Organic Chemistry - What Do You Want to Hear About?

Dear Readers,

For over a year, I have been posting my thoughts on organic chemistry issues from both academic and industrial perspectives.  While the press emerging from many news agencies tends to be negative, I choose to view the chemical industries from a broader and more optimistic perspective.  I view these philosophies as both realistic and necessary.  After all, if chemistry touches almost every aspect of daily life, it seems illogical that this industry, while suffering in the current economy, will disappear.  Furthermore, negative press may tend to dissuade younger individuals from pursuing careers in the life sciences.  Through my efforts, I endeavor to convince students that the future will present many new and exciting opportunities.

While this blog generally reflects my thoughts and opinions on subjects I choose to address, I also want to speak to issues important to others.  In this vein, I ask you to send me questions and/or concerns relevant to the scope of this blog.  I look forward to your queries and the discussions that will follow.

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.

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.

Consulting in Biopharma

Just a quick note today.  I was recently asked to describe my experiences as a consultant.  Part 1 and part 2 of the resulting interview are posted on the Chemjobber blog.

New Paradigms in Drug Discovery

With ongoing uncertainty in the economy, two issues impacting potential rebounds in industry are:

• the lack of new funds available for investment, and
• the need to deliver a rapid return on investment capital.

There is perhaps no sector impacted more by these two issues than pharmaceuticals.  The reasons are in fact quite plain.  Products cannot be advanced from research through the clinic without appropriate funding.  Furthermore, the drug discovery process is inherently slow requiring up to 15 years for successful programs to reach market.  As I have discussed in various postings, these issues, while formidable, can be addressed through creative business models. In this vein, at the ACS meeting in Boston, I learned of Lilly's PD2 program.  This effort, effectively recruits small companies and academic laboratories by offering free and confidential compound screening with the intention of mining this chemical space for potential products to develop and/or potential collaborative relationships.  

The PD2 program is innovative in that it utilizes the broad capabilities and chemical space provided by a broad network of settings for the purpose of advancing its drug discovery pipeline.  Within the parameters of this program, 

• potential collaborators submit compound structures to a confidential on-line evaluation tool
• following evaluation of submitted structures, those deemed interesting to Lilly's programs are selected for screening
• following screening of interesting structures, those with promising activity profiles become subjects for collaborative development activities

If you are a small company or an academic group with limited screening capabilities, how can you lose?  This is especially important regarding compounds that are not of interest to Lilly - companies/academics retain all IP rights.  In the end, small companies/labs with limited resources identify potential development partners and Lilly gets to enhance its research/development pipelines. From the corporate perspective, this is truly a win-win scenario providing a new dimension to the paradigm shift impacting today's pharma/biotech sector.

Corporate Win-Win Scenarios - Where do Employees Fit In?

Looking at PD2 from inside of Lilly's corporate headquarters or from within the labs of a potential small company collaborator, compounds are changing hands and the no-cost synergistic resources available are enough to entice business personnel from both entities to enter into mutually beneficial contractual relationships.  However, if viewed from above, one can see a slightly different scenario.  On one side, small company scientists engaged in drug discovery activities find a sense of security through potential interest from big-pharma.  On the other side, the potential influx of developable compounds might induce Lilly's drug discovery infrastructure to question its long-term importance to the company.  After all, if Lilly can obtain drug discovery services for free, why should it employ its own efforts?

The above argument, while presenting a black-and-white picture, does illustrate a trend towards new paradigms in the pharmaceutical industry.  Such paradigms clearly depend upon research activities. However, such research activities are executed through peripheral organizations and not within the infrastructure of parent companies. Nobody disputes the fact that without research, there can be no development pipelines.  The only real questions are:

• Who does the research?
• Where will research activities be located?

While research activities will always require the talents of skilled and knowledgeable scientists, the location of such activities is still a point of discussion.  As I mentioned in previous posts, research infrastructure is very expensive to maintain - especially when priorities shift to development.  On the other hand, the ability to draw on research infrastructures without the umbrella of long-term commitments provides an attractive option to parent organizations invested in the success of drug development activities.  Through decentralized research models such as PD2, scientists will be able to continue producing cutting-edge research and, at the same time, feed the development pipelines of companies possessing the financial resources capable of bringing new therapeutics to market.

The Pharmaceutical Industry - The Economy and The Press

Over the past several months, articles appear in the news describing the bleak state of various industries contributing to the overall economic and employment situation facing both future graduates and workers of today.  One such article, "The 10 American Industries That May Never Recover," was on Yahoo this morning.  In this article, the pharmaceutical industry was listed as number 5.  The bleak outlook presented read as follows:

"This industry has bled workers for three years, and that trend is likely to continue. The largest companies in the sector, such as Pfizer and Merck, have a number of blockbuster drugs that have lost their patent protection in the last decade. They have other pharmaceuticals that will lose that protection in the next decade. Sales of most of these drugs will move to generic companies that will sell them for far less, and erode critical revenue sources for the huge pharma firms. Most companies in the industry admit that they cannot replace the drugs that go off patent fast enough to keep their revenue high. The other reason employment in the sector will stay down and may drop further is that big drug companies are merging to save costs, and most of those costs are people. Pfizer has cut 30,000 people since the start of the recession. Merck has cut 25,000, and these companies and their peers expect that they will have to bring down costs even more."

While there is first amendment protection regarding freedom of speech and press, such abbreviated analyses of the present situation provide a far gloomier picture than what can be obtained by applying just a little rational thought.  After all, among all of my colleagues and connections, no one is suggesting that the pharmaceutical industry will collapse altogether.  Furthermore, there remains considerable need for the discovery of new and better therapeutics addressing indications for which there is an unmet medical need.  As long as there is a need, there will be a market.

In looking at the above analysis of the pharmaceutical industry, the author is correct regarding the downsizing trend affecting this sector. Furthermore, with major products subject to patent expiration, this trend is likely to continue - at least in the short term.  However, a greater understanding of the industry should provide hope.  With products losing patent protection and becoming generic, one of the first casualties is sales and marketing.  Employment in these areas is dependant upon two areas - currently marketed drugs and drugs soon-to-be marketed.  With research pipelines being downsized to focus on development, the development pipeline has a limited lifetime.  This trend would lead to the conclusion that employment in drug development may suffer.  However, without research, there will be no new products to develop or market.

While research has been a primary casualty over the past 3-5 years, many experts (professionals and recruiters) are beginning to see a change in the market.  This should bring some hope to those preparing to enter the workforce.  To those graduating with BS/MS degrees, jobs have always been more abundant.  To those completing PhD work, a little more time may be necessary before reasonable opportunities present themselves.  In today's economy, pursuit of postdoctoral research activities may provide the necessary time and additional experience necessary to enter the workforce from the most competitive perspective.

The Pharma Industry Casualties - WHAT IS THERE TO DO?

The above discussion, while providing hope to those entering the workforce, does not really address the problem faced by the thousands of scientists who have lost their jobs due to downsizing, outsourcing and company closures.  To this sector, I refer to the many previous posts I have published regarding maintaining up-to-date and diverse skill sets.  There is work out there and one must be creative in order to identify the appropriate opportunities.  Do not be hesitant to try your hand at consulting or applying your skills to related industries. Such industries include:

• agrochemical
• food
• textiles
• polymers
• biofuels
• medical devices
• patent law
• contract research organizations

While it may take some time to adapt to different industries, or to build a consulting practice, the payoff will be recognized in the diversity of new skill sets.  Most importantly, it is critical to maintain a level of visible activity within your chosen sector.  Potential employers will recognize continued efforts and creative thought. Remember, in today's economy, there are plenty of reasons for not getting paid.  However, there is no excuse for not working.

Pharmaceuticals and Food Products - Regulation and Marketing

Over the past few days, news has emerged focused on two areas of high importance to consumers - pharmaceuticals and food products. From the pharmaceutical side, attention focused on Genentech's Avastin and its potential as a cancer therapy.  While approved for the treatment of lung and colon cancer, Avastin was also being marketed for the treatment of breast cancer - an indication not supported by clinical trials.  This issue, covered in detail by Ed Silverman (see "BCA's Brenner: Avastin and FDA Approval Standards", Pharmalot, 9/14/10), goes hand-in-hand with a post by Derek Lowe (see "A New Way to Approve Drugs", In the Pipeline, 9/14/10) focused on new paradigms for accelerated drug approval through the combined use of biomarkers, conditional approval and adaptive clinical trials.  I will not comment further on these areas, instead referring to the referenced posts, except to say that there still remains significant issues regarding pressure leading to premature drug approval and marketing to consumers.

From the food product side, recent news indicating that manufacturers of high fructose corn syrup are petitioning the FDA to rename the product "corn sugar" have emerged.  Particularly appalling is the report that "two new commercials try to alleviate shopper confusion, showing people who say they now understand that whether it's corn sugar or cane sugar, your body can't tell the difference. Sugar is sugar."  Let me make my perspective absolutely clear - THIS IS A COMPLETE DECEPTION!  To back up this statement, the term "sugar" is loosely used to describe the class of organic molecules known as simple carbohydrates.  More commonly, the term "sugar" relates to table sugar (sucrose, produced from sugar cane or sugar beets). Sucrose is one example from a class of molecules known as disaccharides (chemically joined combinations of two monosaccharide units).  The monosaccharide (simple sugar) units making up sucrose are glucose and fructose.

High fructose corn syrup, obtained from corn starch, begins primarily as glucose.  Enzymes are then added to convert the glucose into fructose.  The resulting product is a mixture of two separate monosaccharides - glucose and fructose.  This mixture is different from sucrose because the glucose and fructose molecules are not chemically bound to one another.  It is interesting to note that fructose is not even the major sugar component isolated from corn - its presence in corn syrup is ENHANCED THROUGH ARTIFICIAL MEANS.

Reasons for wanting to include fructose in food products include cost of production and sweetness.  High fructose corn syrup is cheaper to produce than sucrose due, in part, to corn subsidies.  Regarding relative sweetness compared to sucrose, glucose is less sweet and fructose is almost twice as sweet.

In biology, glucose plays important roles in energy and metabolism. In fact, it is critical to the production of proteins and lipids and is a precursor to the production of vitamin C.  Fructose has no such biological roles.  Additionally, while fructose is introduced into our bodies through consumption of sucrose, this introduction is the result of natural sucrose metabolism.  Consumption of high fructose corn syrup essentially results in flooding our bodies with a non-essential and non-nutritive sweetener.  DOES THIS MAKE SENSE?  DO WE REALLY WANT TO FEED THIS CONCOCTION TO OUR CHILDREN?  The food, candy and soft drink industries were doing just fine before high fructose corn syrup.  Certainly, we can do without it today.

Science and Ethics - CAN WE DO IT? vs SHOULD WE DO IT?

At the Boston ACS meeting, I had the pleasure of speaking with Professor Roald Hoffmann.  Our conversation centered around the principle tenants of his lecture that morning entitled "Science and Ethics: A Marriage of Necessity and Choice for the Millennium." During his speech, Professor Hoffmann focused on public suspicion of science relating to ecological, environmental and ethical/moral issues.  Of these three areas, I would like to focus on ethical/moral considerations.

In his lecture, Professor Hoffmann stated that "The invention or implementation of a tool without consideration of the consequences of its use is deeply incomplete.  Science is not ethically neutral."  He went on to say that "we must consider potential abuses of our well intended work."  While both of these statements are absolutely true, scientists are also humans and subject to the same human flaws as the rest of society.  This is never more apparent than when we make plans for selfish purposes or simply because there is a high likelihood that such plans can be successfully executed.  From this philosophy, consider the following:

• We can plagiarize or falsify data, but we shouldn't.
• We can generate harmful chemical or biological warfare agents, but we shouldn't.
• We can withhold negative clinical data from regulatory agencies, but we shouldn't.
• We can promote pharmaceuticals for unproven off-label use, but we shouldn't.
• We can promote herbal remedies and dietary supplements for unproven health benefits, but we shouldn't.
• We can argue the equivalence between natural substances and manufactured alternatives, but we shouldn't.

For all of the above, there are examples highlighted by the press. Certainly, such examples are exceptions rather than common practice.  However, such exceptions, when impacting high profile topics such as food and medicine, have the potential to make big headlines.  As alternatives to the above, consider the following - all of which are standard practices:

• We can maintain high ethical standards in all publications, and we should.
• We can generate useful chemical and biological agents for the benefit of society, and we should.
• We can fully disclose all clinical data to regulatory agencies, and we should.
• We can promote pharmaceuticals, herbal remedies and dietary supplements for proven health benefits, and we should.
• We can anticipate the potential for abuse of pharmaceutical and biological agents, and we should.
• We can focus our efforts on commercialization of products for constructive uses and not simply because we can make money, and we should.

Whether arguing for Avastin as a treatment for breast cancer or that high fructose corn syrup is the same as table sugar, such examples do nothing more than degrade the trust that is essential between the public and the scientific community.