Biomedicine – Part 11: Curing Technologies in the 21st Century Continued – Finding Cures to Stop the Body Attacking Itself

Not too many people realize that many forms of diabetes are caused by our immune system going haywire. Normally, the immune system is our first line of defence against invasive bacterium. But what happens when our system cannot tell friend from foe? In this blog we identify some of the leading autoimmune diseases and the current state of our research, and a potential cure using nanotechnology as the transport mechanism.

What is an Autoimmune Disease?

Autoimmune diseases are inflammatory response diseases caused by our immune system attacking us. They are non-discriminating and can be found in almost every organ and system in the human body. They tend to be chronic conditions continuing throughout the lifetime of the individual. There can be periods of remission followed by reappearance of symptoms. They tend to strike women more than men. Hormones may play a role. But there are some autoimmune disorders that are more prevalent in men such as Type 1 Diabetes.

How significant is the problem? It is estimated that 24 million Americans and 5 percent of the population in Western countries suffer from autoimmune diseases. Compare that to cancer at 12 million Americans and you begin to see the enormity of the problem.

There appears to be a correlation between our genetic inheritance and autoimmune diseases with children tending to develop diseases that appear in parents, and close relatives exhibiting common autoimmune diseases within extended family groups. Multiple sclerosis represents one of the most common autoimmune diseases that tends to run in families.

What confounds the medical field today about autoimmune diseases is finding the smoking gun or guns, the direct causal link that triggers the immune system response. Lots of circumstantial evidence points to viruses, chemical exposure, foods and environmental toxins but doctors and researchers continue to investigate what triggers these diseases. Having a family member who continues to experience an autoimmune disease has made studying this subject very personal to me.

Autoimmune diseases attack every part of the body. The American National Institute of Health identifies at least 80 different autoimmune diseases that include many familiar conditions you probably never thought were caused by our immune system. See how many you know from this partial list.

• Actinic Prurigo – an autoimmune response to the sun
• Addison’s disease – the autoimmune destruction of the Adrenal Gland – a disease that President John Fitzgerald Kennedy suffered from
• Ankylosing Spondylitis – an arthritic condition that attacks the pelvis and spine
• Autoimmune Myocarditis – a condition that effects the heart muscle
• Behcet’s Disease – a disease that causes oral and genital ulcers, and skin and ocular lesions, and can affect arteries and veins throughout the body
• Birdshot Chorioretinopathy – a disease of the retina in the eye that causes flashing lights and night blindness
• Chronic Urticaria and Angioedema – a condition that causes persistent eruptions of hives traced to drug, food reactions, pressure, infection or toxin response
• Celiac Disease – a disorder of the small intestine
• Crohn’s Disease – a disease that effects the entire digestive tract in the body
• Drug Hypersensitivity – a response to drugs leading to fever, skin rash, and internal organ reactions such as hepatitis, pancreatitis, myocarditis, nephritis, intestinal lung disease and muscle inflammation
• Graves’ Disease – a disease of the Thyroid Gland that leads to hyperthyroidism and goiters
• Guillain-Barre Syndrome – a response to infection that results in nerve inflammation, muscle weakness and potential paralysis
• Hemochromatosis – an adult onset disease resulting in progressive iron overload in the body with complications such as cirrhosis of the liver, diabetes, cardiomyopathy, arthritis, and testicular failure
• Hashimoto’s Thyroiditis – a disease of the Thryoid Gland that leads to hypothyroidism
• Hemolytic Anemia – a disease that attacks red blood cells destroying them prematurely
• Juvenile and Type 1 Diabetes – a disease caused by destruction of insulin-producing Pancreatic Islet cells
• Lupus or SLE (Systemic Lupus Erythematosus) – a disease that predominantly strikes women and causes skin, joint, haematologic, neurologic, renal and other organ problems and leads to seizures, psychiatric symptoms, peripheral neuropathies or stroke.
• Multiple Sclerosis – a neurodegenerative disease more common in women that attacks the myelin sheath surrounding nerves affecting coordination, balance and vision as well as many organs in the body
• Myasthenia Gravis – a neuromuscular disease that causes muscle weakness and fatigue.
• Polyarthralgia – a disease that causes inflammation in the joints and is associated with osteoarthritis
• Psoriasis – a chronic inflammatory skin disease
• Raynaud’s Disease – a response associated with other autoimmune disorders that causes blood vessels in the  hands and feet to overreact to cold temperatures
• Rheumatic Fever – a disease that may occur after a Streptococcal or other infection causing lesions in connective tissue, particularly the heart
• Rheumatoid Arthritis – a chronic inflammatory arthritis that causes deformation of joints
• Scleroderma – a disease that affects tissue fibre, particularly the skin, lungs, gastrointestinal tract, heart, small blood vessels and capillaries
• Sjogrens – a disease that attacks the salivary and tear glands
• Thrombocytopenia – a disease that effects blood platelet production leading to abnormal bleeding
• Ulcerative Colitis – a disease that causes inflammation and ulcers in the large intestine
• Uveitis – an eye disease that leads to blindness

Today’s Autoimmune Controls Create Their Own Problems

Currently autoimmune disease treatment is all about reducing or reversing symptoms. In the case of diabetes we treat sufferers with insulin rather than restore pancreatic cell function. In the case of many of the inflammatory responses from autoimmune diseases we treat patients with a cocktail of drugs that include prednisone and other corticosteroids, anti-inflammatories like aspirin, acid blockers, antihistamines and immune suppression drugs (the kind used to stop rejection in organ transplants). In many cases the side affects of these drug cocktails proves to be worse than the diseases.

HLA, T and B, Autoimmune Diseases and a Potential Cure

When scientists and researchers talk about the immune system the letters in the above title become part of the conversation.

What is HLA?

What does T refer to?

What is the B all about?

HLA stands for Human Leukocyte Antigen, the genes that reside on the 6th chromosome in our cells and that govern immune response. The proteins associated with these genes are called antigens.

The T and B refer to different types of leukocytes, the white blood cells that reside in our circulatory systems and marshal our response to infections. The T and the B refer to T-cells, and B-cells. In addition there are sub-categories to leukocyte groups. One is the T-regulatory cell  or T-reg and researchers study it because these cells play a role in regulating the level of immune response by other leukocytes.

If we could develop a technology to stop specific unhelpful autoimmune reactions while allowing our normal immune response to deal with unwanted bacterium and viruses then we would be making a big leap forward in our ability to deal with autoimmune diseases. That’s exactly what researchers at the University of Calgary in Alberta, Canada, have been working on using nanotechnology as the delivery mechanism for a vaccine that cures Type 1 Diabetes and has implications for other autoimmune disorders.

Dr. Pere Santamaria works at the Julia McFarlane Diabetes ResearcherCentre in the University’s Faculty of Medicine.

Dr. Pere Santamaria has led a team developing a diabetes vaccine that uses nanoparticles to stop immune response cells from destroying insulin-producing cells in the pancreas.                                           Source: University of Calgary

Working with mice with Type 1 Diabetes, Dr. Santamaria and his team looked at stopping the autoimmune response that damages the pancreas leading to the condition. They studied the behaviour of specific T-cells responsible for the disease and the T-reg cells whose role is to inhibit the former from attacking healthy host tissue.  Their goal was to strengthen the T-reg cells to stop the destructive autoimmune response. Using synthetic iron oxide nanoparticles and a cocktail of antigens from insulin producing cells, the team created a vaccine that could be directed at the autoimmune attack, strengthening the T-reg cells. The treatment not only restored normal blood sugar and insulin levels in the mice, it also prevented the onset of the disease. At the same time the vaccine treatment did not compromise the rest of the immune system.

The implication of using nanovaccines such as the one Dr. Santamaria’s team developed to treat other chronic autoimmune diseases is enormous. For those who suffer from one or more of that long list of autoimmune diseases described above, this is technology with great promise.

Biomedicine – Part 11: Curing Technologies in the 21st Century Continued – Curing Cancer

Some Basic Facts About Cancer

When the genes in normal (somatic) cells mutate cell behaviour may change over time leading to cancer. Mutations are a normal part of the life of a cell. That’s because when cells divide they replicate their DNA but imperfectly.

In a previous blog we talked about telomeres, the ends of the DNA strands in our chromosomes and how the telomeres shorten over time with each cell division eventually leading to cellular death. But it is not just telomeres that change during cell division. Other parts of the DNA can get scrambled or lost. We call these changes mutations. Since mutations happen all the time why do some become cancerous while others remain benign?

Medical researchers suspect that specific mutations in sections of our DNA that regulate the cell life cycle, when accumulated over time, cause cancer. Mutations that govern other cellular functions appear to have no malignant implications.

Here are some additional facts about cancer.

1. Less than 5% of cancers are familial, that is, inherited. So when you are told breast cancer runs in your family this is representative of a very small percentage of all the cancers that doctors see.
2. Most cancers happen in older people and are not inherited. They result from accumulated DNA mutations in cells over a lifetime.
3. Some cancers result from epigenetic changes, that is external factors such as environment, food and nutrition and lifestyle that create DNA mutations.

As researchers study cancer they are discovering new ways to treat it and reviewing some old ideas that showed promising results in the past. Let’s look at where we were with cancer, where we are today, and where we will be in the near future in the 21st century.

Seeking a Vaccine that Cures Cancer

Does the name William Coley ring a bell? For most of you, probably not. Born in 1862, Dr. Coley, an American surgeon who decided to devote himself to finding a cure for cancer, was the first to note that exposure to an infection could arouse a person’s immune system to shrink tumors.

William Coley pioneered cancer treatment with patients by injecting them with Coley's toxin, a mixture of heat-treated bacteria. Source: MBVax Bioscience Inc.

Dr. Coley studied sarcoma (bone cancer) at his New York hospital and identified a prior case of a German immigrant who had been operated on several times to excise a tumor in his left cheek. Each time the tumor regrew and after the final operation the remaining wound became infected. Surgeons were convinced that the man’s case was terminal but 4-1/2 months after he was discharged the tumor had vanished. When Dr. Coley studied the case he discovered that Streptococcus Pyogenes, a common bacterium that causes strep throat, was the source of the wound infection. The history of the case showed that the man had several outbreaks of fever and these outbreaks coincided with dramatic changes to the tumor. Dr. Coley concluded that the infection had saved the man’s life by stimulating his immune system to eradicate not only the bacterium but also the cancer.

Dr. Coley tested his theory on late-stage sarcoma patients first injecting them with live Streptococcus Pyogenes bacterium. The injections caused the tumors to shrink but in two cases the strep infections killed the patients. Dr. Coley then experimented with heat-treated bacterium injections. His first patient was a 16-year old boy suffering from a massive abdominal tumor. Known as Coley Fluid and later Coley’s Toxin, when injected into the tumor mass, produced the symptoms of an infectious disease (fever and chills) but not the full-blown illness itself. Repeat injections caused the tumor to shrink and eventually disappear. With no further cancer treatment the patient was discharged and survived another 26 years. Death was from a heart attack and not cancer.

Today the work of Dr. Coley continues at the Cancer Research Institute in New York. Founded by Dr. Coley’s daughter, the Institute studies how our immune system responds to cancer. In the 1970s doctors at the institute discovered that Bacille Calmette-Guerin or BCG could be used to treat early onset cancer of the bladder. The Institute has also studied cell proteins, called cytokines, and their immunotherapeutic effect on tumors.

Far from being Coley’s Toxin, seen by many in the medical establishment as quackery, current research is proving that Dr. Coley’s approach may lead to multiple cancer vaccines similar to the HPV cancer vaccine used to prime the immune system to kill human papillomavirus, a cause of cervical cancer.

Provenge is a vaccine developed by Dendreon, a company in Seattle. Designed to initially treat late-stage prostate cancer, Provenge is patient-specific. Cells from a patient are collected and then exposed to a chemical bath that contains cytokines that activate the immune system to attack the cancer. The cells are reinjected into the patient over the period of a month. Clinical trials on 512 advanced prostate cancer patients have been encouraging with 1/3 of the vaccinated patients remaining alive after 3 years. Plans are to introduce Provenge into earlier stage prostate cancer clinical trials.

We now know through the legacy of Dr. Coley that immunotherapy works. But what is the actual mechanism within our cells that leads to cancer? Research using baker’s yeast is yielding some exciting results.

Why Yeast Holds Clues to Curing Cancer

Saccharomyces cerevisiae is baker’s yeast, the yeast we humans have been using for milennia to make bread and fermented beverages. When a biologist, Leland Hartwell, decided to study cancer he chose yeast to help him model and understand the cell cycle.

Leland Hartwell, 2001 Nobel Prize winner, studied baker's yeast to better understand cancer cell behaviours. Source: Fred Hutchinson Cancer Research Institute

Hartwell was able to identify more than 100 genes directly involved in yeast cells that impacted life cycle. He called these Cell Division Cycle genes or CDCs. Hartwell identifed specific yeast genes responsible for different parts of the cell cycle and found similar characteristics in human cells. Since CDC genes either stimulate or inhibit cell division at very specific times in the cell lifecycle, Hartwell was able to identify the genes that didn’t operate in a normal manner. These included:

1. Oncogenes – genes that act as if they were operating in hyperdrive
2. Tumor Suppressor Genes – genes that inhibit runaway cell division
3. Checkpoint and Repair Genes – genes that detect damage to the DNA and attempt repairs

Any mutation to these genes could lead to what he described as driving with a stuck-accelerator and broken-brakes with no awareness that something has gone wrong resulting in out-of-control cell replication and the development of cancerous tumors.

What are the implications of this research in our search for cures for cancer in humans? Knowing that mutations in genes that control the lifecycle of our cells causes cancer should allow us to develop targeted therapeutic drugs specifically aimed at stopping runaway tumor growth. The tailor-making of drugs, called pharmacogenomics, should result in patient-specific cancer chemotherapy treatment without the side effects we normally associate with today’s treatments.

Having discovered the genetic mechanism that fuels cancer, the challenge is to find a way of delivering the cure and scientists may have discovered that answer. Read on.

RNA, Nanotechnology and Cures for Cancer

We’ve talked about Ribonucleic Acid or RNA in previous blogs. RNA interference or RNAi is a recent discovery and has enormous implications in delivering a cure for cancer. Why? Because RNAi can be used to silence the activity of specific genes within a cell. It does this by destroying messenger RNA or mRNA, the molecular messenger that carries coded information in genes to the protein factories needed to manage the cell’s lifecyle.

The challenge scientists faced was finding a way to dleiver RNAi  to a target without it degrading. When RNA is normally injected into the bloodstream it quickly degrades. That’s where nanoparticles come in. American researchers have developed a vaccine that contains a nanoparticle drug that can deliver RNAi to cancer cells. Using a polymer that self-assembles to create the nanoparticle, and coated with a chemical that provides each particle with protection from binding to any cells it encounters within the bloodstream, the nanoparticles target surface receptors on cancer cells, penetrate and destroy them and cause minimal side effects to surrounding healthy cells.

It has taken 15 years to develop nanotechnology delivery systems. RNAi was discovered in 1998. What will we witness in the next 15 years? We are getting much closer to one of the Holy Grails of modern medicine, a cancer cure.