In this issue, we have reduced some 23,000 words down to some 3,700. It is still a rather large issue, but it packs a lot of information. The length of each Digest is dictated mainly by the volume of advances to report, and by our skill at summarizing. We could reduce the volume by selecting, say, only the “Top N” advances, but that would be arbitrary and in any case we already either cut or miss a large number of advances during our scans through voluminous media clippings.

More importantly, it would detract from our mission of showing you that healthcare is moving at an accelerating pace, both qualitatively and quantitatively, into territory largely undreamed of even a decade ago and still largely ignored by healthcare institutions, practitioners, and policymakers. In this issue, the territory is therapeutics.

We strive to improve knowledge and understanding of the acceleration of innovation in healthcare not only through this publication but also through a global summit on the future of healthcare, to be held in June 2009 in Detroit. Read about it at www.healthquake.org. We hope you will join us.

Tissue Engineering

In one of the most exciting developments to date in tissue engineering, scientists bathed an adult rat heart in detergents to remove all the cardiac cells, leaving behind a “frame” of other heart tissues forming the basic shape of the organ. They then re-seeded the frame with cardiac cells taken from a newborn rat, and nurtured the growing heart in the lab. In four days, contractions began in the developing muscle tissue. After eight days, the engineered hearts were pumping.

In theory, any organ could be engineered in this way and would have a significant advantage over donor organs for transplantation because they could be made to match the patient, with less risk of rejection. One idea is to remove the cells from a pig heart — which is about the same size as a human heart – and re-seed it with human stem cells to produce an organ capable of being transplanted into humans.

Stem Cells

Discounting conscientious but irrational objections, the human embryonic stem cell (hESC) ethics debate would go away if we could create hESC lines without harming embryos. It turns out we can, by extracting a single cell from an embryo and storing the cell in laminin to maintain its pluripotency. For years, single cells have been routinely extracted from viable embryos at in-vitro fertilization clinics to test for genetic defects, without harming the embryos.

This method of generating hESC lines appears superior to another recent breakthrough method: transforming human skin cells into stem cells, which involves many risks and may be a decade or more away from therapeutic application. Acknowledging these limitations, a Muscular Dystrophy Campaign official commented that while the skin cell research is encouraging, it is too early to assume it will replace the need for hESCs.

Nevertheless, the skin-to-stem cell method is grasped at as a straw by hESC objectors as well as by researchers wanting to test, in humans, stem cell therapies that have worked in mice. For instance, one group hopes to use reprogrammed skin cells to test in humans a stem cell transplant therapy that restored partial function to defective muscles in mice afflicted with a human model of Duchenne muscular dystrophy, without causing tumor formation.

Sweden’s Karolinska Institute has also turned away from hESCs in favor of a neural stem cell therapy for Parkinson’s disease. In tests on animals with brain damage similar to Parkinson’s, Karolinska researchers “reversed almost completely” the behavioral abnormalities caused by the disease. In their experience, the neural stem cells proved to be safer than hESCs. Nevertheless, judging by an animal trial using mouse ESCs derived from (also very controversial) therapeutic cloning, hESCs may also have potential against Parkinson’s. The mouse ESCs were developed into dopamine-producing neurons to replace those destroyed by Parkinson’s disease. The treated mice showed “a very significant level of recovery” and because the cells essentially originated in the sick animals themselves, they were not rejected. The researchers’ next step will be to make the process more efficient, but human clinical trials are a long way off.

Another adult stem cell therapy in early-stage human clinical trials, this time for critical limb ischemia, uses a purified form of stem cells produced in the patient’s own bone marrow and extracted from the blood, for transplant into the leg muscles with severely blocked arteries.

In mouse and rat trials, the stem cells assembled themselves into small blood vessels, thereby restoring circulation in the animals’ legs. They also secreted growth factors that stimulated other stem cells to come into the tissue and help with the repair.

Another type of stem cell can be transformed in the lab into cartilage cells known as chondrocytes, which can be used to treat osteoarthritis. The method is expected to produce enough cartilage for transplantation. Animal tests are underway, and a human clinical trial is anticipated to start in 2009.

A protein called Lefty produced by hESCs has been found to inhibit the growth and spread of breast cancer and malignant melanoma, and may have similar effects on other tumor types, including those of the prostate. Other proteins yet to be discovered could also have similar effects on other cancers. Lefty’s discoverers are now looking for partnerships with pharmaceutical or biotech companies to develop anti-cancer stem cell therapies based on their findings.

Diseases on Notice

The finding that Lefty is secreted only by hESCs, and not by stem cells from amniotic fluid, cord blood, the placenta, adult bone marrow, or other sources, further validates the need for and highlights the value of hESC research. But while stem cells of all types represent a new and exciting approach to therapy, there remains a lot of life left in drug therapy, given our growing ability to understand and manipulate drugs at the molecular level. In a particularly exciting recent breakthrough, synthetic enzymes were created purely out of computational models — the Holy Grail of computational protein design. The computer modeling process used is now being improved and followed up with directed evolution (which improves the computed base model) to create more efficient catalysts that could lead not only to new and better drugs, but also to environmental decontaminants and fuels.

Multiple Sclerosis

And never mind syntheic proteins: We have barely begun to tap the potential of natural proteins such as interkeukin-27, which has been used to block the onset, or reverse the symptoms, of the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis in mice, suggesting a potential therapy for MS in humans. In another mouse study, nerve damage caused by MS was repaired using a human antibody to re-grow myelin (the substance that encases nerves) in mice with the progressive form of MS. Myelin repair could restore lost function. A single low dose of the antibody was enough to start remyelination, though the process stopped after five weeks. The antibody also worked when combined with a steroid treatment often taken by MS patients. The work is at a very early stage, but human trials are envisaged when the technique is refined.

Alzheimer’s

Ten minutes after a spinal injection of the rheumatoid arthritis drug etanercept, an 81-year-old man with Alzheimer’s disease was noticeably calmer, more attentive, less frustrated, and had much improved memory. His wife said: “There is something has put him back to where he was before. We almost fell off our chairs watching this,” and his son said the rapid change was the “single most remarkable thing I’ve seen.” More work will be required to see if this single case is reproducible in other patients, and does not cause complications of its own.

Lupus

A spontaneous genetic mutation that halts the development of lupus has been discovered in mice immune from severe or systemic lupus-like disease. The mutation reduced symptoms of the disease by interfering with the development and activation of T cells and other immune responses, and is clearly a potential therapeutic target for lupus in humans.

Myeloproliferative Disorders and Leukemia

Clinical trials are underway of a drug for myeloproliferative disorders, a rare class of blood disease that can evolve into leukemia. The drug blocks a mutation that causes overproduction of red blood cells, with minimal side effects in pre-clinical testing. The drug’s development was dramatic in that it took only a year of collaborative discoveries among stem cell researchers from industry and academia to move from identification of the most promising drug candidate to clinical trials, and unique in that a small pharmaceutical company took a big chance on a rare disease.

Hepatitis C

A drug that blocks a specific microRNA strand involved in the viral replication of hepatitis C and in regulating cholesterol levels resulted in a 30 to 40 percent drop in cholesterol levels, which lasted about three months, and produced a long-lasting effect against hepatitis C. The drug’s Danish developer plans to start human trials this year, though apparently not on patients with hepatitis C.

Vaccines: Three Successes and a Failure

It’s nice to have drug and stem cell therapies available when we get sick, but it’s nicer not to get sick in the first place. Much effort is going into vaccines against a variety of conditions, with some notable successes — and a notable failure. The failure was acknowledged in September last year, when trials of an HIV vaccine called Step were halted. After 10 years of development culminating in three years of clinical trials, Step — which contained HIV genes expected to prompt an immune response against cells containing HIV virus — was judged ineffective.

The successes involved vaccines against high blood pressure, malaria, and influenza A — all major killers:

• Swiss researchers created the vaccine that lowers blood pressure. In tests on 72 volunteers with mild to moderate forms of hypertension, those given a higher dose of the vaccine exhibited lower average blood pressure, especially in the early morning. Lowering early-morning blood pressure may reduce the risk of heart attack and stroke, but one scientist cautioned that in situations involving heavy exertion, high blood pressure helps prevent fainting. A larger trial of the vaccine is being planned.

• Early results of the malaria vaccine trial in 214 African infants, announced last October, were that after three months, vaccinated infants were 65 percent less likely to contract malaria than a control group. These strong results gave the green light to a phase III trial of the vaccine, involving 10,000 children, which will begin this year in ten sites across sub-Saharan Africa. If successful, the vaccine could be on the market in 2011. It would mark a hugely significant step forward in the fight against malaria.

• The vaccine that could give lifelong protection against all strains of influenza A — the cause of pandemics — has produced promising results in human trials. Currently, flu vaccines have to be regularly redesigned because the flu virus keeps mutating. The new vaccine targets a protein that is present on the surface of all A-strains of flu and does not mutate. Nine out of 10 volunteers who had two doses of the vaccine developed antibodies against flu virus. Scientists are now working to perfect the formulation before doing larger human trials. It could be stockpiled in advance of a bird flu outbreak, but it will still be some years before it is widely available.

The effectiveness of these and other vaccines could be boosted by another advance in vaccination technology: vaccines delivered through the nose, which have elicited a dramatic immune response (in animals) against influenza, anthrax, hepatitis B, and other diseases. In some cases, the immune response was exponentially higher than afforded by injection. This would mean, among other things, that vaccine production quantities could be reduced to a fraction of current volume, and that sufficient quantities of vaccines could be produced rapidly in response to a pandemic or bioterror attack.

Mucosal vaccines for influenza, bird flu, hepatitis B, HIV, RSV (respiratory syncytial virus), smallpox, anthrax, and other viral and bacterial infections are in various stages of testing. Animal studies have demonstrated that mucosal vaccines easily penetrate the mucous membrane, where cells rapidly engulf the antigen and present it to the immune system. This rapid response also means that the inflammatory stimulants used in traditional vaccines, which can cause pain and swelling at the site of vaccination, are not needed.

TechnoTherapies

Where stem cells and drugs don’t work and vaccines are not available, technology is increasingly available to work around problems caused by disease and injury. For example, a three-wheeled helper robot is being tested with ALS patients this summer. It could be cheaper and more useful than service animals such as dogs or monkeys. The user points a laser at something on the floor, or on a shelf, a table, etc., for a few seconds. The robot sees and memorizes the laser point, goes to that location, looks for an object, and grabs the object with its mechanical arm and gripper. The user then points the laser at his or her feet, and the robot goes to that spot, looks around for a human face, and proffers the object to the face. It currently completes 90 percent its tasks, and with further development the robot could open doors, turn on lights, and serve as a guide.

Another approach to the problem is to develop brain-controlled prosthetic limbs for the disabled. Japanese and US researchers have built a humanoid robot in Japan that simultaneously mimics the walk of a monkey on a treadmill in the US. The robot responds to the monkey’s cortical brain signals, sent via the Internet. It’s not clear what benefit doing this at such a distance confers — perhaps it was just to show off — and it’s not the first time something like this has been done. About two years ago a monkey was able to control a robotic arm at a distance. Still, it is another welcome step toward eliminating the “dis” in disabled.

A device now on the market enables people who have lost speech capability (ALS patients, for example) to speak, simply by thinking. The user wears a wireless collar that intercepts brain signals going to the vocal cords and sends them to a computer that vocalizes them.

Mental problems are also amenable to technological solutions, such as the videogame “FearFighter” recently approved in the UK to treat panic attacks, mild depression, and phobias. This particular advance has renewed the debate about the value of human vs. computer therapy. Arguments pro and con include:

• Videogames help people with agoraphobia or social phobia who wouldn’t otherwise be able to get out of the house to visit a therapist
• A computer can’t express very well a human therapist’s expressions of warmth and positive regard
• “FearFighter” is as capable as a therapist at asking patients to identify the situations that set off their panic attacks, for example, and then giving instructions on what to do.
• Only a live human can assess risks of serious mental illness or suicide
• Computer flight simulation is cheaper than real airplane flight in treating patients afraid of flying
• Computers let patients face their fears in a controlled manner
• If patients are not evaluated appropriately their problems may be compounded
• Patients might choose videogame therapy instead of interpersonal therapy out of embarrassment and perceived stigma, and thus avoid dealing with their problems altogether
• Videogames may be the only option for patients with no health insurance or who live in a remote location — any therapy may be better than no therapy

Technological solutions are also being found for the problems of loneliness and difficulty making attachments among nursing home residents. It turns out that Sony’s robotic dog, Aibo, is about as effective as the real thing in these regards. In a trial, residents took longer to warm up to Aibo, as compared to a group that was introduced to a real dog; however, within a few days the difference lessened.

Other Therapeutic Advances

Finally, below is a sampling of other encouraging developments, in recent months, in therapies of various forms.

Magnetic Nanoparticles for Arterial Repair

Magnetic fields, such as are delivered by MRI machines, have been used to guide ferrous nanoparticles bearing healthy endothelial to steel stents placed in diseased carotid arteries, in rats. One goal is to enable doctors to recoat old stents in the coronary and also in the peripheral arteries, where stents have proved less effective. The system could potentially be applied to the esophagus, bile ducts and lungs, and also in orthopedic procedures, whose steel nails and screws would serve as targets for magnetized nanoparticles containing bone stem cells to strengthen bony structures.

The researchers have used the same method to deliver DNA to arterial muscle cells in culture. They hope in future to combine their gene and cell therapies, using endothelial cells to deliver beneficial genes to damaged arteries.

Spinal Cord Repair

http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/7240898.stm

A therapy under development to regenerate damaged spinal cord nerve fibers through scar tissue could also stimulate undamaged nerves to bypass the scar tissue. A bacteria enzyme called chondroitinase has been found to be able to digest molecules within scar tissue, allowing some regenerating nerve fibers to get through. The enzyme also promotes nerve plasticity, enabling undamaged nerves to make new connections bypassing the injury.

In preliminary tests in animals, combining chondroitinase with rehabilitation produced better results than either technique alone.

Nerve Regeneration with Keratin

The protein keratin – present in human hair — was found in animal tests to speed up nerve regeneration and improve nerve function compared to current treatment options including microsurgery, unfilled nerve guidance conduits, and nerve grafts. The treatment was delivered as keratin gel-filled nerve guidance conduits to repair a 4 millimeter nerve gap in mice.

Future studies will focus on regeneration across larger gaps and will test whether nerve regeneration results in a return of muscle function.

Bones Strengthened by Removing Marrow

After having their marrow removed, the damaged upper leg bones of anaesthetized rats were considerably strengthened by the growth of new bone in the cavity and the rats recovered more quickly than they would otherwise have done. If the therapy works in humans suffering bone damage or loss, major surgeries such as hip replacement could be replaced by a simple procedure using a needle to remove bone marrow.

The loss of some bone marrow is not expected to compromise the ability to make enough blood cells.

MEG Advances

(Source: Advisory Board Horizon Scan, November 8, 2007 (subscription required.))

Magnetoencephalography (MEG), which non-invasively measures fluctuations in magnetic fields generated by the brain, is still largely un-reimbursed for clinical use, being approved only for epilepsy localization where other modalities have failed and for presurgical functional brain mapping. This is despite the fact that MEG provides temporal (milliseconds, compared to seconds for fMRI) and spatial resolution at a level enabling real-time brain mapping of brain activity, which then enables clinicians to decipher the sequence in which brain centers are activated, which aids diagnosis in seizure cases. MEG is also used in presurgical planning, to identify critical areas of the brain that control speech and movement, though another more invasive technique — invasive intracranial electrophysiological (IEEG) mapping – is generally preferred for brain tumor resection.

Despite increasing evidence of its clinical benefits, MEG’s price tag of US$2.8 million and the unwillingness of insurers to reimburse for it relegate the technology mainly to regional neuroscience referral centers. However, it has potential uses — some of them, years away — in traumatic brain injury, cognitive disorders, monitoring treatments for depression, anxiety, and stress, imaging the location and amplitude of depression in the brain, and diagnosing learning and social disabilities in children.

TMS Advance

A new understanding of how transcranial magnetic stimulation (TMS, a noninvasive method to stimulate neurons in the brain) works could substantially improve the therapeutic effectiveness of TMS for various clinical disorders, including depression. TMS could also be used to help determine what parts of the brain are used in object recognition or speech comprehension. Other techniques for studying neural activity in humans, such as functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG), only measure ongoing activity. TMS offers the opportunity to non-invasively and reversibly manipulate neural activity in a specific brain area.

TMS could non-invasively modify neural activity to improve learning and memory, or suppress abnormal activity that underlies neurological disorders. Although its effects vary in different brain regions and individuals, they can be determined empirically by clinicians, using fMRI.

Nanomedicine

A nanovalve that opens in response to pH changes could eventually be used in a targeted drug delivery system for cancer treatment, where it could help deliver drugs directly to tumor cells, treat degenerative diseases where a particular cell type is affected, or control the release of insulin to treat diabetes. But there remains much refinement and safety testing before the nanovalves could be tried in animals and eventually humans.

Potential Anti-Aging Drug

The antidepressant drug mianserin has been found to lengthen the lifespan of the nematode worm by an average of 30 percent. The drug seems to mimic the effects of calorie restriction, which has also been found to extend insect lifespan and seems to be working for (currently middle-aged) primates involved in calorific restriction studies.

Potential Pain Reliever

A combination of capsaicin — the substance that makes chili peppers hot — and a drug called QX-314 has been found to block pain-sensing neurons in rats without impairing movement or other sensations such as touch. The finding may lead to better treatments for both acute and chronic pain. Most pain relievers used for surgical procedures today block activity in all types of neurons, which can result in numbness, paralysis, and other nervous system problems including impaired thinking, alertness, and coordination.

The new drug combination blocks the activity of nociceptors (pain-sensing neurons) without impairing signals from other cells. Injected into the paws of rats, the drug combination enable the rats to tolerate much more heat than usual. Rats injected near the sciatic nerve showed no sign of pain and some continued to move and behave normally. The drug combination took half an hour to fully block pain in the rats, but the effect then lasted for several hours.

Sticky Tape for Suturing

An elastic, biodegradable, sticky tape that can be laced with drugs could replace surgical sutures and staples and be made into drug-delivery patches for placement directly on organs including the heart. The tape has high adhesive strength on wet, soft, slippery, and rough tissues, and has been successfully tested in mice.

Traditional sutures and staples are invasive, difficult to put in place, and can cause punctures and other damage that leads to necrosis. The new tape could be placed in one motion, potentially shortening the time that patients are on the surgical table, including laparoscopic surgeries, where tying knots in sutures is a challenge. The tape could also be used to reinforce sutures and staples in gastric bypass surgery, where leaks are rare but catastrophic if they occur. The tape could release antibiotics as well as drugs that promote healing, and could serve as a drug patch in tissues that stretch and contract, such as the heart.

Both the mechanical properties of the tape and its rate of degradation can be tuned to suit different tissues. The developers plan to work with doctors to identify medical applications that have the most to gain from the use of the tape, and then develop the tape to suit them.