Author: andy

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

There are a few ways to approach the general idea of drug discovery, but I’m going to try and tackle it from the historical treatment first, and maybe revisit it in a future Primer.  I am part of the Division of Medicinal and Natural Products Chemistry at the University of Iowa, and the two components of it, Medicinal Chemistry, and Natural Products, are both integral to the idea of developing new drugs.  Medicinal Chemistry is just as it sounds: the study of designing and synthesizing new drugs, using principles of chemistry, pharmacology and biology.  The idea of Natural Products, however, is a bit more interesting in that, just as it sounds, it studies chemical compounds “developed” in other organisms that may be useful as drugs.

The oldest records tend to cite the ancient Chinese, the Hindus and the Mayans as cultures that employed various products as medicinal agents.  Emperor Shen Nung, in 2735 BC, compiled what could be considered as the first pharmacopeia, including antimalarial drug ch’ang shang, and also ma huang, from which ephedrine was isolated.  Ipecacuanha root was used in Brazil for treatment of dysentery and diarrhea, as it contained emetine.  South American Indians chewed coca leaves (containing cocaine) and used mushrooms (containing tryptamine) as hallucinagens.  Many different examples of drug use in ancient, and more modern cultures, can be pointed to as early forerunners of today’s drug industry.

However, it was the 19th and 20th centuries that really kick-started the trend, as this is when modern chemical and biological techniques started to take hold.  It was in the 19th century when pharmacognosy, the science that deals with medicinal products of plant, animal, or mineral origin, was replaced by physiological chemistry.  Because of this shift, products like morphine, emetine, quinine, caffeine and colchicine were all isolated from the plants that produced them, allowing for much purer, and more effective, products to be produced.  Advances in organic chemistry at the time really helped with the isolation, so these discoveries wouldn’t have been possible previously.

In today’s world, there are a few ways you can go and discover a new drug:

1. Random screening of plant compounds
2. Selection of groups of organisms by Family or Genus (i.e. if you know one plant that makes a compound, look for more compounds in a related plant)
3. Chemotaxonomic approach investigating secondary metabolites (i.e. Drug A functions in your body, then is metabolized in your liver to Drug B, which also happens to be functional)
4. Collection of species selected by databases
5. Selection by an ethnomedical approach

I think the latter two are the most interesting, especially with a historic perspective.  With the latter, we’re talking about going into cultures (a la the movie “Medicine Man“) and learning about the plants that they use to cure certain ailments, then getting samples of those plants and figuring out what makes them effective.  It has been estimated that of 122 drugs of this type used worldwide from 94 different species, 72% can be traced back to ethnic groups that used them for generations.

The discovery of new drugs of this type is actually somewhat worrisome as these cultures die out or become integrated into what we’d consider “modern society.”  These old “medicine men” and “shamans” die before imparting their knowledge to a new generation and these kinds of treatments are lost.

The collection of species and formation of databases is interesting, and only more useful in recent history due to the advent of computers that can actually store and access all the information.  With this process, we’re talking about going into a rain forest, for example, and collecting every plant and insect species you can find, then running various genetic and proteomic screens on the cells of each plant and insect to see whether they produce anything interesting or respond to anything.  This process can involve thousands of species across a single square mile in a rain forest, necessitating a great deal of storage space for the samples themselves, but also computing power to allow other researchers the ability to search for information on that given species.

An example of a “screen” that one could carry out would be to grow bacteria around your plant or insect samples.  If you ever heard the story of penicillin, you’ll know that Alexander Fleming (1928) noticed that his culture of Staphlococcus bacteria stopped growing around some bread mold that had found its way into the culture.  From that bread mold, penicillin, was developed as our first antibiotic.  The same kind of principle can be applied here: mix your samples together and “see what happens.”  If anything interesting happens, you then continue investigating that sample until you isolate the compound that is doing that interesting thing.

The isolation of that “interesting compound” can be very tricky, however.  In many cases, a particular anticancer agent or antibacterial agent may be housed inside the cells of our plant species.  Getting that compound out may be difficult, as it could be associated with the plant so tightly that you have to employ a variety of separation techniques.  And even after you apply those techniques, what you are left with may be nonfunctional, as the compound may require the action of that plant itself to work properly (i.e. the compound you want may still need other components to work).  Even after you isolate the compound you want, in order to make it a viable drug, you have to be able to synthesize it, or something like it, chemically in a lab setting.  Preferably, on a massive scale so you can sell it relatively cheaply as a drug to the masses.  These processes can be daunting and costly.

So basically, it can be fascinating to discover new drugs, especially ones that were actually “discovered” thousands of years ago by cultures that have long since died out.  However, you may find that “discovering” the drug may be the easy part – mass producing the drug could be the most challenging aspect of the ordeal.

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

One would like to think that major universities spend their money on research for their various faculty members, but unfortunately for me, that typically isn’t the case.  Sure, there is a reasonable amount of money going to fund the research carried out by faculty members in biology, physics, and chemistry departments, but the reality is that in order for that research to occur, and moreover almost all of the important discoveries under the umbrella we call “Science,” money must come from sources other than the university.  In many cases, your tenure and rank at your given institution is determined by how much outside funding you bring in and where it comes from.

The majority of scientific funding in the United States comes from the Federal Government, mostly in the form of the National Institutes of Health (NIH) and, to a lesser degree, the National Science Foundation (NSF) and Department of Energy (DoE).  Scientific American did a great job recently summing up how much money goes into which pot at the Federal level with an easy-to-read graphic that I suggest you glance at.  Basically, the NIH gets $28.5 billion to divide amongst its various projects, including grants that professors and other individuals apply for.  The NSF gets $4.2 billion, and the DoE gets about $3.5 billion to devote to research.  For comparison’s sake, the Department of Defense gets $56.2 billion (excluding special funding in war-time).

Obviously, NIH is getting a substantial piece of that pie.  For the most part, if you are doing biomedical research like I am, then the NIH is the first place you apply to.  They will generally fund anything that you can tie to a disease or disorder.  Alternatively, NSF won’t touch any grant that even implies it could help with disease research, instead focusing on really basic research.  Chemists and Physicists can find applications in the NIH, but usually NSF and DoE (or others) are where they have to look for funding.  And that pot is much smaller than the NIH pot.

The process of applying in each agency varies, but for the most part, you go about it the following way:

1. Find a grant application that applies to your research
2. Write the application according to their explicit instructions
3. Submit the grant by a given due date (usually a few times per year)
4. The grant is assigned to a division of the agency and then further assigned to a committee
5. The committee is made up of people who should know what they’re doing, and then rank each grant they get in a pile based on its merits, need, and contribution to science
6. The committee is given a number of grants that they can fund (usually between 5-20% of total grants submitted)
7. Funding is decided and you are notified of the decision

There are usually three decisions that can be made.  Either a). the funding agency can grant you the money and accept your project as-is; b). the agency can give your grant a rank or score and suggest you make some changes and resubmit it; or c). they can “triage” your grant, basically saying they didn’t even score it, and that it needs significant work to make the cut.  The committee in question will usually give you some kind of pointers as to why your grant was or wasn’t funded, but that experience will vary across agencies and committees.

The NIH has a few different grant series that you can apply for.  Some, like the one I applied for in early December, are considered “training grants.”  So in this case, the grant I applied for was a post-doctoral training grant (designated “F32”) that would pay my salary for 2-3 years, based on the project I outlined to them.  No equipment or anything would be paid for – just my subsistence.  Alternatively, the “Big Daddy” grant to get is designated “R01,” which is a big league research grant that awards up to $5 million to a researcher and their lab, paying for salaries, equipment, and even some travel money to conferences.  At many big academic institutions, you need to get an R01 before you can achieve tenure.  At some of them, you need two.  The going funding rate for these grants has been in the 8-10% range, which is pretty low.  It’s tough to get an R01 and you can spend a lot of your time writing these grants and trying to get them, rather than actually doing research.

There are alternatives to federal money, of course.  You could call these Private, or “Foundation Grants.”  These entities are frequently not-for-profit groups that are set up to fund research according to their specifications.  The Michael J. Fox Foundation for Parkinson’s Research is one you may have heard of.  The American Heart Association is another.  The grants these foundations fund are typically quite a bit smaller than those funded by the government, rarely reaching in the millions of dollars.  They are also quite competitive, and some could argue more competitive than federal funding.  Generally, you end up spreading yourself thinner across multiple foundation grants if that’s how you have to fund your lab, or you get a single federal grant (or two…).  It all depends on how large your operation is, how many people are under you, and how many projects you have running at a given time.

I’ll leave you with one last point about the funding of science (insert soap box here): the majority of scientific innovations and true breakthroughs come from the funding agencies listed above:  NIH, NSF and DoE.  Private Industry, such as Pfizer or Merck, carry out their own research and development programs, but they rely heavily on basic research carried out in academic settings.  They do this partially because these companies cannot patent what is published in a journal article by someone else, so they have to take other research, apply it to their own needs, and then create a patent that they can make money off of.  When federal funding for science drops or doesn’t even increase with inflation, that means that professors make less money and cannot afford to pay their workers.  That means that less basic research is done.  That means that Private Industry has to devote more money to R&D in order to make new discoveries.  That increases the amount of money they need to put into developing a drug (more on that in a future Primer…).  Finally, that means the drugs and treatments that then go to you cost more money, adding to the sky-rocketing health care costs we already have, mostly because that basic research that Private Industry did is now covered under a patent for 10 years and no one else can make money on it and compete.

Funding of science at the federal level is incredibly important.  It’s hard enough as it is to get a grant, and it is vitally important that the money NIH, NSF, DoE, etc. get does not decrease, but instead increases.  That’s where scientific innovation comes from in the United States.  It’s why people from all over the world come here to get a Ph.D. and do research.  Because the United States values innovation and discovery.

As well they should.