physicians and the treatment team are having great difficulty keeping his lungs inflated, even with the assistance of the mechanical ventilator. Finally, he is now having seizures, some of which produce visible physical symptoms, and scans (MRIs) of his head show progressive loss of brain tissue.

Dr. Brendle Glomb, pediatric pulmonologist, then discussed Emilio’s pulmonary status, which as noted above has continued to deteriorate. He explained the current functioning and support provided by the ventilator, and then described why Emilio would no longer benefit from a tracheostomy. He also noted that the repeated collapse and reinflation of Emilio’s lungs is damaging to the lungs, and increases the risk that they will tear or even burst during attempts at re-inflation.

Dr. Jeffrey Kane, pediatric neurologist, then discussed Emilio’s current neurological status, which has continued to deteriorate since the last consultation. Overall Emilio shows no purposeful response or movement, which is evidence that the deeper functioning of the brain is absent. In addition, Emilio’s EEG suggests that Emilio is experiencing many more seizures than those at the bedside can see. Based on his review of Emilio’s most recent EEG, Dr. Kane believes Emilio’s brain may be experiencing seizures between 1/3 and ½ of the time. Dr. Kane believes that the seizure activity will continue to increase, and that continued seizures will accelerate the death of Emilio’s remaining brain tissue. In response to a question, Dr. Kane noted that the current brain damage is not reversible, even if the seizure activity for some reason should slow or stop. Instead, he believes that Emilio will continue to experience the relentless and progressive loss of his brain tissue and brain function, and that no therapy or other intervention has been identified which could stop or reverse this process.

Dr. David Anglin, a pediatric intensivist involved in Emilio’s care, then discussed Emilio’s care-setting. He noted that during the Ethics Consultation on February 19, 2007, there was some hope that Emilio might be able to be transferred to a lower-acuity care setting or discharged home, and particularly if he were to undergo a tracheostomy and receive a feeding tube. However, given Emilio’s continued deterioration, he is too ill to survive anywhere but an intensive care setting, and he certainly is not a candidate to be discharged to home.

Edit 03/19/07 at 21:30 - cleaning up grammar.

Umbilical Cord vs. Embryonic Stem Cells

The Proceedings of the National Academies of Science (PNAS) has published the article that was the subject of this blog last week, and which claims that researchers at the University of Texas at Houston have produced the "first transplantable source of lung epithelial cells." There is no evidence that these cells are "transplantable," and they are definitely not the first team to produce Alveolar Type II ("ATII") lung cells from more primitive stem cells. The article does an excellent, if technical, job of explaining the importance of ATII lung epithelial cells:

The alveolar epithelium covers [approximately] 99%of the internal surface area of the lung and is composed of two major cell types, the alveolar type I (ATI) cell and the alveolar type II (ATII) cell. ATI cells are large flat cells through which exchange of CO2/O2 takes place. They cover [approximately] 95% 0f the alveolar surface and comprise [approximately] 40% of the alveolar epithelium and 8% of the peripheral lung cells. In contrast, ATII cells are small, cuboidal cells that cover [approximately] 5% of the alveolar surface and comprise 60% of the alveolar epithelium and 15% of the peripheral lung cells. They are characterized by the unique ability to synthesize and secrete surfactant protein C (SPC) and by the distinct morphological appearance of inclusion bodies, known as lamellar bodies. Important functions of ATII cells are (i) to synthesize, store, and secrete surfactant, which reduces surface tension, preventing collapse of the alveolus; (ii) to transport ions from the alveolar fluid into the interstitium, thereby minimizing alveolar fluid and maximizing gas exchange; (iii) to serve as progenitor cells for ATI cells, which is particularly important during reepithelialization of the alveolus after lung injury; and (iv) to provide pulmonary host defense by synthesizing and secreting several complement proteins including C3 and C5 (1–3) as well as numerous cytokines and interleukins that modulate lymphocyte, macrophage, and neutrophil functions (4). Severe pulmonary diseases can be caused by deficiencies or genetic mutations in proteins synthesized by ATII cells that are important in maintaining normal lung homeostasis. For example, complete deficiency of surfactant protein B (SPB) is caused by genetic mutations in the SPB gene. This deficiency results in impaired pulmonary surfactant composition and function and is a major cause of fatal neonatal respiratory disease (5, 6). In addition, ATII cells synthesize and secrete the serine protease inhibitor alpha-1-antitrypsin (alpha-1 AT) which also plays a key role in alveolar homeostasis by regulating protease imbalance and adjusting fluid clearance (7, 8), the importance of which is supported by the association of alpha-1 AT deficiency with the development of pulmonary emphysema (9). Cystic fibrosis is thought to be primarily a disease of the upper airway and submucosal epithelia and is caused by mutations in the cystic fibrosis transmembrane conductance receptor (CFTR) (10). CFTR is an important regulator of Cl and liquid transport in the lung (11–14) and is functionally expressed by human ATII cells, strongly suggesting a critical role for CFTR in regulating ion and fluid transport in the lung alveolus in addition to the upper airway (13).

(The numbers in parentheses refer to footnotes. Also, I had to change some of the characters to words: "alpha" and "approximately")

The PNAS report and UT Houston's Press Release do not contain any note about the earlier umbilical cord blood stem cell research, although the latter was published on line and in print in Cytology, at least 2 weeks before the initial submission of the PNAS article.

Both research teams report that they followed the techniques developed and reported in the lab of another researcher, Samadikuchaksaraei, in growing, multiplying and guiding the differentiation of their primitive cells toward the more specialized lung cells that were desired. Both report the successful production of ATII lung cells, as demonstrated by the way the cells look and by demonstrating the production of Surfactant Protein C - which, in human development is only found in mature ATII cells after the unborn (or premature) child has reached 36 weeks of gestation.

The Houston team claims that one reason their process is superior to the earlier Embryonic Stem Cell research is that they were able to produce mature cells in 10 days, while Samadikuchaksaraei's team took 15 days. If the ability to produce the cells in what Wetsel, et. al., describe as a "timely manner," then it is important to note that the Minnesota team produced their mature ATII cells in 3 to 8 days.

The Houston team also claims that is possible that their new cell lines might one day be transplanted, although there has never been any research reporting the successful transplantation of epithelial cells into the lungs. Another problem is that the cells were guided to change by "transfection" with a segment of DNA that is inserted into the genes of the cells, using a retrovirus. Any use of these cells, even if anyone ever proves that we can transplant cells into the lung and cure a disease, will be complicated by years of research to prove that the gene therapy that produced these cells is safe and stable in the lungs of the patients. The authors do not give us any references to support this hypothesis.

From the Discussion section of the PNAS article:

"Lung injury due to chronic pulmonary diseases, such as chronic
obstructive pulmonary disease and asthma, and inherited genetic disorders, such as cystic fibrosis and
1-AT deficiency are leading causes of morbidity and mortality worldwide. Cystic
fibrosis and
1-AT deficiency are two of the most common inherited genetic defects affecting Caucasians. In addition, SPB deficiency is a major cause of respiratory disease and fatality in neonates. All three of these diseases are caused by single-gene defects and therefore have been logical candidates for gene therapy. However, efficient vector delivery and sufficient transgene expression needed for therapeutic benefit have remained elusive. Recent research advances indicate that gene delivery via transplantation of cells derived from human stem cells may provide an attractive alternative to viral or liposome vector based gene therapies. Moreover, transplantation of cells derived from human stem cells may prove ideal for the repair and regeneration of injured lung tissue.

Because of its ability to proliferate as well as to differentiate into ATI cells, the ATII cell is an excellent choice of lung cell for possible therapeutic use in gene delivery and repair of the alveolus.

. . . The use of ES cells as a source of transplantable cells in the lung alveolus will require the generation of significant quantities of highly pure ATII cells. To achieve this goal, we chose to genetically modify hES cells so that resulting differentiated ATII cells could be enriched through antibiotic selection. Our approach was to establish a stable transfected hES cell line containing a single copy of the human SPC promoter-Neor fusion gene. When subjected to differentiation in vitro, it was hypothesized that ATII cells derived from this genetically modified hES cell line (SPCP/NEO.74) would express the Neor gene and would therefore survive G418 antibiotic selection, whereas, all of the other differentiated cell lineages as well as the pluripotent cells would be eliminated by G418 selection. Immunocytochemical and flow cytometric analysis of the surviving G418-selected cells supported this hypothesis, indicating that this genetic selection approach resulted in an enrichment of hES-ATII cells to 99% when cultured on Matrigel-coated plates. Our protocol reproducibly produced from each 10-cm culture dish 106 essentially pure ATII cells within 15 days of differentiation. These differentiated ATII cells survive for at least 2 days in culture in the absence of G418 and will provide in a timely manner sufficient numbers of pure ATII cells for future transplantation investigations."

(No footnote references were removed from this quoted portion.)


The abstracts are available on line for free, but the actual articles are available only by subscription or by paying for temporary access:

From Proceedings of the National Academies of Science, published online March 2, 2007

"A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells"

Dachun Wang, David L. Haviland, Alan R. Burns, Eva Zsigmond, and Rick A. Wetsel. Research Center for Immunology and Autoimmune Diseases and Laboratory for Developmental Biology, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center; Department of Biochemistry and Molecular Biology, University of Texas Medical School; and Cardiovascular Sciences Section, Department of Medicine, Baylor College of Medicine. Communicated by C. Thomas Caskey, University of Texas Health Science Center, Houston, TX, January 4, 2007 (received for review November 22, 2006)

Alveolar epithelial type II (ATII) cells are small, cuboidal cells that constitute 60% of the pulmonary alveolar epithelium. These cells are crucial for repair of the injured alveolus by differentiating into alveolar epithelial type I cells. ATII cells derived from human ES (hES) cells are a promising source of cells that could be used therapeutically to treat distal lung diseases. We have developed a reliable transfection and culture procedure, which facilitates, via genetic selection, the differentiation of hES cells into an essentially pure (>99%) population of ATII cells (hES-ATII). Purity, as well as biological features and morphological characteristics of normal ATII cells, was demonstrated for the hES-ATII cells, including lamellar body formation, expression of surfactant proteins A, B, and C, alpha-1-antitrypsin and the cystic fibrosis transmembrane conductance receptor, as well as the synthesis and secretion of complement proteins C3 and C5. Collectively, these data document the successful generation of a pure population of ATII cells derived from hES cells, providing a practical source of ATII cells to explore in disease models their potential in the regeneration and repair of the injured alveolus and in the therapeutic treatment of genetic diseases affecting the lung.
Keywords: complement , differentiation, surfactant proteins, alpha-1-antitrypsin, cystic fibrosis transmembrane conductance receptor

And here's the abstract of the report from November in Cytotherapy, (2006) Vol. 8, No. 5, 480-48 (Note the association with BioE, Inc., the company that's doing the cancer research with MD Anderson):

"Differentiation of umbilical cord blood-derived multilineage progenitor cells into respiratory epithelial cells."

MJ Berger, SD Adams, BM Tigges, SL Sprague, X-J Wang, DP Collins and DH McKenna, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA, Clinical Cell Therapy Laboratory, University of Minnesota Medical Center, Minneapolis, Minnesota, USA, and BioE Inc., Saint Paul, Minnesota, USA

Background - Umbilical cord blood (UCB) has been examined for the presence of stem cells capable of differentiating into cell types of all three embryonic layers (i.e. endo-, ecto- and mesoderm). The few groups reporting success have typically confirmed endodermal potential using hepatic differentiation. We report differentiation of human UCB-derived multipotent stem cells, termed multilineage progenitor cells (MLPC), into respiratory epithelial cells (i.e. type II alveolar cells).
Methods - Using a cell separation medium (PrepaCyte-MLPC; BioE Inc.) and plastic adherence, MLPC were isolated from four of 16 UCB units (American Red Cross) and expanded. Cultures were grown to 80% confluence in mesenchymal stromal cell growth medium (MSCGM; Cambrex BioScience) prior to addition of small airway growth medium (SAGM; Cambrex BioScience), an airway maintenance medium. Following a 3 - 8 day culture, cells were characterized by light microscopy, transmission electron microscopy, immunofluorescence and reverse transcriptase (RT)-PCR.
Results - MLPC were successfully differentiated into type II alveolar cells (four of four mixed lines; two of two clonal lines). Differentiated cells were characterized by epithelioid morphology with lamellar bodies. Both immunofluorescence and RT-PCR confirmed the presence of surfactant protein C, a protein highly specific for type II cells.
Discussion - MLPC were isolated, expanded and then differentiated into respiratory epithelial cells using an off-the-shelf medium designed for maintenance of fully differentiated respiratory epithelial cells. To the best of our knowledge, this is the first time human non-embryonic multipotent stem cells have been differentiated into type II alveolar cells. Further studies to evaluate the possibilities for both research and therapeutic applications are necessary.
Keywords - endodermal differentiation, respiratory epithelium, stem cells, umbilical cord blood.

$17.9 Million plus for Texas: ethical stem cells

The UT Austin Daily Texan has the only report that I can find in the news about Wednesday's announcement that the University of Texas Health Center in Houston is the recipient of $17.9 million for stem cell research on treatments for heart disease.

The National Heart Lung and Blood Institute granted $17.9 million for the research of stem-cell treatments for cardiovascular disease to the UT School of Public Health Coordinated Center for Clinical Trials.

The school was established in 1967 as part of the UT Health Science Center in Houston.

The new funding will bring the institution to the forefront of stem-cell, cardiovascular research. Charged with coordinating the network's participating centers, the school will serve as the hub for the Cardiovascular Cell Therapy Research Network.

"This research will examine the promise of approved stem-cell research of cardiovascular disease," Dr. Lemuel A. Moye said.

The network's centers include the University of Florida, the Cleveland Clinic, the University of Minnesota, the Texas Heart Institute and Vanderbilt University. Dr. Lemuel A. Moye, biostatistics professor and principal investigator of the program at the UT School of Public Health, was excited that the institution was selected to coordinate the other centers.

"It was a pleasant surprise," he said.

I wonder whether this grant will help one of the Houston Health Center Hospitals begin collecting cord blood?

Or will the docs at the UT School of Public Health work with Dr. Willerson and Dr. Perin at the Texas Heart Institute, who are testing a system to select progenitor cells to repair heart tissue, using a commercial product, Aldagen?

Hopefully there's a coordinating board somewhere that's watching over the efficiency of these different research groups.

Texas, Adult Stem Cells, Multiple Sclerosis

Opexa is a division of Pharmafronteirs (or it's the other way around, I'm not sure) which is based at the Woodlands, near Houston, Texas.

The company specializes in cell therapies, based on adult stem cells and the controlled manipulation and replication of adult cells.

Multiple sclerosis (MS)is a disease that causes the loss of the myelin around nerves. Think of myelin as insulation that speeds the transmission of nerve signals. When myelin is lost, nerve signals can't go where they're needed, as fast as they are needed. People end up weak, with tremors, and the lack of balance, loss of coordination and the loss of the ability for the muscles that enable us to breathe and cough to function.

We know that MS is a sort of autoimmune disease in most cases. The cells that are supposed to fight infection and keep abnormal or injured cells that can cause cancer actually decide that the myelin needs to be destroyed.

For over 4 years, Pharmafrontiers or Opexa has been running a series of experiments using T cells - the specialized white blood cells that mature in the Thymus and which are supposed to kill foreign cells, like bacteria or cancer cells.

The company has a technique for isolating the patient's specific T cells that attack their myelin, growing them in the lab until they have millions, and then treating them so they can't multiply. The treated cells are then injected under the skin of the patient, and the body really notices the cells, and uses all the immune system to attack them - and all or most of the T cells in the body that act like them. So the myelin is not destroyed anymore - or at least not as fast.


Opexa are now in Phase IIb - meaning that they know it's safe to use in people (Phase I tests) and are finding out more about how much is needed and who can be helped.

There's a great first-person story about someone who is being treated as part of the experiment at "I Have MS."

For a couple of very pretty videos that explain all this much better than I ever could - and the press release by the company about the Phase IIb trial -- take a look at the Opexa site, at this page.

Added:

Opexa is selling the treatment as "Tovaxin™" - a vaccine.

That's how vaccinations work, by the way. Our bodies are convinced to make antibodies and specialized white blood cells to kill or destroy the foreign bacteria, virus -- and someday, cancer and all sorts of cells that inappropriately make those antibodies and attacks against our own normal cells, treating them as though they are damaged or foreign. As long as our bone marrow is healthy, we seem to be able to make a nearly unlimited number of those white blood cells (there's also some "depots" or reserves out in the lymph nodes and in the liver, spleen and the gut lining where the cells lurk and wait for their chance to multiply and fight disease, evidently). And I think this is how "allergy shots" work.

WARF relaxes embryonic stem cell fees and rules

The Wisconsin Alumni Research Foundation holds the patents on virtually all embryonic stem cells that have ever been produced, that ever will be produced, and of all the technological and medical results of that research. At least according to them, and at least in the United States.

And they've been sued by other researchers because of those patents - and not only because of the money involved.

However, early this week the Foundation announced that they will relax some of their earlier restrictions and that they will not charge some researchers for licensing fees. According to the Sacramento Bee,

The Wisconsin foundation that holds patents covering U.S. embryonic stem cell research will waive some of its fees to encourage more industry-sponsored research.

The changes follow criticism from scientists who said the Wisconsin Alumni Research Foundation's fees and its licensing system were driving some investment overseas.

Scientists around the country hailed the policy changes, which will let researchers share their cells for free and allow companies to sponsor research at universities without having to obtain licenses that cost up to $400,000.

"The notion of reducing fees and sharing cell lines and enabling companies to sponsor research at academic institutions is a good thing and should help push the research forward," said Brock Reeve, executive director of the Harvard Stem Cell Institute.

The Wisconsin foundation controls three patents covering research by University of Wisconsin-Madison scientist James Thomson, who in 1998 became the first to grow and isolate human embryonic stem cells. The patents are broadly written to cover the cells and research techniques used by many American scientists.

Nevertheless, the lawsuit will not be dropped, according to SignOn San Diego, by the Union Tribune

But despite the policy changes, the patent challenge will not be dropped, said Loring and John Simpson, of the Foundation for Taxpayer and Consumer rights, one of the groups challenging the patents.

“A change in licensing policy of the human ES cell patents doesn't solve the fundamental problem that the patents should not have been issued in the first place,” Simpson said. “The right thing for WARF to do is admit that it doesn't deserve the patents and abandon them in their entirety.”

Nanofiber Scaffolds for Neural Stem Cells (and some truth)

Johns Hopkins researchers report that they have developed "nanofibers" impregnated with special proteins which allow them to grow neural stem cells from embryonic stem cells without "requiring high concentrations of growth factors."

One of the researchers, Neuroscientist Hongjun Song, comments on the immediate results of the research, which will not include actual patient therapy:

“Eventually, stem cells will be very important for treating disease using cell replacement therapy, but more immediately stem cells offer the opportunity to model human disease and find ways to screen for therapeutic drugs to treat the disease.”

Song is a member of the body which oversees stem cell research at Johns Hopkins, the "Stem Cell Policy and Ethics Program." This means that even though he has a vested interest in maintaining his own lab and promoting his research, he is among those at Johns Hopkins who determine how to follow the institution's mission:

• Facilitate the ability of the public to benefit from advances in cell engineering in morally responsible ways;
  
  
• Anticipate moral and policy challenges in stem cell science and cell engineering; and


• Provide opportunity for careful and interdisciplinary analysis of these challenges that will be of assistance to both policymakers and the public.

The inclusion of Song in justifying and lobbying for his own work under the guise of "ethics" is a serious conflict of interest and can not be called "morally responsible."

The good news is that some people see an end to the use of embryo destruction. From the article posted earlier today on trading eggs for in vitro fertilization fees:

In any case, the need for eggs may only be temporary.

They are, in fact, only a tool to reprogram the inserted DNA so that it will drive the development of an early embryo. Scientists hope to learn enough about that reprogramming process to let them take an ordinary cell from a person and use it to produce other kinds of cells, perhaps without going through an embryo stage. That might happen in 10 years, Murdoch estimated.

And then they wouldn't need eggs any more.

Brain wave biometric key

New Scientist Tech reports on news of a possible personal identification device in the works:

This novel biometric system should be difficult to forge, making it suitable for high-security applications, claim the researchers behind it. The system was developed by Dimitrios Tzovaras and colleagues at the Centre for Research and Technology Hellas, in Greece. It uses an established method for measuring activity in the brain, called electroencephalography (EEG).

EEG measurements identify the location and intensity of millisecond-long fluctuations in electrical activity in the brain via electrodes positioned around a person's scalp.

First tests are planned in Germany this year. Polish scientists working on the technology in another lab have found the identification to be 88% accurate.

However, John Daugman, a biometrics researcher at the University of Cambridge, UK, questions the practicality of the approach. He says an EEG cap could prove too cumbersome and invasive. "Wearing a wired helmet with sensors on one's scalp might change the ambiance of the workplace somewhat," he says.

Similarly, neuroimaging expert Olaf Hauk, also at the University of Cambridge, believes using the system in a wide variety of situations, particularly stressful ones, could complicate the results significantly. "EEG varies greatly depending on a person's alertness, or mental operations," Hauk told New Scientist. "You might not want to be taken for someone else at the airport just because you had a bad night before."

The authors of spy thrillers and milliners should be especially interested. Here's one hat designer who must be prescient with the motto, "The hat on your head is remarkably representative of what's going on inside your head.™"

HT to Kristina Kirby at Emerging Technology

Short course (long post) on medical ethics.

Are doctors killing patients or taking life when they withdraw or withhold care? Do families who don't insist that "everything be done" kill their loved one? Do patients who refuse ventilators, dialysis, etc., commit suicide? For that matter, does a ventilator equal dialysis equal a feeding tube?

Can the patient who refuses all attempts to resuscitate and the family who demands that every effort be made to keep the patient’s body alive even if there is no hope of awareness, both be right?

There's an old saying that pneumonia is the old man's friend. If the surrogate decision maker for a patient with Alzheimer's demands that she be allowed to die while suffering from an easily treatable condition such as pneumonia, but the doctor believes that it would be medically inappropriate to withhold nutrition and hydration, who is right? What if the patient is a child?

At what point does care become medically inappropriate? Who is best qualified to make that determination? Is there a place to say, “This much, and no more?” Is there a point where we say that the last step was where we went too far? And are we doing all this for us, or as care for the patient?

How many events must happen before we "Let go, and let God?"

These are some of the questions raised by the Texas House Committee on Public Health on August 9, 2006. You can watch the full 12 1/2 hour archived video at Texas Legislature Online. (Free RealPlayer necessary) I recommend moving the cursor to 2:20/12:38 and watching until 4:10/12:38. If you only have 30 minutes, Dr. Bob Fine, MD, is very informative (3:12 to 3:40) as a physician who helped develop the practice of hospital clinical ethics in the U.S.

The only question allowed under Section 166.046 of the Texas Advance Directive Act of the Health and Safety Code should be whether or not medical treatment is "inappropriate medical care" for the patient. Section 166.046 is an attempt to allow clinical judgment by doctors carrying out Advance Directives, for oversight of doctors by hospital ethics committees and for disagreements between doctors and the patient or surrogate by allowing time for transfer to another doctor who does not believe that the treatment is medically inappropriate.

Examples of medical procedures and technology that are not medically appropriate care are sometimes clear-cut, and sometimes professional judgment or conscience is needed to make the distinction. The same medicines and procedures used to relieve pain and symptoms carry known, but unintended side effects. Something as simple as oxygen by nasal canula or face mask can sometimes blunt a patient's drive to breathe and force a decision on whether or not to use a ventilator.

At the end of life, even “life sustaining” treatment such as pacemakers, ventilators, dialysis and tube feedings may not always be medically appropriate care. Doctors and family members are faced with decisions about whether a given technology or procedure is life saving or only prolongs dying in patients.

Today, we have the ability to keep the body alive for a few days, even after the brainstem is dead. This is not bad for the patient, because if the brainstem is dead, the part of the brain that could be aware of pain, is also dead. It is not good for the patient either, for the same reason.

If the patient is not brain dead, we can keep them alive much longer because signals from the brain help us maintain blood pressure and heart rate.

In order to keep the heart beating and the lungs breathing on the ventilator, we have to add IV feedings and do frequent blood draws, maintain arterial blood lines to follow the oxygenation, nutrition and blood pressures. Medicines to regulate blood pressure may actually decrease blood flow to the fingers and toes. The patient who is not brain dead or in a coma will require some level of sedation until we are able to create a tracheostomy. Sometimes, we have to paralyze patients and then completely sedate them to make the ventilator tube in the throat tolerable.

When dialysis is needed over months and years, we don't have the ability to prevent the side effects. Patients begin to have “pathological” fractures in their arms, legs, and ribs, simply when they are repositioned in their beds. If the patient only communicates with us to tell us that he or she is in pain, should we continue to hook the patient up to the dialysis machine three times a week because his surrogate insists that “everything” be done? What should we do when he has a heart attack, a stroke, or seizures and the family insists on chest compression, ventilator support or a surgical procedure to place a permanent feeding tube? How about when our efforts keep a patient in physical or mental pain that is uncontrollable – when the doctors cannot control pain or (as in the case of my mother)the patient can’t process stimulation as anything but excruciating pain?

Next: what can we do?

Edited November 29, 2007, to add labels.