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.

Biomedicine – Part 8: Robots to the Rescue – Advances in Imaging and Irradiation Technology in the 21st Century

Image-guided therapy has revolutionized medicine in the latter part of the 20th century and into these first two decades of the 21st. The operating room, once the exclusive domain of surgeons, is today a very different world. Radiologists, oncologists, cardiologists, nephrologists, lung specialists, gastroenterologists and other medical specialists have invaded the operating room space using sophisticated imaging and interventional technology that replaces surgical procedures.

These disciplines just like surgeons, are more and more using robotics because robots can be far more precise in delivering therapy to a specific location in a patient’s body, and because robots can use technology with no ill effect to the machine, but if undertaken by a physician could unduly expose them to excessive radiation.

In this blog we will look at interventional radiology, cardiology and other medical disciplines to describe where we are using robotics today and where we are headed in the near future.

Today it is hard to tell where the surgical suite ends and radiology begins. Radiology labs like the one illustrated below look as sophisticated as operating rooms.

Interventional Radiology technology supports both diagnosis and treatment. Source: Indiana University, School of Medicine

A Short History of Radiology Before Interventional

Radiology began with a late 19th century discovery by Wilhelm Roentgen, a German scientist. In 1901 he won the first Nobel Prize ever awarded in physics. Roentgen’s first application of the technology involved x-raying his wife’s hand including the wedding ring she was wearing. X-ray technology became a standard in the first half of the 20th century as a diagnostic tool for everything from skeletal injuries to welded metal plate seams.

In the 1950s contrast agents made it possible to use X-ray technology to see soft tissue and body organs. Development of X-ray movies made it possible to view internal organs at work expanding the capability of this technology as a diagnostic tool.

The 1960s saw the development of sonar imaging using ultrasound, sound wave frequencies of 20,000 or more vibrations per second. The marriage of ultrasound and computer software  further perfected this new imaging technology leading to today’s 3D and 4D ultrasounds used in looking at heart, kidney, uteri and abdominal organ studies. Today expectant mothers and fathers throughout much of the world can get a first look at their future child through fetal ultrasounds. Some even post these images on Facebook.

The 1970s saw the emergence of computed tomography or CT, the digital mapping of the human body producing detailed images of anatomy and physiology.

In the 1980s magnetic resonance imaging or MRI was added to the arsenal of diagnostic tools, creating images in fine slices that could be assembled to provide detail never seen before.

Interventional Radiology

Moving X-rays made it possible for radiologists to become more than diagnosticians. I first encountered the power of X-ray in this format as a new father when my daughter underwent a cardiac catheterization study involving the insertion of a catheter into a vein in her leg that was threaded into her major blood vessels and heart. A cardiologist injected contrast dye into the catheter to measure my daughter’s pulmonary arteries, heart chambers, lungs and study her blood flow patterns. The results confirmed a diagnosis of complex heart and lung disease, first imaged through ultrasound, and now studied in greater detail using X-rays. Although purely diagnostic in nature these initial catheterization my daughter experienced were forerunners of what is today a significant medical breakthrough, the implanting of medical devices to repair the body using catheters.

Today radiologists, cardiologists and other specialists routinely do procedures called angioplasty, using catheters with balloon tips that are inflated to open blocked arteries, or to insert stents and heart valves into patients (see pictures below).

The picture on the left shows two stents. The top one has been inflated after insertion using a balloon-tipped catheter. The picture on the right shows a catheter with an implantable heart valve in stages of insertion and deployment.

Catheters give radiologists other means to deliver treatment. A catheter can be outfitted with a heatable tip containing a platinum electrode with a temperature sensor. Using radio-frequency (microwave) energy, the catheter can literally nuke tissue in the body to kill it. Called radio-frequency ablation or RFA, catheterizations of this type cure arrhythmias (abnormal heart rhythms), and reduce cancerous tumors in the liver and esophagus. A catheter containing an optical fiber can use lasers to treat cancers. Called laser-induced interstitial thermotherapy or LITT, the laser can deliver heat to destroy or shrink a tumor. Another laser treatment called photodynamic therapy, or PDT, activates photosensitized agent chemicals that specifically target cancer cells.

Catheters can deliver chemicals and drugs to a body site to attack a tumor or destroy abnormal tissue. A procedure developed in 1994, called alcohol septal ablation (ASA) is commonly used today to treat a deadly heart condition called hypertrophic cardiomyopathy, where abnormal muscle thickening reduces the heart’s ability to pump leading eventually to blockage of the aorta, the main artery in the body. In the case of the latter the alcohol is injected directly at the point of the muscular blockage site to kill the excessive tissue restoring normal blood outflow.

Catheters can deliver freezing fluids to perform cryoablation or cryotherapy, used to treat prostate, liver and some forms of bone cancer.

Enter the Robots

As interventional treatments have become more the norm than the exception in dealing with many complex health and disease problems, the need for precision and accuracy has led to the development of robotics devices. Some of these devices provide real-time magnified imaging in 3D. Others are used in conjunction with surgical applications to assist in minimally invasive procedures. Most are designed to reduce exposure of both patient and physicians to X-ray irradiation with the latter able to operate these devices remotely.

Siemens has been a pioneer in robotics in manufacturing and other industries and is now applying this expertise to the medical field by building a number of  systems and devices. One of these is Treago, an image-guided robotic treatment table designed to position patients for radiation therapy treatments. Other Siemens devices include Artis Zeego, an radiology system capable of rotating 360 degrees in 6 seconds producing detailed images of entire tumors including blood vessel feeds. Because Artis Zeego is so fast it minimizes patient exposure to X-rays and radioactive contrast.

The CyberKnife, a product of Accuray, a California-based company, features a robotic arm capable of moving around a patient to deliver precise radiation to tumors with sub-millimetre accuracy. The system can sense movement in the patient such as the rise and fall of the chest during breathing and adjust the radiation beam to compensate. How does the CyberKnife know where the tumor is located? The technology communicates with CT scanners and uploads data from these sources to create an accurate location map for the targeted tumor and for healthy surrounding tissue. The medical team creates a treatment plan for the CyberKnife along with desired radiation dosage. CyberKnife’s precision allows for larger doses of radiation focused on the cancer, not healthy cells. Where typically a patient would undergo 20-30 visits using conventional radiation therapy, a CyberKnife treatment plan requires from one to 5 sessions. Because of this precision CyberKnife can treat complex, dispersed and inoperable tumors in the prostate, lung, brain, spine, liver, pancreas and kidney.

As the 21st century continues to unfold we will see more robotic-assisted technology in radiology designed to be less invasive and more precise in treating cancers and other diseases.

Cath Lab Robotics

The same can be said about the use of robots in cath labs where computer-guided catheters combined with navigation systems are allowing cardiologists to do procedures that were once far more invasive and done exclusively by surgeons.

The first use of a robotic system in cardiology dates to 1997. The robot was named Aesop (see our previous blog). Today, catheter-based therapies increasingly rely on robot-assist devices for both diagnostic and interventional procedures. These labs include catheter manipulation by robots directed by computer-aided imaging, and therapeutic robotic devices.

Corindus Vascular Robotics, in Massachusetts, is the developer of the CorPath 200, a robotic system for doing percutaneous coronary intervention procedures, called PCIs. Remember when I mentioned my daughter in this article. Less than 3 years ago she had a PCI done to implant a pulmonary valve and stent. But in her case it was done without robotic assistance and involved a full cardiac team of doctors and nurses. CorPath 200 provides an articulated robotic-arm combined with a remote cockpit containing a workstation with multiple screens and joystick controllers. The cardiologist, from the comfort of the cockpit, does a procedure using the robot arm to accurately place stents and other implanted devices using balloon catheters.

Corindus' CorPath 200 System represents where cardiac cath labs will be in the very near future. Note the similarities betwwen the interventional radiology lab setup and cath labs. Source: Philips Healthcare

Even more interesting are robotic devices that can get inserted into the chest cavity and placed on the surface of a beating heart. One of these is HeartLander, a miniature mobile robot designed to facilitate minimally invasive therapy. Designed to adhere to the outer surface of the heart (the epicardium), this devices moves like an inchworm to position itself on the heart muscle for administering a variety of therapies.

HeartLander is an insertable robotic device that navigates autonomously across the surface of the heart muscle to deliver therapy. Source: Carnegie Mellon University

It navigates autonomously using suction to adhere to the surface and an internal drive wire to create push and pull. The cardiologist can control HeartLander using a joystick and view its progress through a graphical computer interface. The current device is 8.5 mm in diameter with plans to shrink it further to 3 mm.

HeartLander in trials has been used for ablation treatment of arrhythmias, to place leads on the heart muscle for pacing and for delivering medication and chemicals to targeted areas of the heart muscle.

Currently still in the laboratory and being used in animal studies, HeartLander represents the next stage in the evolution of robotic systems for use in biomedicine.