______________________________Arrow-Pushing in Organic Chemistry: An Easy Approach to Understanding Reaction Mechanisms, 2nd Edition (111899132X) cover image

Sunday, December 5, 2010

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.

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.

Tuesday, October 19, 2010

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.

Friday, October 15, 2010

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.

Thursday, September 16, 2010

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.

Tuesday, September 14, 2010

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.

Saturday, August 28, 2010

Academic Institutions and Drug Discovery - New Perspectives

Last September, I posted a blog (Academic Institutions and Drug Discovery, 9/30/09) focused on the question of where the next generation of drug candidates will emerge.  In that post, I described a movement to utilize graduate research programs as drug discovery engines.  I also described why I believe that "this is a very bad idea."  I still hold strongly to that philosophy and maintain that academic institutions are best suited for education.  Any retooling to support commercial efforts as primary activities will serve little more than to dilute the quality of the education provided to graduate students. Notwithstanding, there has been a steady emergence of medicinal chemistry research emanating from academicians.  This is perhaps most noticeable when browsing the poster sessions at the recent American Chemical Society meeting in Boston.

Since the beginning of my affiliation with the American Chemical Society, I have consistently paid dues to the division of organic chemistry and the division of medicinal chemistry.  Both divisions had solid strengths and identities.  Specifically, the division of organic chemistry provided a forum for academic institutions to highlight the most cutting edge developments in organic chemistry - whether total syntheses, new methodologies or the identification of novel natural products.  On the other hand, the division of medicinal chemistry provided an appropriate forum for the presentation and discussion of efforts emerging from industry.  This division made a great deal of sense - especially since these complementary divisions frequently collaborated on symposia where the bridges between organic and medicinal chemistry could be highlighted.

One particular observation from last week's meeting in Boston centered around the fact that the distinctions between the organic and medicinal chemistry divisions are becoming blurred.  I am not implying that the quality of the contributions is suffering.  Walking through the organic posters, the strength of the research presented is clearly represented by the diversity of work emanating from academic institutions worldwide.  What truly surprised me was the number of academic institutions presenting posters in the division of medicinal chemistry.  I estimate that academic posters exceeded industrial posters by at least 60%.  Based on my previously published convictions, I am concerned with this trend.  So, if academic institutions insist on supporting drug discovery programs, how can these activities support education and not result in diverting efforts away from the cutting edge research essential to the training of the next generation of scientists?

Dual Purpose Chemistry - The Merging of Education and Drug Discovery

At the Boston ACS meeting, I attended a session on the concept of open-source chemistry.  In one lecture, I learned about the Distributed Drug Discovery (D3) effort developed by researchers at Indiana University-Purdue University Indianapolis.  The model was loosely compared to the SETI project in which computers around the world, not in use by their owners/institutions, were used to analyze data. Applied to chemistry, this translates to the use of undergraduate laboratory activities simultaneously being used to generate compounds for biological evaluation.

Before going deeper into this topic, when I was an undergraduate at the University of California - Berkeley, solid supported chemistry was in its infancy.  There were a few supports (Wang resins, TentaGel resins) being studied for use, but mainstream combinatorial chemistry was still a few years off. Notwithstanding, Affymax was one of the first companies to emerge using this technique for commercial purposes and the resulting libraries were generally limited to peptides.

As the field of combinatorial chemistry developed, new solid supports became available - many of which were complemented by novel deconvolution techniques allowing for the identification of a single structure amongst millions.  Furthermore, techniques became available for the generation of compound libraries via parallel synthesis of discreet compounds.  No matter which approach, combinatorial chemistry, in general, is limited because only a subset of chemical reactions are compatible with the solid supports essential for generation of compound libraries.  That being said, combinatorial chemistry is now considered a valuable tool for the mining of structural space in order to identify potential lead molecules suitable for further structure-activity analysis.

With the utility of solid phase chemistry to industrial applications, it is not surprising that undergraduate programs are beginning to teach these techniques in their educational labs.  As such, it seems logical to simultaneously and peripherally involve undergraduate students in drug discovery efforts.  Through the D3 effort, students are expected to prepare a library of six compounds using solid-phase parallel synthetic techniques.  In this program, each student prepares the same reference compound along with 5 unique compounds.  If the reference compound is correct, the assumption is that the novel compounds were prepared as expected.

Because target compounds are designed using the combined computational power of multiple personal computers around the world (similar to the SETI efforts), these efforts are truly open-source in nature.  Through these efforts, Professor William Scott and Professor Martin J. O'Donnell have successfully introduced a way to utilize academic institutions for drug discovery activities without compromising the education process.  In fact, these activities only add to the educational experiences of numerous undergraduate chemistry students.  Through this type of creativity, I believe that solutions to the difficult issues at the heart of early-stage drug discovery can be found.

Monday, July 26, 2010

Knowledge and Experience - Answers to Questions from Soon-To-Be-Graduates

We are now in the middle of summer and many of those participating in the career networking session of January's CSU Biotechnology Symposium have graduated.  As this class, and those following, come to the realization that today's economy presents significant challenges to those entering the workforce, questions regarding required knowledge and experience become relevant.  As I address the last group of questions raised at the symposium, it is important to understand that knowledge and experience are very subjective metrics.  Many skills can be obtained on the job while other skills require advanced training and/or further education.  The best advice I can offer to those of you entering the workforce is for you to evaluate what you want to do and then to make sure that your knowledge and experience is current and reflects the state-of-the-art of chemistry-related technologies.  There is a great deal of competition for jobs today and your greatest assets live within the breadth and depth of your skill sets.

How important are analytical techniques (NMR/HPLC/MS/etc.) for new hires?

In industries dependent upon chemistry and biology, solid understanding of modern analytical techniques is essential. Specifically, nuclear magnetic resonance (NMR) spectroscopy is the workhorse technique used to prove molecular structures.  High pressure liquid chromatography (HPLC) is important to assess chemical purity, to purify chemicals and to identify chemical components in complex chemical or biological mixtures.  Mass spectrometry (MS) provides information regarding molecular weights of pure chemicals or, when used in conjunction with HPLC, helps to identify components of interest in complex mixtures.

While the instrumentation utilized among various companies varies, the type of data generated will be more consistent.  Therefore, it is more important to understand the basic principles associated with data analysis than it is to know how to operate the instruments. Instrument operation is learned on the job but understanding data requires more in-depth knowledge and education.

What opportunities exist for BS/MS level chemists in this economy?

Throughout the pharmaceutical industry, there has always been a greater demand for BS/MS level contributors compared to candidates with higher degrees or significant years of experience.  This trend reflects the hierarchical nature of organizational charts where those with more experience generally manage those with less experience. In today's economy, corporate structures are generally the same as those in better economies.  The difference lies with the size of corporate structures.  In lean economic times, there are fewer opportunities available across the board.  The good news is that, compared to senior level contributors, research associate candidates are in higher demand.

In short, there are opportunities for BS/MS level chemists in today's economy.  However, candidates for these jobs must be able to present themselves as the most qualified and knowledgeable candidates available if they are to be competitive.

What are the requirements for an entry level chemistry job?

Requirements for entry level chemistry jobs in the biopharmaceutical industry vary depending upon the needs of a given program.  I have personally hired individuals with BS, MS and PhD degrees.  At the BS level, I generally look for individuals who have significant laboratory experience beyond laboratory coursework.  This experience can be obtained through working with a professor as an undergraduate researcher, working as a summer intern or working in a company environment.

At the MS level, most candidates have some academic research experience.  When hiring MS level candidates, I generally look for a documented abilities to independently follow protocols and to work in a laboratory environment with minimal supervision.

At the PhD level, candidates should be able to demonstrate their abilities in working independently in a laboratory environment, identifying/solving problems and evaluating the direction of their projects based upon emerging data.

How do supervisors interact with BS/MS level chemists in the lab?

I cannot speak for all supervisors in this area.  However, having interacted with many BS/MS level chemists, I can describe the way I work.  From my perspective, all members of my team are valuable contributors.  Regardless of the level of experience, I always emphasize that my direct reports work with me and not for me.  I try to give each member of my team ownership over various aspects of our projects.  Through this structure which focuses on collaboration and empowerment, I have had tremendously successful and productive team relationships.

How can I learn more about molecular modeling?

Molecular modeling/computational chemistry is a technique used to predict the structure and properties of chemicals, enzymes and polymers using computer algorithms.  When applied to medicinal chemistry, computational chemistry can provide insight into the binding modes of potential inhibitors as they interact with enzymes. Use of this tool has the potential to speed up the drug design process and guide chemistry efforts to more potent and useful compounds.

Many universities offer degrees in computational chemistry - both at the MS and PhD levels.  For independent study, two recent books were published addressing the principles of molecular modeling:

Molecular Modelling for Beginners

Molecular Modeling: Basic Principles and Applications

With this posting, I have now addressed all of the questions raised during my participation in the career networking program at January's CSU Biotechnology Symposium.  I hope that my answers have been helpful.  Moving forward, as I continue writing this blog, I am happy to address topics raised by my readers and look forward to hearing your thoughts.

Thursday, June 3, 2010

Empolyment Opportunities Part 2 - Answers to Questions from Soon-To-Be-Graduates

In these challenging economic times, it is natural to wonder where employment opportunities can be found.  This question is not unique to the many students preparing to enter the workforce.  In fact, everyone working to protect their career options, from the gainfully employed to those seeking new employment, is continually evaluating options.  In my last post, I began addressing questions focused on employment opportunities.  In this post, the following questions raised by graduating life sciences students are addressed:
  • Are part time opportunities with tuition assistance available in pharma/biotech companies?
  • For new hires, what degrees are more valuable - organic chemistry or medicinal chemistry?
  • Is there job security in the life sciences?
  • What are the trends in outsourcing?
Are part time opportunities with tuition assistance available in pharma/biotech companies?

Having worked for companies of varying sizes, benefits extended to employees can vary widely.  The larger organizations I have seen, having more available operating capital, tend to be more generous regarding career development benefits.  Some even offered tuition reimbursement programs to employees wishing to enhance their skill set through education.  However, such programs did not include provisions for part-time work.  While I am sure that arrangements of this type are available, they are not common and employees eligible for tuition assistance programs should be prepared to study at night while working full time.

For new hires, what degrees are more valuable - organic chemistry or medicinal chemistry?

This is an excellent question because while most research universities offer degrees in organic chemistry, degrees in medicinal chemistry are also available.  In my post of September 30, 2009 (Academic Institutions and Drug Discovery), I addressed this question in detail and stand by my assertion that organic chemistry degrees are far more valuable to drug discovery efforts than degrees in medicinal chemistry.

Is there job security in the life sciences?

While some employment is associated with unions, most jobs - including those in the life sciences - are not.  However, even with union-backed employment contracts, the nature of at-will employment virtually assures that employment is not guaranteed to those working at a given company.  Furthermore, in today's climate of mergers and acquisitions, job security is non-existent.

While we cannot count on any level of job security, there are steps we can take to preemptively enhance our employability as we transition from one job to the next.  In my posting of August 21, 2009 (Maintaining Marketability in a Shrinking Job Market), I talk at length about employment trends and the opportunities they provide.  Remember, while jobs come and go, we all have the ability to adapt and enhance our skill sets to meet the needs of our future employers.  It is our responsibility to develop our careers if we want to continue to be employable.

What are the trends in outsourcing?

In my post of October 25, 2009 (Chemistry Outsourcing - New and Challenging Career Opportunities), I discussed outsourcing in great detail.

In today's industrial climate, there is likely to be more dependence on outsourcing as a means of slowing cash burn rates and minimizing the need for dedicated infrastructure.  However, I do not see this as a sustainable alternative to the development of novel technologies at dedicated facilities controlled by parent companies.  If we are to maintain a competitive edge in a global marketplace, it is essential that we maximize productivity and fully control all intellectual property supporting our innovations.  In the meantime, outsourcing provides novel opportunities for the management of complex and diverse infrastructures - in many cases, extending across cultures.  Such opportunities should be embraced, as associated skill sets are broadly valued throughout the biopharmaceutical industry.

    Saturday, May 15, 2010

    Empolyment Opportunities Part 1 - Answers to Questions from Soon-To-Be-Graduates

    Due to the current turmoil with the economy and job market, many of my postings focus on areas where chemistry expertise is a desirable commodity.  While these discussions broadly focus on different industries and technologies, there are many employment-related issues I have yet to discuss.  Many of these were, in fact, brought to light at January's CSU Biotechnology Symposium.  As a career mentor, I was asked many good questions by life sciences students approaching graduation.  Those of  you who follow this blog know that I have been addressing these questions over the past few months.  Beginning with this post, I will focus on those questions specifically related to employment opportunities.  The specific questions to be addressed are:
    • What will industrial employment opportunities look like in the next 5 years?
    • What is the future of in-house dedicated medicinal chemistry programs?
    • Are opportunities available in pharma/biotech for people with experience outside of the life sciences?
    • Are part time opportunities with tuition assistance available in pharma/biotech companies?
    • For new hires, what degrees are more valuable - organic chemistry or medicinal chemistry?
    • Is there job security in the life sciences?
    • What are the trends in outsourcing?
    In this post, the first three of these are answered.

    What will industrial employment opportunities look like in the next 5 years?

    As most people are aware, the industrial landscape in biotechnology and pharmaceuticals is undergoing massive transition.  This cannot be more apparent than through the trend of layoffs that began approximately five years ago and continues today.  Recent examples include the closure of Xenoport and a 40% downsizing of Exelixis.  Thus, it is understandable that significant students entering the workforce do so with some trepidation.  In order to maintain focus, all employees must understand that JOB SECURITY IS ONLY AN ILLUSION.  Once this fact is realized, it becomes easy to embrace the possibilities presented through a career that not only spans many years but also extends across many companies.  The breadth of experience to be had through career growth and development truly dwarfs that available to individuals dedicated to the same corporate organization for the full tenure of their professional careers.  This would not be possible without some instability in the job market.  I, myself, have been employed by four different companies - all of which have been shut down.  Being again on the hunt for new employment, I embrace the potential opportunities and look forward to entering the next phase of my career - whatever that may be.

    Regarding the employment outlook over the next five years, I believe that that landscape will look very much like that of today.  Our society and economy have long evolved away from the model of dedicated employment for the duration of one's career.  In the wake of this evolution, we are forced to protect our professional aspirations by the continual expansion of skill sets.  I cannot emphasize enough the importance of performing both within and outside of comfort zones in order to establish expertise that is valuable to both current and future employers.  Finally, all wishing to contribute their talents to industrial activities must be open-minded regarding where and how to express their interests and exercise their expertise.

    What is the future of in-house dedicated medicinal chemistry programs?

    Having served as a medicinal chemist since the beginning of my career, I have seen the role of outsourcing slowly increase.  Presently, significant outsourcing efforts are utilized to supplement the activities of in-house chemists.  In addition, many small companies rely solely on outsourced chemistry as a means of meeting their needs.  Reasons for this trend include less overhead dedicated to laboratory facilities and reduced commitment to dedicated personnel.  However, there are some factors that strategically preclude some companies from fully utilizing contract organizations in favor of in-house activities.  These include protection of intellectual property and the development of more rapid solutions to project-critical activities.  With both of these viewpoints in mind, I believe that there will always be a need for dedicated in-house chemistry (or its equivalent) where such dedicated resources lay groundwork enabling optimal use of supplemental contract synthesis programs.

    Are opportunities available in pharma/biotech for people with experience outside of the life sciences?

    This is an excellent question.  While the vast majority of pharma/biotech opportunities require relevant experience, there are some that can fall outside of this paradigm.  Such opportunities, however, are not likely to fall within drug discovery/development efforts.  These opportunities are more likely found in areas such as:
    • human resources
    • facilities management
    • environmental health and safety
    • finance/purchasing
    • IT support
    • program management
    All of these roles are critical to successful business operations and should not be discounted.  In fact, many opportunities in these areas require advanced degrees and/or significant years of experience in order to be efficiently executed.  Finally, careers in these areas can have advantages because they are fully transferable from one industry to another, whereas individuals with life sciences expertise are generally committed to careers within life sciences companies.

    Wednesday, April 14, 2010

    Medicinal Chemistry Part 3 - Answers to Questions from Soon-To-Be-Graduates

    In this post, I am returning to questions asked at January's biotechnology symposium.  In particular, the final two medicinal chemistry questions are addressed.  These questions are:
    • What is the impact of small protein design?
    • What are the advantages/disadvantages of biologics vs small molecule drugs?
    Future postings will address questions relevant to employment opportunities as well as what kinds of knowledge and experience are helpful in the biopharmaceutical industry.

    What is the impact of small protein design?

    Proteins are highly complex structures assembled by nature from the complement of naturally occurring amino acids.  The complexity of proteins comes not only from the structural diversity of the amino acid residues contained in the protein chain, but also from the secondary structure obtained as the protein chain folds into its biologically relevant conformation.  To this end, many academic research groups are studying how various amino acid sequences fold into the different structural motifs found within proteins and enzymes.  Additionally, many software platforms were developed to help predict how proteins fold.

    With the complexity associated with amino acid sequence and secondary structure, it seemed somewhat unlikely that amino acid sequences can be designed to both fold like proteins and induce an intended biological response.  However, in 1997, at least this first part was realized.  As reported (J. Am. Chem. Soc. 2007, 129, 1532) Professor Alanna Schepartz and her group succeeded in designing a synthetic protein sequence capable of folding in much the same was as natural proteins do.  This synthetic protein was prepared from beta-amino acids as compared to naturally occurring alpha-amino acids.

    While the design of therapeutically useful synthetic proteins is still a long way off, shorter peptide sequences have contributed to the arsenal of therapeutically useful structures for years.  Such peptide-based therapeutics include hematide (treating anemia), integrilin (treating acute coronary syndrome) and natrecor (treating congestive heart failure).  To this end, synthetic peptides provide valuable therapeutic agents for indications which, in many cases, have no conventional small-molecule drug alternatives.

    What are the advantages/disadvantages of biologics vs small molecule drugs?

    Currently, there are two classes of therapeutic agents - biologics and small molecule drugs.  Classical drug discovery efforts generally target small molecules (average molecular weight is ~500) as therapeutic agents.  These are advantageous because they are generally easy to synthesize and can be administered orally. Furthermore, small molecule drugs can be designed as either agonists or antagonists of biological processes for use against either extracellular or intracellular targets.  Unfortunately, small molecules cannot presently modulate all biological targets with the specificity and potency required for useful therapeutics.  Additionally, the lead identification and lead optimization processes can be slow for this class of drugs.

    Complementary to traditional small molecule drugs is the class of therapeutics collectively referred to as biologics.  This class includes proteins, enzymes and antibodies.  Such large molecules (molecular weights range from ~10,000-50,000) are generally not suitable for oral administration and must be delivered by injection or infusion. This is inconvenient because these methods of use are generally not compatible with patient self-administration.  Like small molecule drugs, biologics are useful as either agonists or antagonists of biological processes.  However, unlike small molecules, biologics are only useful for extracellular targets. Additionally, biologics are generally highly selective and highly potent against target processes. Finally, like small molecules, lead identification and lead optimization are very slow processes.

    For many years, the pharmaceutical industry focused on small molecule drugs.  With the advent of the biotechnology industry, biologics have become increasingly important as evidenced by commercial successes from companies such as Genentech, Amgen and Biogen.  Through the combined efforts of traditional drug discovery and the development of biologics, advances will continue to provide treatments for medical disorders providing improved qualities of life for all.

    Thursday, April 1, 2010

    Green Chemistry and Drug Discovery

    In my recent posts, I have been focusing on questions raised by soon-to-be graduates from life science programs.  While these posts have been well received and I still have many questions to answer, one event of the recent week warrants a brief detour.  Last week, at the San Francisco American Chemical Society meeting, I was invited to participate in a panel discussion on green chemistry and its role in industry.  This was an interesting opportunity for me because, while I am aware of and fully support the philosophies behind green chemistry, I had never reduced these philosophies to practice in the execution of my laboratory responsibilities.  When asked to serve as a panelist, I was forced to reflect on the following questions:
    • Why have I not utilized green chemistry?
    • What I contribute to this discussion?
    • How I can incorporate green chemistry into my department?
    For those of you who have never heard of green chemistry, green chemistry is defined as the design of products and processes that minimize the use and generation of hazardous substances.  This definition is supported by the 12 principles of green chemistry developed by Paul Anastas and John C. Warner.  The 12 principles are:  
    1. It is better to prevent waste than to treat or clean up waste after it is formed. 
    2. Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 
    3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 
    4. Chemical products should be designed to preserve efficacy of function while reducing toxicity. 
    5. The use of auxiliary substances (e.g. solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used. 
    6. Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure. 
    7. A raw material or feedstock should be renewable rather than depleting wherever technically and economically practicable. 
    8. Reduce derivatives - Unnecessary derivatization (blocking group, protection/deprotection, temporary modification) should be avoided whenever possible. 
    9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 
    10. Chemical products should be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation products. 
    11. Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 
    12. Substances and the form of a substance used in a chemical process should be chosen to minimize potential for chemical accidents, including releases, explosions, and fires.  
    In accordance with this definition and principles, green chemistry aims to incorporate the highest efficiency reactions with generation of the least amount of waste - in most cases a very formidable challenge. However, for the commercial manufacture of medications such as Lyrica and Ibuprofen, green chemistry has led to reductions of greater than 80% of their respective toxic waste streams!  Therefore, the manufacture of pharmaceuticals is, in fact, well-suited for incorporation of environmentally friendly production processes. However, this is generally not the case for research oriented activities.

    Adapting Green Chemistry to Discovery Research

    One of the most intriguing areas of green chemistry involves the use of chemical reactions that conserve atoms - that is, all atoms in reactants and reagents are incorporated into the reaction product.  While, in principle, this philosophy reduces waste, in practice, such chemistry is not available in a diverse enough toolbox to allow for the synthesis of compounds with structural diversity necessary for success in drug discovery.

    Compare green chemistry to the promise advertised for combinatorial chemistry.  Combinatorial chemistry utilizes polymer supports on which reactions can be executed.  However, the diversity of reactions compatible with the polymers limited the applicability of solid-phase chemistry to a subset of pharmaceutically interesting molecular scaffolds.  Thus, while combinatorial chemistry is a useful tool for some structural classes, this technique is currently not the answer to the rapid discovery of novel drug candidates.  This may, one day, change with a large enough toolbox of reactions that can be utilized on various types of polymer supports.

    From another perspective, consider that the definition of green chemistry relates to the design of products that minimize the use and generation of hazardous substances.  If we, in the pharmaceutical industry, were to design our target structures with waste streams in mind, we would be limited in the types of reagents we could use and we would certainly not have access to the diversity of structures necessary to succeed.  While, at first glance, this reality might lead one to believe that green chemistry is not applicable to discovery research, the first of the 12 principles reverses that perception.  In the execution of research activities, waste is generated - the vast majority being solvent waste.  Some strategies for solvent waste reduction are:
    • responsible execution of reactions utilizing minimal amounts of solvents
    • non-use of environmentally toxic solvents such as carbon tetrachloride and benzene
    • replacement of column chromatography with recrystallization techniques whenever possible
    • using supercritical carbon dioxide as an HPLC solvent
    • segregation of waste solvents and solvent recovery through distillation
    Through incorporation of these techniques, coupled with efficient containment of waste streams, discovery research can be environmentally friendly. Furthermore, upon reflecting on these philosophies, I feel justified in saying that:
    • I daily utilize green chemistry through maximizing reaction concentrations and minimizing solvent use.
    • I routinely incorporate green chemistry into my department through efforts to minimize and contain waste streams.
    • I have a great deal to contribute to this ongoing philosophy through advocacy in favor of environmentally friendly practices.
    Finally, as academic groups continue to develop reactions that adhere to the 12 principles of green chemistry, such reactions will find their way into broader industrial use.

    Saturday, March 20, 2010

    Medicinal Chemistry Part 2 - Answers to Questions from Soon-To-Be-Graduates

    At January's CSU Biotechnology Symposium, soon-to-be graduates from life sciences programs had many questions about relevant career paths.  This is the second of three posts addressing questions specifically related to medicinal chemistry.  The questions addressed in this post are:
    • How does molecular modeling influence medicinal chemistry?
    • How does natural product research relate to medicinal chemistry?
    • How can natural products be matched to enzyme activity?
    How does molecular modeling influence medicinal chemistry?

    In my last post, the question "What is medicinal chemistry?" was answered. In that post, I discussed the role of a medicinal chemist in the context of a drug discovery program.  In such a program, success is dependent upon the synergistic activities of scientists of many disciplines.  Some of these disciplines are:
    • organic chemistry
    • biochemistry
    • biology
    • pharmacology
    • analytical chemistry
    • computational chemistry
    Organic chemistry is necessary for the generation of drug candidates. Biochemistry is used to design the enzyme-based assays used to test drug candidates.  Likewise, biology is used to design the cell-based assays and animal models of diseases.  Pharmacology is applied to the actual testing of drug candidates in live animals and analytical chemistry is necessary to provide meaningful data regarding blood serum concentrations as well as initial drug purity assessments.  Based on these specific roles, it is entirely appropriate to wonder where computational chemistry fits in.

    Computational chemistry utilizes mathmatical algorithms and computer technology to: 
    • predict the achievable structural conformations of drug candidates
    • image protein/enzyme structures based on X-ray crystallographic data
    • predict protein/enzyme structures based on X-ray crystallographic data of related proteins/enzymes
    • compare biological data of related structures as a tool to predict the activity of planned compounds
    • study the enzyme binding site in the presence and/or absence of drug candidates
    • design novel structures optimized to the shape and properties of relevant enzyme binding sites.
    Because all of the above applications of computation chemistry effectively visualize what cannot be directly seen, each of these systems is a model designed to represent intended interactions within biological systems. Because these systems are models, computational chemistry is frequently termed "molecular modeling."  While this technology was routinely unavailable to medicinal chemists until the 1980s, such technology is now indispensable in guiding the activities of medicinal chemists to more rapid successes. 

    How does natural product research relate to medicinal chemistry?

    Nature has provided numerous biologically active compounds useful for medicinal purposes.  Such compound classes include opiods, antibiotics and antifungals.  While some compounds from these classes are commonly used as medicines (morphine, cocaine, penicillin, erythromycin, taxol, nystatin), most induce undesirable and potentially toxic side effects when administered to humans.  The reason for this is clear - these compounds were designed by nature to benefit their non-human host organisms.

    Because of nature's relatively inefficient optimization of biologically active molecules for human use, most natural products are best utilized as lead molecules in drug discovery programs.  Through the systematic modification of natural substances, drug-like properties can be enhanced while minimizing undesirable and/or off-target effects.  Thus, natural product research provides medicinal chemists a rich and valuable goldmine of lead molecules and potential drug candidates.

    How can natural products be matched to enzyme activity?

    Natural products are organic molecules produced by living organisms. While there are numerous living organisms that produce interesting substance, plants fungi and marine creatures generally receive the most attention.

    The process of natural product discovery generally involves homogenization of large quantities of a given species such as a marine sponge.  The liquefied sponge is then extracted with organic solvents. The materials being dissolved into the organic solvents are then isolated and separated by techniques such as high pressure liquid chromatography (HPLC).  This initial chromatography step produces fractions that contain multiple natural compounds.  As only natural products with biological activity are generally of interest, these crude fractions are screened against various enzymes.  If a given fraction shows interesting activity, it is further purified to isolate its individual molecular components.  These components are then screened against the enzymes of interest and the most active component is identified.

    From this point, a map from a given sponge to a given natural product is identified.  Using this map, the natural product of interest can be repeatedly isolated from the same species.  However, the structure of the natural product is not yet known.  In order to establish the structure, larger quantities must be isolated and subjected to analytical techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy.  Additional structural information can be obtained by studying the products of chemical degradation.  When a final structure is proposed, often the best proof of structure is total synthesis - the process of preparing a natural product from non-natural sources using synthetic organic chemistry. In fact, it is this process of total synthesis that provides some of the best training for graduate students interested in entering industries dependent on the discovery of pharmaceuticals, polymers and agrochemicals.

    Sunday, March 7, 2010

    Medicinal Chemistry Part 1 - Answers to Questions from Soon-To-Be-Graduates

    Students preparing to enter the workforce have a great many questions. Some of these relate generally to career paths while others relate more specifically to various professions.  In my last two posts, I focused on career paths.  I hope the answers I provided are helpful and look forward to reading your comments.

    At January's CSU Biotechnology Symposium, I had the opportunity to listen to both questions and concerns of soon-to-be graduates from life science programs.  Those participating at my table (medicinal chemistry) provided me with a forum to address qustions specific to my area of expertise.  These questions, related to medicinal chemistry, are:  
    • What is medicinal chemistry?
    • Do medicinal chemists participate in the testing of compounds?
    • What is a typical day like for a medicinal chemist?
    • How does molecular modeling influence medicinal chemistry?
    • How does natural product research relate to medicinal chemistry?
    • How can natural products be matched to enzyme activity?
    • What is the impact of small protein design?
    • What are the advantages/disadvantages of biologics vs small molecule drugs?
    In this and the following posts, I will address all of these questions.

    What is medicinal chemistry?

    Medicinal chemistry is the discipline focused on the discovery of new medications.

    Many medications are derived from natural sources such as plants, sponges and animal toxins/venoms.  Specific examples include aspirin, morphine and cocaine.  However, while nature provides many biologically important molecules, these molecules are the result of evolutionary pressure upon the organisms from which they are isolated.  As such, they are not necessarily optimal for use in humans. In order to make use of such naturally occurring compounds, medicinal chemists work to modify these structures in order to enhance desirable properties and minimize toxic side effects.

    Complementary to naturally occurring compounds are the vast libraries of chemicals available for biological screening.  These compounds are generally man-made and provide equally enticing structures as lead molecules for drug discovery programs.  

    Because medicinal chemistry involves the systematic modification of natural or man-made organic molecules, a background in organic chemistry is essential to the medicinal chemist.

    Do medicinal chemists participate in the testing of compounds?

    Medicinal chemistry is only one component essential to the drug discovery process.  Another aspect of this process involves the testing of the compounds that are produced by medicinal chemists.  The biological assays generally include enzyme assays, cell-based assays and biologically relevant animal models of diseases.  These studies are generally designed and carried out by biologists and pharmacologists.  

    Medicinal chemists do not carry out biological assays.  However, the feedback generated by biologists and pharmacologists is essential to helping medicinal chemists design their next modifications to lead molecules.  Thus by correlating the structures of related compounds to their respective biological data, medicinal chemists can determine if they are moving towards or away from improved drug candidates.

    Although medicinal chemists do not generally participate in compound screening, it is not unheard of.  Early in my career, I was curious as to whether a class of matrix metalloproteinase inhibitors (MMPI)s would act as inhibitors of endothelin converting enzyme (ECE).  At the time, there was no enzyme assay available for ECE.  However, there was an way to measure ECE activity in rats by measuring their blood pressure in response to dosages of big endothelin (big-ET) in the presence or absence of an MMPI.  With this knowledge, a colleague of mine in the pharmacology department taught me how to surgically cannulate rat carotid arteries and, together, we were able to demonstrate that MMPIs could inhibit ECE. This was the only time in my career that I actually participated in biological assays and it taught me a great deal about the role and importance of pharmacologists to the drug discovery process.

    What is a typical day like for a medicinal chemist?

    Medicinal chemists typically spend their days making target molecules for biological testing.  Approximately 70% of their time is spent initiating reactions, completing reactions and isolating/purifying products.  The remaining 30% may be spent generating analytical data (NMR, HPLC, MS) for isolated compounds, reviewing biological data provided by biologists, searching scientific literature for information/procedures needed for chemical transformations, and attending group meetings.

    The role of a medicinal chemist is highly intertwined with related operational groups such as biology, pharmacology, formulations and process chemistry.  The medicinal chemist must be able to effectively communicate with all of these disciplines in order to share necessary information and glean important insight valuable to program advancement.  Each day is different from the last and each day begins with the hope of new discoveries.

    Tuesday, February 16, 2010

    Career Paths Part 2 - Answers to Questions from Soon-To-Be Graduates

    In my previous post, I began to address questions regarding career paths.  In this post, the remaining career path questions are answered.

    What are the differences between academic and industrial careers?

    The differences between academic and industrial careers are significant. Beginning with academic careers, professors are expected to:
    • teach classes
    • raise funding
    • train graduate students
    Each of these areas require exceptional scientific knowledge/expertise, excellent people skills and outstanding communication skills.  For example, to successfully teach classes, professors must be able to engage the students and coherently communicate concepts.  Furthermore, to raise funds, professors must be able to influence decision makers.  They must be able to articulate the rationale and intent of the program for which funding is desired, and to do so in a dynamic and convincing manner.  These programs must maintain a high level of competitiveness in order to compete with the large number of programs that are vying for the limited amount of funds available.  Finally, training graduate students requires clear communication, strong people skills and an outstanding ability to attract potential students through a solid scientific reputation.

    With all of the above in mind, there are several different academic career tracks including:
    • non-tenure track
    • tenure track
    • administrative track
    Non-tenure track positions generally involve class instruction only. Such programs can, in some cases, include research activities.  

    On the other hand, tenure track positions require both class instruction and research activities, and are much more involved. Success in tenure track positions depends upon an ability to obtain funding for programs and on a consistent stream of peer-reviewed publications - professors must be prepared to write interesting and innovative publications on a regular basis.   

    Administrative opportunities can come from both non-tenure track and tenure track roles.  However, higher profile opportunities are generally filled by tenured professors.  It is important to note that to participate in any of these roles, a PhD is required.

    Finally, anyone considering a career in academia must recognize that the goals of academia are education and basic research.   In contrast, the goals of industry are to bring products to market and generate returns for investors.  Bearing this in mind, it is easy to understand why salaries in academia, particularly during the first few years, are considerably lower than those available from industry.

    Industrial careers offer opportunities to contribute to the development of products for introduction to commercial and consumer markets.  Such products have direct applications to healthcare (pharmaceuticals and medical devices),  food (packaging materials, food preservation, artificial flavors/sweeteners, etc), electronics (semiconductors, memory media, etc.) and energy (synthetic fuels, catalysts, recycling, etc.).

    The industrial career track generally begins at the scientist level (PhD) or the associate level (BS/MS).  Projects are assigned based on corporate priorities.  Unlike academic careers where projects are selected based on scientific interest, projects in industry are selected based upon marketing potential.  Thus, while those participating in industrial programs may not be able to select their programs, they can use their individual creativity to devise novel strategies to solve their assigned problems.  Furthermore, corporate fundraising activities are generally under the realm of corporate executives - leaving the scientists to concentrate solely on the science.

    In industry, there are generally two career paths:
    • scientific
    • managerial
    Both of these tracks start at the scientific level.  However, when a scientist reaches a certain level, that individual may choose to pursue roles such as group leader/director or research fellow.  While these titles may differ from one company to the next, group leaders generally have more managerial opportunities while research fellows generally are active scientists on the bench.  Both of these paths offer unique opportunities for professional development.

    In summary, both academic and industrial careers provide exciting opportunities for those interested in contributing to the sciences.  There are differences in each path that may appeal to certain individuals and I encourage all students to better understand themselves and their goals as they evaluate the numerous variables when choosing where to apply their talents.

    Is there more competition for academic positions in this economy?

    There is considerably more competition for academic postions than for industrial positions because:
    • Professorships are high profile
    • There are more available industrial positions than professorships.

    Monday, January 25, 2010

    Career Paths Part 1 - Answers to Questions from Soon-To-Be Graduates

    In my last post, I discussed my experience as a career mentor and summarized the questions asked by soon-to-be graduates of life sciences programs.  Over the next several posts, I will address each of these questions. 

    How did I decide upon my career path?

    Ever since I was a child, I knew I wanted to be a chemist.  The funny thing was that I did not know what a chemist was, or what a chemist did.  My influence clearly came from the cool racks of tubes and bubbling solutions shown in sci-fi movies.

    As I advanced through school, I was very good at math and science. Furthermore, I was frequently and dangerously curious about electricity, gunpowder and fire. While I am not inclined to elaborate at this time, it is interesting to note that one of the hallmark experiences of almost every chemist I know is an early desire to experiment, coupled with a lack of fear of the consequences.

    Entering college I enrolled as a chemistry major at the UC Berkeley and enthusiastically pursued the required curriculum.  However, at that time, I still had not decided on what I wanted to do as a chemist. All this changed when I began to study organic chemistry.  When I realized how organic compounds interact with and influence biological processes, I knew that I wanted to work towards improving the quality of life for people suffering from conditions for which there was no treatment.  From that point on, I embraced organic chemistry, took all available organic chemistry courses, and pursued undergraduate research under the direction of Professor Henry Rapoport.

    Through Professor Rapoport's guidance, I began to develop my laboratory skills in preparation for graduate school.  While I knew that a PhD was required in order for me to fully achieve my goals, I had not yet decided if I wanted to pursue a career in academics or in industry.  That decision developed during my graduate studies at MIT under the direction of Professor Satoru Masamune.

    Having always been attracted to the idea of designing my own research programs, I initially felt that my best opportunities would be in academics. However, while in graduate school, I realized that there was an intense amount of competition for funding, tremendous politics regarding the tenure track and significant non-scientific activities required in order to keep a research group running.  These observations were contrasted to the fact that in industry, while I would not be required to fund my own programs, I would be required to work on programs to which I was assigned. Both sides had tremendous advantages.  In the end, I felt that even though I would be assigned programs, industry does not dictate how I solve the problems to which I would be assigned.  To this day, I enjoy the tremendous freedom to contribute novel solutions to the design and development of pharmaceutical agents.

    Can you describe your industrial experiences and career path?

    Industry has been very good to me.  Following completion of my PhD, I took a scientist position at Glycomed.  This was a great fit for me because the pharmaceutical technologies being studied at Glycomed made excellent use of my graduate school experiences involving the chemical modification of sugars.  At Glycomed, I contributed to the design of anti-inflammatory agents (selectin inhibitors and fucosyl transferase inhibitors) as well as drugs targeting angiogenesis, cancer and multiple sclerosis (matrix metalloproteinase inhibitors). As I developed my experience, I ultimately led the matrix metalloproteinase inhibitor efforts and took responsibility over three direct reports.

    Following Ligand Pharmaceuticals' acquisition and the subsequent closure of Glycomed, I joined COR Therapeutics.  My charge was to develop a chemistry program targeting selective inhibition of type V adenylyl cyclase for use in the treatment of congestive heart failure. In this role I developed my knowledge of heterocylic compounds and synthetic nucleoside mimics. While this project yielded extremely potent compounds with activity in whole cell assays, corporate priorities resulted in termination of the adenylyl cyclase project.  For the remainder of my tenure at COR, I contributed to the design and synthesis of novel ADP receptor antagonists for use in treating deep vein thrombosis.

    When COR Therapeutics was purchased and subsequently closed by Millennium Pharmaceuticals, I took a group leader position at Scios, Inc.  My role as group leader was to design and execute a medicinal chemistry program targeting calmodulin dependent kinase for the treatment of post-operative arrhythmia.  This was by far the largest team I had ever managed. At the peak of this effort, I had a team of ten dedicated scientists and associates.  Furthermore, I managed additional resources operating from contract research organizations (CROs) in the United States and India. Unfortunately, this program was terminated when Scios was purchased by Johnson & Johnson and subsequently shut down.

    The closure of Scios was particularly difficult for me because it led to my first significant stretch of unemployment.  Jobs were scarce - especially for more experienced scientists looking for leadership roles.  I networked every day and built relationships with many industry insiders and recruiters. Realizing that I could not simply wait for new opportunities to present themselves, I decided to start consulting.  Through my consulting efforts I was able to secure laboratory space.  With this resource available to me, I was able to build on a networking connection and start an independent custom synthsesis effort.  My client was Intradigm Corporation and I was hired to prepare a compound critical to their development programs. My efforts were actually in competition with a CRO preparing the same compound.  In the end, I was able to prepare the target, provide necessary starting materials to the CRO and transfer synthetic protocols enabling the CRO to scale up the process.  Because of my work on this program, Intradigm created the role of Director of Synthetic Chemistry for me - a position which I currently hold.

    While I do not know what opportunities lie in the future, I always strive to embrace the possibilities.