Defy Your DNA: How the New Gene Patch Personalized Medicines Will Help You Overcome Your Greatest Health Challenges

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Preface

Some years ago, I was a family doctor in Evesham, a quaint, medieval market town on the banks of the River Avon in Worcestershire, in the United Kingdom. I was getting to the end of my morning surgery when the phone rang. A worried patient was hoping I could see her son.

I knew the patient, Mrs. Singh and her son Deepak, as I did most of my patients. But like most parents, she didn’t come very often so I did not know her well. Her son was just over three, and I had looked after Mrs. Singh and her husband since before she gave birth to her daughter Jasminder five years earlier. Deepak had been a happy, healthy baby who had passed his 18-month assessment with me despite being a little slow in walking.

Mrs. Singh came in pushing a grinning and content three-year-old in a stroller. As Deepak stared at me, I wondered if maybe he was just enjoying a little extra attention. Mrs. Singh described how her son had become reluctant to walk in the afternoons and evenings. She was worried that he had hurt his leg or, perhaps, had an infection.

I turned to Deepak, squatting down in front of his stroller so that my eyes were on his level. What have you got there? I asked, pointing to a tatty toy he was holding, which I suspected had once resembled a tiger. Deepak beamed but said nothing.

Hoping to entice him to walk, I walked over to a large treasure chest of my own children’s discarded toys that were stowed beneath a couch. I pulled out a squeaking elephant toy. That got his attention.

Look, Deepak, I offered, poking the head of the elephant round the lid of the box and then quickly withdrawing it and squeezing it forcefully. Deepak immediately dropped his tiger and raised himself out of his stroller. He waddled across my examination room toward me - only a few steps, but he seemed indeed rather reluctant. My heart sank. This was not the nimble confident stride of a normal healthy three-year-old.

I gave him the elephant and he sat down with a thump.

I went back to my desk and quickly scanned Deepak’s medical records. There was nothing to suggest he was not entirely normal. I quizzed Mrs. Singh about the health of her immediate family, but again there was nothing notable. I continued eyeing Deepak who was playing contentedly. Then he rolled over and struggled to his feet.

With that, I was alarmed.

At medical school, students are taught about rare diseases, but most doctors, especially those with a list of less than 3,000 patients never see a single case of most of them. So the memory fades. But could Deepak have Duchenne muscular dystrophy? It is very rare. It only occurs in boys, often with no family history, and is often undetectable at birth. It could present pretty much the way Deepak appeared now with difficulty walking at around age three with what looked like enlarged calf muscles on his legs.

I got down on my hands and knees and looked carefully at the now standing Deepak, who had become interested in a colorful paperweight on my desk. Certainly he had large calf muscles for a three-year-old. Quite chunky little legs, but were they abnormally so?

This would be a complex diagnosis to make, and a terrible blow to the Singhs. The disease gradually robs boys of muscle power. They lose the ability to walk, and later to even stand with braces, becoming dependent on a wheelchair for mobility. Then they get breathing trouble and require portable ventilators. But despite all the support, they become totally unable to move and often die in their early twenties when their heart muscle also fails, if they survive that long.

Little progress has been made on this terrible disease since it was first described by the French neurologist, Guillaume Duchenne, in 1891. Despite intense study by scientists and doctors over the last century, there is no cure. In 1986, scientists discovered any one of many mutations in a single gene can cause the muscle cells of these boys to fail to make a vital protein. As a result, their muscles waste away. High doses of steroids temporarily delay the inevitable, but no effective treatment existed then or now, and steroids bring problems of their own.

It is a terrible, unforgiving disease, and the knowledge that the best I could do, if I was correct, was to watch Deepak slip away, is one of the most unpleasant professional situations a doctor can encounter.

Therapeutic impotence is something we were taught to cope with at medical school. However, lectures can’t prepare a doctor for the horror of telling a mother the devastating future she and her family may face. How could I explain that we could put men on the moon, but I could not stop Deepak from slowly dying over the next twenty years as every muscle in his body stopped working?

Many years later, that horrible feeling remains fresh.

At the time, I thought of my own son who had been born with a rare disease, multicystic dysplastic kidney. He was expected to die soon after his birth, and my world had changed with his arrival.

He survived and thrives to this day, which is not how it would be for Deepak if he had Duchenne muscular dystrophy.

I continued to chat with Mrs. Singh while I desperately considered the other possible diseases, illnesses, and injuries that could have befallen Deepak. None of them seemed likely. Attempting nonchalance, I convinced Mrs. Singh of the need for a blood test and drew the sample from a struggling and howling Deepak.

Several weeks later, the worst case scenario was confirmed. Deepak had Duchenne muscular dystrophy (DMD). The diagnosis was understandably difficult for the Singhs to absorb. No parent wants to limit the dreams they have for their children, much less accept that they would likely outlive their offspring.

Later that same evening, after reading stories to my own children, and marveling at my own son who had miraculously survived the fate that his doctors had predicted for him, I wondered if we would ever develop a treatment, let alone a cure for DMD. By we, I meant all the scientists, doctors, laboratory workers, and everyone else involved in healthcare.

Deepak may be dead now, or struggling in a wheelchair and on a ventilator. What more could I have done for him back then? Nothing. Absolutely nothing. I couldn’t even offer hope. That was, perhaps, the hardest lesson and most unpleasant duty I ever had as a doctor.

However, now, in 2012, I am confident that physicians will soon be able to offer more than hope to families like the Singh’s. Maybe not this year and maybe not next, but soon. The hope comes from a new class of medicines that can patch the defective message that comes from a faulty gene that cause diseases like Duchenne’s. Some of these patches work by stopping the production of a disease causing protein, either within the sick patient, or by an invading bacteria or virus. Others of these new medicines work by triggering a naturally occurring alternative process in the human cell to produce a new version of a vital missing protein. This book focuses mostly on this latter category, which offers great hope. In the future, these new gene patch medicines will allow you to defy your DNA.

My eldest son qualified as a doctor himself in 2011. Because of these new medicines, he will be able to offer hope to ALL of his patients, no matter what their diagnosis. In the not too distant future, when a child is born, they’ll be required to have two documents: a birth certificate and a map of their DNA. The map will show which roads to take to get to their destination and which to avoid. Avoiding a bad ending may involve behavioral modification, or traditional medicines or the help of one of these new gene-patch oligomers as they gain acceptance. They are like molecular Band Aids that will hide damaged pieces of the genetic message.

Chapter One

Medicine on the Brink

When, nearly a decade ago, scientists painstakingly documented the entire genetic instruction book for a human being, the human genome, it was a seedling for a new era in medicine. This new era is one where doctors will treat and prevent diseases based on the subtle differences in our DNA.

That feat and subsequent efforts at refinement have unleashed a torrent of information that is just beginning to trickle into physicians’ offices as they diagnose and treat more diseases at earlier and earlier stages.

As that trickle becomes a stream, I grow increasingly convinced that the physicians of today, those who graduated at the same time as my son in 2011, will have new tools to treat diseases never before treatable. They will predict and prevent many others. The whole emphasis of medical care will change from treating illness to creating and preserving wellness.

Medicine, western medicine in particular, suffers from an imperfect, but understandable focus. Physicians usually don’t intervene until a problem exists. Ever since the first human suffered an ache or pain, our species has sought to alleviate suffering whether through the ministrations of a witch doctor, or a simple brew of the aspirin-like willow bark tea, or in recent times, the newest modern blockbuster drug. For the past five thousand years, medicine has focused on diagnosing and treating already sick and symptomatic people.

Physicians aren’t entirely to blame. Patients generally only show up when symptoms appear. Too often that means treating a disease at a very late stage when much damage has already been done. Surgeons have become quite adept at replacing clogged arteries that feed oxygen to the heart, but physicians have been less successful at identifying people at risk for that coronary artery-clogging disease in the first place.

It’s not that doctors wouldn’t prefer to help their patients stay healthy and well. Intervening in a disease process at its earliest stages is always preferred. Treating a disease before today’s laboratory tests or images would show the telltale damage, or being able to prevent it altogether, offers an unprecedented opportunity to deliver optimum health and life expectancy. Doctors just haven’t had tests capable of detecting potential problems or the tools needed to avert them.

That is all changing.

Medicine is moving rapidly from a diagnose and treat model to a predict and prevent model and that will have huge implications for both patients and society.

Imagine going to the doctor who looks at your individual genetic makeup and uses that information to advise you on the most appropriate lifestyle adjustment to prevent a condition years or even decades before it starts causing symptoms. Better still, your doctor may prescribe a precisely targeted medicine for you that will work at the level of a faulty genetic message. So you should never have to worry about falling prey to the condition at all.

This fundamental change in medicine is already taking place.

Driving that change is the torrent of genetic information emerging from efforts to sequence the entire human genome.

In 2003, Nobel Prize winner James Watson was the first to undergo full sequencing of his genome. This effort cost about three billion dollars and took thirteen years.

Now, science and medicine are beginning to harness the information contained within the genome to aid drug development.

At the time of writing this book, there are roughly thirty thousand drugs used in the world. They target about two percent of the proteins found in human cells. This has led to the concept of the druggable genome. This is the subset of the human genome that contains codes for proteins that small molecule drugs can interact with and affect.

Small molecule drugs are those with a low molecular weight, less than one thousand Daltons, compared to biological molecules that have a much greater weight, and oligomers whose weight is typically between six and seven thousand Daltons. A Dalton, named after the English chemist and physicist, John Dalton (1766 – 1844), is a measurement first coined in 1803 and is set as one-twelfth of the weight of an unbound carbon atom. It is equivalent to 1.66 x 10-27 kg. To make that more meaningful, a small grain of sand weighs about 0.67 mg, or 6.7 x 10-4 kg, meaning that it would take roughly 2 x 10²² atoms of carbon, each weighing 1 Dalton, to weigh as much as a single grain of sand.

Small molecules are chemically synthesized and are manufactured to high levels of purity. In addition, they rarely cause an immune response in humans and generally have the same positive and negative effects in animals. That allows them to be tested in animals first before testing in humans. Biological products, especially the newer monoclonal antibodies, are capable of triggering a marked immune response but often only with a specific species.

Scientists, led by Andrew Hopkins and Colin Groom of the drug company Pfizer, looked into the druggable genome in 2002 and found that a mere 399 proteins had successfully been targeted. Later Hopkins lowered this figure to 207.

About half of the targets fell into one of five protein families: G-protein coupled receptors (GPCRs), kinases, proteases, nuclear hormone receptors, and phosphodiesterases.

But not all of the protein targets may actually modify disease. Some examples within each class may be too difficult to target. With fewer and fewer new small molecule drugs reaching approval, there is great anxiety within the medical and pharmaceutical communities that we may be getting close to having identified all the potential targets that small molecules can reach, and that we are reaching the limit of drug discovery, at least for small molecule drugs.

Since Watson’s genome was sequenced, scientists have discovered multiple genes that can predict the risk of one day developing a multitude of diseases. They have discovered genes that can predict how you will burn fat and whether you will develop diabetes. At present, we know of six different genes that affect your chances of developing dementia as a result of Alzheimer’s disease. Those genes, however, only play a role in about sixty percent of all Alzheimer’s cases. Dr. William Thies, the Chief Medical and Scientific Officer for the Alzheimer’s Association, speculates that up to one hundred genes could ultimately play a role.

One approach to Alzheimer’s disease is already being explored in a rather unique situation. In the area around Medellin in Colombia, approximately five thousand people are participating in an experiment. They are all descended from 28 original families who carried a single mutation, E280A of the presenilin 1 gene, a gene that causes Alzheimer’s disease. These people are at risk of developing the disease not as senior citizens, but in their forties and fifties. In this area of Antioquia, subjects with the mutation are being identified and tested with potentially preventative drugs in their thirties, in the hope that early onset, familial Alzheimer’s disease can be prevented.

Here are some other DNA-related health discoveries that are important: Several genes residing on chromosome five turn out to be related to developing asthma, another common disease. A genetic component has yet to be identified for many cases of schizophrenia, as well as obesity and diabetes. Genes are likely to play a part in whether you develop heart disease and chronic obstructive pulmonary disease (COPD), although a much greater risk is run if you smoke. But if you do smoke, maybe it is because you have inherited the desire, or have the gene that predisposes you to become addicted to nicotine.

The list goes on.

Some diseases are described as complex because they result from the interplay of a number of different genes and biological systems, such as your environment.

Cancer is the poster child for complex diseases among those where scientists have discovered that genes confer risk. Because cancer can affect any organ or tissue in the body, it is actually a set of diseases rather than a single ailment. There are faulty genes, named BRCA1 and BRCA2 that increase the risk of developing breast and ovarian cancer in women and breast cancer in men. Similarly, defects in the genes APC and MLH1 raise the risk for developing different types of colon cancer. The ever-growing list of cancer-causing genes is broadly divided into those that cause or promote cancer and those that usually suppress cancer (tumor-suppressor genes). One that was discovered at the Memorial Sloan-Kettering Cancer Center in New York City in 2005, originally called the Pokemon gene and now renamed as Zbtb7, plays a key role in promoting cancer proliferation in surrounding tissues when triggered by another cancer causing gene.

While sequencing Watson’s genome proved time consuming and expensive, genome sequencing today can be completed in days and the cost is plummeting towards the one thousand dollar mark. Genetic Testing Laboratory Inc., 23andMe and deCODE genetics are companies that offer a limited service for considerably less than a thousand dollars, directly to consumers or via a healthcare professional.

Many people are already getting their genomes (i.e. all of their ~25,000 genes) sequenced. All it requires are a few cells from inside your cheek that can be provided in a spit sample. Several biotech companies responsible for sequencing the genome have actually held spit parties to advertise how easy it is now to provide a suitable sample to permit a full genome sequence. In fact, a party hosted by 23andMe even made the Fashion & Style section of The New York Times. A photo of a young couple spitting into collection tubes was captioned, When in doubt, spit it out.

Patients who enjoy being in the vanguard are taking these analyses into their physician’s office to serve as a basis for decisions about their health.

It’s at the physician’s office where the excitement about tomorrow’s personalized medicine can come up against today’s cold hard reality. The field of genomics has moved so quickly that many physicians haven’t learned how to interpret the results of genome sequencing, which are often quite complex.

Personalized medicine is a developing field and there is a learning curve associated with implementing it. Physicians will be grappling with that learning curve for the next five years, but by the end of this decade, reading the results of genome sequencing will be commonplace for them.

So far the revolution has focused most on detecting risk for disease and many books are being written on the subject. But that is a far cry from being able to effectively treat it.

A doctor who learns that you are harboring genes that increase your risk for diabetes will still advise you to lose weight, especially if other obesity-related genetic variations are part of the mix. However, with a genetic map your doctor may have some extra tools in his arsenal. He may be able to use the genetic information to advise you about the type, frequency and duration of exercise and even the best foods to consume, either before or after exercise, to improve your chances of losing weight. In addition your physician will start more frequent screening for elevated blood sugar levels.

Your physician would be able to advise another patient with a genetically greater risk of developing colon cancer to start routine colonoscopy screening at a younger age and to have those screenings more frequently.

Admittedly, these are today’s routine recommendations that you hear from your doctor based on your family history.

But a personalized medicine approach can more precisely define and even