____________________

Wednesday, November 17, 2010

Chemistry and the Teenage Mind

Today, I had the unique experience of visiting my son's middle school science class.  The teacher, as part of the curriculum, is bringing in guests to teach his class about real-world science.  I was the first.

In preparation for this class, I thought about how I could impress upon the students the importance of chemistry.  Initially, I thought about discussing anecdotes from my childhood that reflected my interest in science.  However, realizing that some of my "experiments" were extremely dangerous and certainly not executed under adult (or parental) supervision, I opted to omit details in this area.  After all, I did not want to give ideas to these young and impressionable (and somewhat unpredictable) teenagers.  After some thought, I decided that a two-part discussion was appropriate.  The first part was to focus on how chemistry impacts everyday life and the second part was to be a brief presentation based on one of the drug discovery projects I worked on.

When I was introduced to the class, I initially took questions from the students.  These generally related to what my area of expertise is and what are the steps involved in the discovery of new medicines.  These questions, as they related directly to my slide presentation, were tabled until the second half of the class.

The second half of class was uneventful.  I described the drug discovery paradigms of past and current years along with exploratory research relating matrix metalloproteinase inhibitors to inhibitors of endothelin converting enzyme.  The students were engaged and sufficiently grossed out when I discussed studying urine and feces for drug-related metabolites.  While this discussion gave them a flavor for the exciting opportunities available to those pursuing careers in the life sciences, the students seemed much more enthusiastic about the chemistry in everyday life challenge presented in the first part of my visit.

Teenagers, by nature, take a great deal for granted.  They are quite reliable in their abilities to not think about where things come from. For example, money comes from parents, toilet paper comes from Costco, gasoline comes from gas stations and food/medicine comes from stores.  So, when I presented the possibility that chemistry was everywhere, the students actually thought about this idea.  As a follow-up, I went around the class asking each student to name something that they felt was not related to chemistry.  Interestingly, at least one fourth of the class felt that chemistry was everywhere. The other students managed to come up with rather creative questions.  Such questions tended to involve biological processes (vision and movement of limbs) rather than materials.  Still, realizing that biology involves numerous biochemical reactions, these questions were relevant.

Towards the end of this discussion, I directed the students to consider materials.  A door, for example, is made of wood.  The wood is held together by glue, laminated with a coating and stained to a desired color.  While the wood may be from a natural source, agriculture plays an important role in obtaining such products.  Thus, the finished door was the direct result of chemical substances including:
  • adhesives (glue)
  • pigments (stain)
  • polymers (laminate)
  • pesticides 
As a direct result of this conversation, the class understood that chemistry does, in fact, impact practically every part of our daily activities including, but not limited to:
  • clothing (polymers, pigments)
  • toothpaste/soap/shampoo
  • food (pesticides, ingredients, preservatives, packaging)
  • water
  • medicine
  • building materials
  • cars
  • roads
Regarding the roads, one student suggested that if a road was made by hand using only gravel found on the adjacent hillside, and the road was only used by people walking barefoot and naked then there would be no chemistry involved.  No chemistry, that is, except for the natural mineral composition of the gravel.

So, chemistry is truly everywhere.

Friday, November 12, 2010

Personalized Medicine - Treating the Patient vs Treating the Disease

Through the evolution of the drug development process, many factors have been changed and policies adjusted to improve safety, to assure quality and to prove efficacy.  Much work in this area was driven by a core philosophy, enforced by the FDA, that in order to protect patients, medications must be proven both safe and efficacious.  In order to prove these claims, drug candidates are subjected to rigorous assays designed to assess the following responses in various patient populations:
  • maximum tolerated dosages
  • potential adverse effects (both chronic and acute)
  • disease/disorder/symptom response
Throughout this process, certain parameters must be standardized in order to design feasible animal and human protocols because the physical traits among animal and human populations are heterogeneous. Examples of such traits include metabolism and body weight.

Metabolism relates to the speed at which a therapeutic agent, once introduced into the body, is eliminated.  Based on an individual's dietary habits and genetic profile, metabolic rates can range from rapid to slow.  Such variances are often reflected in body weight where individuals with rapid metabolism may weigh less than those with slow metabolism.  Where pharmaceutically active substances are concerned, patients with high metabolic rates will eliminate these agents more rapidly than those with slow metabolic rates.

Body weight is not necessarily a result of dietary habits.  It is, in many cases, dependent upon an individual's genetic profile.  While body weight is not necessarily an indication of one's health, it does impact how one will respond to pharmaceutically active substances.  For example, a heavy person will generally be able to tolerate more alcohol consumption than a leaner companion.  This effect easily translates to medications where a given dosage will induce a stronger pharmacological response in a leaner individual than in a heavier person.

Thus, from the simple perspectives of weight and metabolism, it is easy to see that all patients are not the same - even if they present with similar symptoms.  If this is the case, why does the pharmaceutical industry market medications in a one-dose-fits-all paradigm?  The answer is very simple.  It is not practical to produce an individual dosage for an individual person based on the biological variables within our heterogeneous population.  Medications must be standardized based upon the maximum tolerated dosages and then recommended for patients presenting with symptoms classifying them as suffering from a common disease/disorder.  In this manner, the pharmaceutical industry has historically targeted the disease and not the patient.  With advancements in personalized medicine, all that is changing.

Genetics - Links Between Patient Populations and Drug Efficacy

While weight and metabolism may explain the extent of a patient's response to a given medication, these factors provide little information as to why one patient with a given set of symptoms responds to a given therapeutic while another patient with a similar set of symptoms shows no response to the same treatment.  In many cases, the cause of such variances in response rates lies within an individual's genetic code.  Thus, in order to truly treat the patient, an understanding of genetics is essential.

Today, there are few examples of truly personalized medicine.  One notable exception applies to breast cancer.  While breast cancer is commonly classified as a single disease, it is actually a family of diseases - all affecting breast tissue.  Because different types of breast cancer have different genetic profiles, specific biological markers have been identified which help to determine appropriate therapeutic regimens.  One potential component of such regimens is the drug herceptin.

Herceptin is a monoclonal antibody targeting HER2 proteins.  When a breast cancer cell line overproduces HER2, introduction of herceptin to the chemotherapeutic regimen increases both survival time and response rate compared to chemotherapy without herceptin. Furthermore, when the cancer is not HER2 positive, there is no significant therapeutic benefit to the use of herceptin.  Thus, herceptin represents an example of a medication useful for a specific form of breast cancer in a specific population of patients.

While most new medications are still targeting the diseases, the concept/philosophy of personalized medicine is the driving force behind a new wave of interest in the biopharmaceutical industry. Since the first sequencing of the human genome, the time required for a complete human genetic profile has been reduced from years to days.  Furthermore, the costs associated with genetic sequencing have been proportionately reduced.  One leader in these endeavors is Pacific Biosciences - a company dedicated to the development of real-time genetic sequencing.

One problem slowing the realization of truly personalized medicine is the lack of information on genetic variations throughout human populations.  In this area, efforts are underway to catalog genetic diversity amongst thousands of individuals.  Pilot data has already revealed more than 15 million genetic differences in a population of only 179 people from various populations (C&EN Nov. 1, 2010, pg 8). Furthermore, each individual was found to average from 250-300 genetic mutations preventing normal gene function and 50-100 gene variants implicated in congenital disorders.

While true personalized medicine is still on the horizon, adoption of this philosophy to the life sciences is creating new opportunities in fields including:
  • cell biology
  • genetics
  • drug discovery
  • diagnostics
Through personalized medicine, our understanding of diseases will be improved, patients will receive appropriate medications and side effects will be reduced - resulting in better healthcare for all.