New Finding May Aid Alzheimer’s Treatment Options

A protein recently found in the brain -- gamma secretase activating protein or GSAP -- increases the production of beta-amyloid, the presumed culprit in Alzheimer’s disease. In a mouse model, reducing GSAP led to reduced beta-amyloid disposition ( Nature, 2010, 467, pp 95-99.) This prompts in turn the appealing notion that a drug could be found to inhibit GSAP and thereby forestall or prevent the onset of Alzheimer’s disease.

Imatinib (Gleevec, used to treat chronic myelocytic leukemia or CML) does inhibit GSAP and, in laboratory models, reduces beta-amyloid creation. Unfortunately, imatinib does not cross the blood brain barrier so it cannot be used clinically. A search is now on for a compound that acts like imatinib yet can get into the brain. If found, it would be a very exciting discovery.

The Implications of Chronic Disease

I have written frequently about the importance of chronic illnesses. Most of us are just not aware that their incidence is rising - and rapidly. We tend to think instead about acute illnesses and injury but chronic illnesses are now not only common but last a lifetime once developed and are inherently expensive to treat. On top of that there are enormous losses in quality of life, personal productivity and economic impact on the individual and society.


The Milken Institute quantified some of these issues in a research report a few years ago. They evaluated cancer, diabetes [presumably type 2], hypertension, stroke, heart disease, pulmonary conditions and mental disorders. Here are some of the key findings:

• “More than 109 million Americans report having at least one of the seven diseases, for a total of 162 million cases.

• The total impact of these diseases on the economy is $1.3 trillion annually.

• Of this amount, lost productivity totals $1.1 trillion per year, while another $277 billion is spent annually on treatment.

• On our current path, in 2023 we project a 42 percent increase in cases of the seven chronic diseases.

• $4.2 trillion in treatment costs and lost economic output.

• Under a more optimistic scenario, assuming modest improvements in preventing and treating disease, we find that in 2023 we could avoid 40 million cases of chronic disease.

• We could reduce the economic impact of disease by 27 percent, or $1.1 trillion annually; we could increase the nation's GDP by $905 billion linked to productivity gains; we could also decrease treatment costs by $218 billion per year.

• Lower obesity rates alone could produce productivity gains of $254 billion and avoid $60 billion in treatment expenditures per year.”

To me the important point is that “each has been linked to behavioral and/or environmental risk factors that broad-based prevention programs could address.” Restated, we as individuals need to take responsibility for our own health. Not every illness is preventable, but a very large percentage are. It is up to us to eat a nutritious diet in moderation, exercise our bodies, seek ways to reduce chronic stress and avoid tobacco. These four steps would make a huge difference in our health and our lives.

Meanwhile, we each need to have a primary care physician and that physician needs to accept the responsibility to assist us with our prevention strategies and to coordinate our care should we develop a chronic illness. This will mean better health and much lower costs.

Encapsulated Pig Islet Cells For Diabetes Type 1 – A Trial

Here is a follow-up to the post on islet cell xenotransplantation for type 1 diabetes mellitus. A group in New Zealand has been studying the use of islet cells derived from pigs which have not been genetically modified. The cells are encapsulated to protect them from immune cells. The company reports that they are self regulating (meaning that they will produce insulin as needed based on the body’s blood sugar levels) and efficient at secreting the insulin produced into the patient’s body. The investigators report on one patient that is now nearly 10 years since transplantation with persistent functioning islet cells. Dr John Baker and Living Cell Technologies are conducting the human trial after having tested their product in multiple animal models. The material below, taken from the US National Institutes of Health Clinical Trials web site [http://tinyurl.com/2fmcnp6 ], was prepared by the company and its investigators:

“Intraperitoneal islet transplantation has the potential to ameliorate type 1 diabetes mellitus and avert the long-term consequences of chronic diabetes which cannot be achieved by conventional insulin treatment.

As donor human islets are not available in sufficient numbers, porcine islets are the best alternative source as they are recognised as the most physiologically compatible xenogeneic insulin-producing cells. Although the use of pig-derived cells raises the risk of xenotic infections, this can be minimised by obtaining cells from designated pathogen-free (DPF) animals bred in isolation and monitored to be free of specified pathogens. The worldwide experience to date in more than 200 patients who have received transplants of pig tissue has not demonstrated evidence of transmitted xenotic infections.

As animal-derived tissues have to be protected from immune rejection when transplanted into humans, transplants are usually accompanied by immunosuppressive therapy. However, porcine islets are preferably transplanted without the use of immunosuppressive drugs which cause significant morbidity. To protect them from immune rejection, the islets can be encapsulated in alginate microcapsules which permit the inward passage of nutrients and glucose and the outward passage of insulin. Alginate-encapsulated porcine islets transplanted without immunosuppressive drugs have survived rejection for many months in animal studies, and have been retrieved from a diabetic patient over 9.5 years after intraperitoneal transplantation and shown to contain viable islets that stain positive for insulin.

DIABECELL® comprises neonatal porcine islets encapsulated in alginate microcapsules. DIABECELL® has been safely transplanted in healthy and diabetic mice, rats, rabbits, dogs and non-human primates. Following DIABECELL® transplants, the requirement for daily insulin was significantly reduced in diabetic rats and non-human primates.

The optimal dose and frequency of transplantation of the current DIABECELL® preparation for the treatment of type 1 diabetes in humans can only be determined in clinical trials. The intention of this phase I/IIa clinical trial is to obtain at least 52 weeks safety and preliminary efficacy data in type 1 diabetic patients following transplantation of a single low effective dose of DIABECELL® into the peritoneal cavity.”

The results of this study, still a few years off, will be of great interest to those whose diabetes is hard to control with standard insulin approaches.

More on Transplanted Pig Organs – Xenotransplantation

Although xenotransplantation has not progressed far enough to allow transplanting a pig organ to a human, there are other exciting opportunities in the works for xenotransplantation in the not to distant future.

Individuals that develop liver failure often die before a suitable donor can be found or before the damaged liver can heal on its own. There is no artificial liver comparable to the dialysis machine for kidney failure. But using a specially develop pig liver outside the body to cleanse the person’s blood of noxious compounds is a possibility. There have been some positive results using a normal or a genetically modified pig liver for such “extracorporeal” perfusion until a donor organ is available or until the patient’s liver recovers on its own.

Progress has also been made with genetically modified insulin-producing pancreas islet cells for treating diabetes. One approach is to place the transplanted islet cells into a “capsule” that allows insulin to exit out and nutrients like glucose to enter in yet keeps immune cells that would destroy the islet cells at bay outside the capsule.
Further progress in xenotransplantation is likely but there are significant barriers to success. Genetic modification of the pig is possible but it is not yet clear all of the modifications that will be necessary. Concurrently, work is progressing to develop immune modulation with drugs just as is done to suppress the immune system with human to human organ transplants. Further development of encapsulation may aide the process, especially with islet cell transplantation for diabetes.

Despite all of the progress to date, the barriers to success are very real and only time will tell if xenotransplantation will become a truly viable path to organ replacement

Transplanted Organs From A Pig

There are many more individuals with end stage kidney failure, heart failure, chronic lung disease, or liver failure who would benefit from a transplanted kidney, heart, lung or liver than are available. Similarly, there are many people with unstable, difficult to control diabetes that could benefit from a ready source of pancreatic insulin-producing islet cells.

Today the only option for more organs available for transplant is to encourage more individuals to pre-certify their desire for organ donation should they die in a traffic or other accident.

But another approach, still in the future but gaining traction, is to use organs from an animal – known as xenotransplantation.

Most efforts in xenotransplantation focus on the pig, in part because the organs are near to the same size as humans and the physiology is similar. Very real progress has been made in recent years. The steps required to make this approach effective include genetic modification of the pig so that the human immune system will no longer “reject” the transplanted organ. This has included removing the genes that produce the most important pig carbohydrate antigen that human immune cells recognize. Another step has been to add genes that create certain protective proteins in the complement regulatory system (another part of the body’s mechanism to eradicate “foreign” materials like bacteria, viruses or a cancer.) So far, these steps have been major advances but not sufficient so further efforts will be necessary in order for say, a pig heart or kidney to be successfully transplanted into a primate and eventually into a human. But the progress is real, exciting and promising. Stay tuned.

Thought Controlled Artificial Limbs

I wrote about the possibility of brain-controlled artificial limbs in “The Future of Medicine” but now there has been real progress. At Johns Hopkins Applied Physics laboratory, scientists have progressed with their design of an artificial limb that will have a brain controlled interface. The model came about through a contract with the Defense Advanced Research Projects Agency (DARPA) which has been looking for a prosthetic arm that would be many leagues advanced from those in use today and which in fact date back to the World War II era.

Not all that much progress has been made over the past few decades in artificial arm development. Perhaps it is because losses of legs are much more common than losses of arms. But the loss of an arm is especially devastating to the individual and a truly useful replacement is of critical need.

The new device will have remarkable dexterity with the degrees of freedom of a human wrist and the ability to control individual fingers. Look at your wrist. It can move in six different directions or “degrees of motion.” When you consider the entire arm, there are 27 degrees of motion and the new limb will have about 22 of them included. It weighs just eight pounds which is about what an average arm weighs yet can hold up to fifty pounds. The motive power comes from a rechargeable battery. These are advances of some great import indeed but the next step is the amazing one – brain control. The first step is to use outputs from the nerves in the shoulder that used to control the arm before the injury and loss. These nerves carry outputs from the brain that can be accessed to drive the various internal motors that operate the artificial arm. Later, the plan is to develop microchips to implant in the brain that will sense the “thought” to, say, “lift the arm” or “push that button.”

Johns Hopkins APL is engaged with multiple other groups to bring this work to fruition. One of the major hurdles is to develop the algorithms that take the signals from the brain or the nerve and convert them into mechanical activity. Signal analysis algorithms have now been developed that take outputs from the motor and the premotor cortex of the brain and decode them into specific dexterous movements such as grasping that can drive the electro-mechanical apparatuses in the limb.

The research needed to move this project ahead are daunting but the principals believe that the technology exists and can be turned to good use here. Perhaps one of the first types of patients to be tested will be quadriplegics because to offer such an advance would be dramatic for the involved patient. It sounds like science fiction but instead it is the result of the combined efforts of many engineering and computer scientists along with rehabilitation physicians and others. 

Are Physicians Knights, Knaves or Pawns?

An interesting article in JAMA [Sept 1, 2010] by Drs. Jain and Cassel referred to the British economist Julian Le Grand who suggested that public policy “is grounded in a conception of humans as knights, knaves or pawns.” Basically, are we motivated by virtue, by self interest or are we just passive victims? The authors suggest that this is a good question not only for physicians to contemplate but for our politicians and the general public to consider as well along with the implications of the answer.

Physicians need to examine whether we are working for the greater good and especially the good of our patients; and if so, then to consider why society generally does not think we are. Or do we work with our own income and other gains in mind as the foremost driver of action and work? Or perhaps do we just go about our daily efforts as unfortunate passive victims of insurer and government dictums?

Often the individual likes their physicians and thinks of him or her as a “knight.” This is the belief that the physician has the patient’s best interests in mind at all times and takes the needed steps to be sure that the patient is always placed first. But society overall does not think this way of physicians. To most, physicians have long ago lost their “Marcus Welby” status and instead are driven by the desire for a high income, reduced work load and less attention to the patient and the patient’s needs. With this sort of attitude, society through its elected officials and through the insurance apparatus erects many polices and procedures to guard against the “knave” doing harm, reaping too much income, etc.

Many physicians think of themselves today as just “pawns” in a large bureaucratic maze, unable to practice medicine as they believe it should be practiced; unable to earn a reasonable salary given the work burdens and the work content; and overwhelmed with paperwork and needless regulations. Unfortunately, society has indeed put the physician all too often in this setting and established regulations that presumably will ensure that the physician does what is needed.

There was a time in the clouded past when physicians were thought of as knights, when they looked upon themselves as members of the middle class with a special and higher calling, and government largely left them alone. But as costs of care have risen, as more safety lapses have been recognized, as quality has not been forthcoming commensurate with new knowledge, the public has come to believe that the physician is the problem and not the solution.

I would echo Jain and Cassel’s urging that physicians need to “thoughtfully consider whether and how they contribute to the perception that they are knights, knaves or pawns.” It is time to look in the mirror and, if the vision is not as desired, then to take the needed actions to make mid course corrections. To do nothing is to allow the system to characterize physicians as “knaves” and then to push them into the role of “pawns.”