Chapter One
Genomics-A New Era for Medicine
We have entered into a new era in medical care, the era of genomic medicine.
In coming years, we will see an improved ability to diagnose a disease
and even to predict diseases to come later in life. A much more accurate
prognostication of what will happen as the disease progresses and how it
responds to medications will be offered, and treatment will improve. Drug
therapy will change so that new drugs will be more effective and much safer.
Physicians will be able to select a drug based upon an individual patient's personal
way of responding to that drug, both in terms of greater effectiveness
and in terms of reduced side effects.
Even the foods we eat will be understood in terms of how they affect a
specific individual. Vaccines will be "designed" for an individual patient who
has, for example, a particular type of cancer that has been reduced but not
totally eliminated. Finally, actual gene therapy-the introduction of a new
gene to correct one that is diseased or will cause disease-will become commonplace,
such as a true cure for sickle cell anemia or perhaps cystic fibrosis.
Genomics will permeate all branches of medicine.
Medical practice changed dramatically in the middle of the last century.
Earlier, a physician attempted to understand what disease was present so that
he could tell the patient and family its likely outcome. Specific therapies were
few and far between. Then medicine became a true science with an increasing
understanding of the cellular and molecular mechanisms that underlie each
illness. With that developing knowledge, doctors could begin to treat disease
with greatly improved medicines, such as penicillin for infections, tPA for
breaking up blood clots in a stroke or heart attack, and drugs like phenothiazides
for serious mental illnesses like schizophrenia.
Doctors and patients both saw penicillin as a miracle drug when it first
was used to treat serious pneumonias. I am still in wondrous amazement
when I see a person with a stroke come to the emergency room unable to
move his left side, only to watch him stand up and walk an hour later after
receiving tPA. And the state mental hospitals-long used to "warehouse" individuals
with chronic mental illnesses-have been eclipsed by the use of potent
drug therapies that get people back home and enjoying life again.
But now we are entering a whole new era. The genomic era will allow for
a change in your physician's basic approach, from one focused on detecting a
disease and treating it, to one where she is focused on predicting a disease later
in life and prescribing a preventive approach. (I use the pronoun she here to
emphasize another major trend in medicine-today over 50 percent of medical
school students are women.)
Consider Anna Blumenthal, a thirty-four-year-old single woman employed
as a financial consultant with a major accounting firm in the mid-Atlantic
area. She began to have intermittent episodes of breathing difficulty and her
doctor diagnosed asthma, a condition in which the smooth muscles around
the airways deep inside the lungs begin to constrict, making it difficult to
move air in and out and creating the characteristic wheeze during exhalation.
Her doctor reviewed a variety of things she could do at home to reduce her
chance of developing asthma attacks and gave her some preventive medications
as well. He also gave her a prescription for an albuterol inhaler and told
her to keep it handy for use in case of an asthma attack.
She followed her doctor's instructions, making some changes in her environment
and taking the preventive medications regularly. However, at about
two o'clock one morning, she woke up, struggling to breathe. Alone at night,
it was scary. But she remembered the albuterol that was in her medicine closet.
She had read the instructions before but now read them again.
Albuterol comes in a spray canister; you put your lips around a mouthpiece,
press down on the canister, and out comes a measured amount of very
fine spray. The idea is to press the canister while taking a deep breath in, so that
the medicine will get deep into the lungs. Albuterol works because it interacts
with a receptor on the lining of the airways of the lung, a receptor that can relax
the smooth muscles that are causing the constriction. When albuterol finds
that receptor, it breaks the action of the smooth muscle constriction. It doesn't
cure the underlying cause that created the constriction in the first place, but it
can turn the attack around in the short term. This receptor is the product of a
specific gene that is part of our DNA. So we can say that our DNA directs the
production of this receptor along our airways that will respond to albuterol.
Anna knew that after breathing in the albuterol she should begin to feel
relief within a few minutes. She put the mouthpiece in, depressed the canister,
breathed in the spray, and repeated it about a minute later, as directed. Then she
waited, but nothing happened. Indeed, it was getting more difficult to breathe
not less difficult. Now she really was scared because the promised relief had not
arrived. Why? Because Anna is one of those rare people who are born with a
gene that directs the production of a slightly different receptor on the lining of
her airways, and this slightly different receptor does not respond to albuterol.
The middle of the night during an acute asthma attack is hardly the time
to discover that you are among the unfortunate few. But for years physicians
have been unable to predict which patients would not respond to albuterol.
As a result of genomics, soon it will be possible to know who will not respond,
so that an alternative medication can be prescribed and a long night of distress-and
fright-can be avoided.
DNA and the Creation of Proteins
The genomics era began at the start of this century with the preliminary
sequencing of the entire human genome, a task that was completed in 2003.
What does this mean? How does it affect your medical care? A brief review of
the structure and activity of DNA will be helpful before I attempt to answer
these questions.
Deoxyribonucleic acid (DNA) is made up of molecules of four substances(nucleotides) that are named adenine (A), thymine (T), cytosine (C), and guanine
(G). For our purposes let's just use the letters A, T, C, and G. They are attached
to a "backbone" of sugars and phosphate. DNA has two main jobs. One is to
replicate itself and the other is to direct the production of proteins.
Replicating itself allows a copy of DNA to be created whenever a new cell
is created. Proteins are critical cellular compounds that control a cell's basic
functions and structure. DNA ultimately establishes what a cell is and what it
does. Proteins, in turn, are made up of molecules called amino acids of which
there are twenty types, all arranged in a specific sequence that is different for
each protein. DNA directs the sequential arrangement of amino acids, a task
accomplished by the arrangement of the A, T, C, and Gs of DNA.
Each and every cell has our entire DNA. Half of it comes from Mom and half
comes from Dad. It's arranged in units (chromosomes), twenty-three from each side
of our family for a total of forty-six. DNA is basically a long chain of those four
letters A, T, C, and G. These four letters make up the genomic alphabet. They
can be put together in groups of three that code for a specific amino acid.
For example, ACA is the code for the amino acid histidine, which is one
of the twenty that make up proteins in the body. CAC is the code for threonine,
another amino acid that makes up protein. These three-letter codes are
called codons, and we can think of each of them as a "word" in our genetic dictionary.
Consider a long chain of ACACACACACACAC, and so forth. This
would be a code for alternating the amino acids histidine and threonine.
A set of codons, which we can call the gene, is the blueprint for the structure
of a protein. In my example of ACACACACAC, we are not making a true
protein but an alternating chain of these two amino acids. The process goes like
this: Our gene, which would be part of the entire strand of DNA, directs the
creation of a related compound called mRNA (messenger RNA). The mRNA,
which holds the same code,2 travels to a part of the cell called the ribosome; a
ribosome is basically a protein manufacturing factory. The ribosome takes the
mRNA and follows the code, in this case alternating ACA, CAC, ACA, etc.,
and puts together the alternating amino acids histidine and threonine.
A real protein, such as insulin or hemoglobin, is made up of many different
amino acids and usually is many hundreds of amino acids long. After it's manufactured
by the ribosome, it "folds" into a complicated shape that might look
like a ribbon sort of wiggled together on the floor after coming off a Christmas
package. In fact, that shape is very specific and allows for the creation of an
active site on the protein, which is the part of the protein that causes something
to happen, such as relaxing the smooth muscles around the airways.
How much DNA do we have in each of our cells? If we were to "read" one
letter each second it would take about one hundred years to read all the DNA
in those forty-six chromosomes. We have about thirty thousand genes and
more than 99 percent of these are exactly the same in each and every human
being. It's the few that are different that create the differences among us and
explain why one person will respond to a drug and another will not. Or why
one person will have no side effects while the same drug in another person will
cause major toxicity. But more about this later. What I hope you have gathered
so far is that DNA is indeed the "code of life" and that our new understanding
of the genome will open many previously closed doors.
IMPLICATIONS OF GENOMICS ON MEDICAL CARE
Still to come is to understand the exact sequence (those coded four letters
A, T, C, and G) in each of the thirty thousand genes and to determine the
function of each gene.
As this is done during the coming years, it will become possible to predict
who might be more susceptible to a disease, such as atherosclerosis (clogging
of the heart's blood vessels), diabetes, or perhaps colon cancer. Knowing that
a person is at higher risk will allow the physician to recommend a preventive
approach, such as diet and lifestyle changes, for each of these diseases-attention
to cholesterol levels for the person at risk for atherosclerosis, weight control
for the person predisposed to diabetes, and to an early start with screening
colonoscopies for the person at risk of colon cancer. It will allow drug companies
to create specific drugs to counter a disease while avoiding unwanted side
effects and will allow the physician to choose the drug that will be known to
work in a given patient and known not to cause any unwanted toxicities.
As we'll see as we move forward, genomics also is allowing scientists to
better understand bacteria and viruses. For example, remember when the serious
infection SARS started in Southeast Asia a few years ago and quickly spread
to a number of distant cities such as Toronto, Canada? Microbiologists were able
to quite quickly figure out the entire genome of that virus. That helped them
understand how it would spread and infect-and possibly how it could be
treated. Luckily, the SARS epidemic died out, but not before scientists discovered
the nature of this particular "bug" faster than had ever been done before.
Genomics also has led to gene expression profiling, a new technique that
we'll discuss later. But in a nutshell, gene expression profiling creates an opportunity
to understand a tumor in much more detail. Scientists can determine
if it is likely to spread or not (which aids in determining the long-term prognosis)
and as a result recommend proper therapy. Profiling will also allow us to
determine the risk of a disease, such as a heart attack (acute myocardial infarction),
and genomic analysis will let us look at how a person is likely to respond
to a drug, such as those used for seizures.
I suspect it will be some time before there will be much true gene therapy,
that is, the insertion of a new gene to counteract for a deficit or abnormal gene.
So in the meantime, medicine will focus on changing the environment rather
than the genetics. If we know that a person won't respond to albuterol, then
we can simply prescribe a different drug.
If we can identify a gene, then we can move on to identify what proteins
or enzymes the gene produces and what that protein or enzyme actually does
inside the cell. With that information we can then create a diagnostic test and
from that either develop a preventive approach or we could modify the treatment.
So in Anna's case it will one day be possible with a simple finger stick
in the doctor's office to know that she will not respond to albuterol. In her
case the doctor would prescribe a different drug.
Another result of identifying a gene and then its protein product is that
we can now understand the basic defect in a disease and as a result create a
specific drug. We can call this approach to medicine "targeted therapy." Chronic
myelocytic leukemia (CML) is a good example. Two pieces from two chromosomes
that have broken off rearrange themselves so that the piece from the
first chromosome-containing part of a normal gene called BCR-attaches
to the other chromosome next to a normal gene called ABL, creating a new
gene and hence a new protein, each called BCR-ABL. The problem is that this
is not a normal protein, and this new protein is what causes the disease we call
chronic myelocytic leukemia.
The abnormal BCR-ABL protein allows this one cell to divide and divide
and then divide again until eventually there are millions and then billions of
these abnormal cells in the person's body. Until now, the approach to treating
this disease has been to use fairly aggressive forms of cancer chemotherapy to
kill off the dividing cells. But these drugs all have their own side effects, and
they kill off other dividing cells as well. Knowing the underlying gene (BCRABL)
and its protein product (BCR-ABL protein) and using some sophisticated
techniques, such as nuclear magnetic resonance imaging and X-ray
crystallography, researchers determined the site of the active protein-the part
that causes something to happen, such as cell division. With this information
in hand, scientists found a compound that would neatly insert itself into this
active site, blocking the action of the protein. This compound, Gleevec, has
had a major impact on those who suffer with chronic myelocytic leukemia.
Taking the drug blocks this active site and hence the disease seems to "disappear."
Of course, because the underlying abnormal gene is still there, it will
continue to produce the abnormal protein. But as long as the patient takes
Gleevec, the abnormal protein's action is suppressed. This is one of the first examples
of what is known as "targeted therapy," meaning that the drug is selected
specifically because it blocks the action of this very specific abnormal protein.
In the past, if drugs were found to be effective and free of major side
effects, then they could be used for whatever conditions seemed to respond.
The difference here is in precisely knowing the activity of the BCR-ABL protein
and what it does that is abnormal in the cell-and then learning what the
active site is and how to specifically block it. (The Novartis Corporation actually
had the drug Gleevec on its shelves. Developed for a different purpose
years ago, it didn't work. But when scientists discovered the active site of the
BCR-ABL protein, they were able to review a large drug database and determine
that Gleevec might well be what was needed. And indeed it was.)
PHARMACOGENOMICS
All this is leading to pharmacogenomics, a new field that will create these
targeted therapies. Watch the newspapers and magazines, and during the
coming years you'll see quite a few drugs that have been created to respond to
an understanding of how the protein actually works within the cell. The new
science of genomics will also give us some other opportunities to advance
medicine.
We will be able to determine in advance whether a drug will work and
whether it will work in a specific person. Likewise we'll be able to determine
in advance whether a drug will cause side effects or toxicities in an individual
person. This is the beginning of what some are terming "personalized
medicine." Will a drug work? Let's return to Anna Blumenthal, her asthma,
and albuterol.
(Continues.)
