New Paper: Controlling Membrane Active Peptide Activity

Hello Everyone,

I’m happy to say that I was able to publish what was the bulk of my PhD thesis work in the Journal of the American Chemical Society and that it is finally available.  This work formed the initial basis of my ideas around Molecular Yoga, the ability to control the ways in which molecules can change conformation and activate certain functions.  In short, we created a combinatorial library based on the membrane active, toxic peptide Super-Melittin (derived from Melittin from honeybee venom).  This peptide has excellent antimicrobial and potent anti-cancer capabilities but it is very harmful to our own body’s cells as well.  I believe that by changing just a few of the amino acids we could create a peptide that would be inactive at neutral pH but could fold into an alpha-helix and activate at a low pH.  Low pH environments are often found in tumors and with fungi and bacteria, making it an good activating key for these peptides.  We’re currently working to develop a patent for these exact purposes and some of my colleagues, Sarah and Elmer are still working very hard to improve these peptides further.  Please give it a read and let me know what you think!

I have another announcement too.  I’ll be reporting next month as part of the 61st Biophysical Society Meeting blog in New Orleans.  I hope to use this as a way to bring science to the public and to help them to interact with the scientific community.  Look for updates along these lines in the next few weeks!  Thanks for reading!

Sincerely,

GRW

 

Paper:

pH-Triggered, Macromolecule-Sized Poration of Lipid Bilayers by Synthetically Evolved Peptides. Wiedman G, Kim SY, Zapata-Mercado E, Wimley WC, Hristova K. (2016)  JACS

http://pubs.acs.org/doi/abs/10.1021/jacs.6b11447

 

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Skepticism versus Denial in Science

Hello Everyone,

Before the year is out I wanted to make one last post on a topic I feel is becoming increasingly more important in today’s academic climate.  That point is about the difference between skepticism and denial.  We hear a lot in the news (fake or real) about how different people are either “deniers” or “skeptics” of various ideas.  The utility of vaccines, climate change, AIDS, are just a few topics that come up with these labels on them.  Perhaps it would be best to have a discussion of the topic with, instead of politically charged rhetoric, a view towards science itself.

The reason that I’ve been thinking about this topic recently stems from a book I got as part of a Secret Santa gift: “Dancing Naked in the Minefield” by Kerry Mullis.  Kerry Mullis won a Nobel Prize for his part in developing Polymerase Chain Reaction synthesis of DNA.  He’s a man I deeply disagree with but whom I think has a good point nonetheless.  Mullis, in the early 1990’s challenged the prevailing wisdom that Autoimmune Deficiency Syndrome (AIDS) was caused by infection with the Human Immunodeficiency Virus (HIV).  By the mid-1990’s, however, there were several cases of isolated HIV accidentally being introduced to healthy individuals and these individuals eventually developing AIDS. These cases established a link between HIV and AIDS(1).    For his part, Mullis would describe himself as a “consummate skeptic” always questioning whether or not the scientific community has sufficiently tested and evaluated a hypothesis.  In a sense he’s right; as scientists we should always be skeptics, no matter how established the dogma in our field has become.  We can go back to Copernicus (and earlier Greeks) challenging the idea that everything revolved around the Earth or Louis Pasteur and others challenging the idea of Spontaneous Generation as examples.    There comes a point, however, where to make progress in a field we have to accept that our data point towards a scientific consensus on a topic. From this consensus we can test new hypotheses and create new ideas.

Then we reach what we would call “denial”.  Denial, in as non-political of terms as I can put it, is ignoring the scientific consensus and the data that support it and instead interpreting results based on your own biases and beliefs.  The correct way to do science is to make as objective observation as possible, create a hypothesis objectively, and then evaluate that hypothesis without presuming any specific outcome.  Contrary to popular belief, scientists actually really love to prove things wrong, especially well, established ideas.  You have to approach it though as if you don’t already know what is going to happen.  A really good scientist will know how to ask new questions regardless of the answer they get.  This then gets us into another discussion about transparency in science and the perils of a “results-driven scientific culture” but I’ll get back to that another day.  Overall there’s an important difference to highlight:  Not all skeptics are deniers but all deniers are bad skeptics.

Finally something to think about for 2017 for both scientists and non-scientists is how we view those in academia and who we look to for authority on a subject.  The best defense of the Liberal Arts I ever heard was from a man I greatly admire and respect: Dr. Phil Nichols a professor at the University of Pennsylvania who said (and I’m paraphrasing), “People who study history, language, culture, are the people we turn to when the world is in moral crisis”.  People who’ve studied an area very intensely are in unique position to help others understand the world around them.  Education is not something to lord over other people like some kind of medieval sale of Indulgences.  Rather, it’s a calling and a responsibility; it’s service to humanity at large.  Therefore, scientists have a responsibility very clearly communicate what we mean by skepticism and what we mean by scientific consensus.

On that note thank you for reading and have a Happy New Year!

Sincerely,

GRW

 

(1) O’Brien SJ, Goedert JJ, “HIV causes AIDS: Koch’s Postulates Fulfilled” Current Opinions in Immunology: 1996, 8(5) 613-618.

 

Science, Government, and Globalization

Hello Everyone!

I wanted to finally post something this month related to science now that the US election is over.  A fair warning, this will be another opinion piece of mine; I welcome the opportunity to discuss all manner of opinions.

I, as a scientist in the United States, like many other scientists, apply for funding from the US government.  This can come from a number of different places: The National Science Foundation, the National Institutes of Health, the US Department of Energy, US the Department of Defense and many other government sources.  There are also outside sources of funding: The Gates Foundation, MacArthur Fellows Program, and The Beckman Foundation all of which provide funding for projects with specific goals in mind.  This brings up the obvious question: what sort of bias does receiving funding from a given institute introduce into the scientific process?  To address this first point I want to highlight the fact that when scientists apply for a project grant they have already developed a project to fit a specific funding call.  From all I can tell faceless government organizations are not handing out projects to push political agendas.  Ideas are the currency of the scientific community; few people with good ideas rely on somebody else to pursue them!  As scientists we constantly look for new areas to expand the knowledge of the scientific community and we’re always willing to challenge our own views.  So while, yes, funding directives might limit the scope of scientific inquiry the scientific community will always look for ways to expand beyond just the easy funding opportunities.

Along this point as well, the scientific community is a global community that goes beyond nationalism.  There are nationalistic biases in research as well.  People may question the ethics of research done in certain parts of the world or whether or not the results produced there are reliable.  I’ve heard people say more than once to take authors’ papers from a particular part of the globe “with a grain of salt.”  Still that doesn’t mean that they should be shut out.  Their ideas should be put to the test like anyone else’s ideas and if they hold up to scrutiny then they hold up.  As scientists from the United States of America we can stick our heads in the sand and say that we are the best and we don’t trust work done outside of the US.  This ignores the fact, however, than many other countries are on par or even above our level of R&D spending in terms of per capita GDP. (1)  We ought to be proud of the excellent work done in the United States and of the universal respect that the world at large has for US academia.  This does not entitle us to narrow our view and miss out on ideas from other parts of the world.

Finally the question that’s been on my mind recently and that I want to discuss is: what is the way forward for the scientific community?  What does our global community do in the fact of increased isolationism and reactionary rhetoric throughout the world?  I’ll hark back to what I spoke about in previous posts: we need to increase scientific outreach and to help improve public scientific literacy.  People would benefit from a better understand of the role that the scientific method plays in their everyday life.  They can observe the world around them, make hypotheses about it, test their hypotheses, and analyze the results to come to a logical conclusion.  Then, in sharing their conclusions, they will perpetuate a global scientific discourse.  This requires all of us to donate our time to reaching out, to teaching the young and the old.  Not because we want recognition for it, not because we are afraid of what might happen if we don’t but because we have conviction to do so!

 

Move forward!  Find an opportunity and get involved!

Volunteer at a Children’s museum such as:

The Indianapolis Children’s Museum

https://www.childrensmuseum.org/content/volunteer

The Franklin Institute in Philadelphia

https://www.fi.edu/join-our-team/volunteer

The Maryland Science Center in Baltimore

http://www.mdsci.org/get-involved/volunteer/

Participate in Public Debates in your local municipality on science issues that are important to you!

 

Consider organizing a “Science Night” at a local restaurant to promote discussion!

 

Start a discussion club, invite people from your community to participate!

 

Do anything you can!  Move forward!

 

Sincerely,

 

GRW

 

 

 

What’s in your Guts? Part 2: Using Gut Bacterial Genomes to Predict Useful Drugs

Hello Everyone,

For this post I am going to talk again about drug discovery but in a manner that is really an emerging area of research.  The lab I’m working in, though not I personally, have been collaborating with another group at Rockefeller University to study the genomes of the bacteria Rhodococcus equi and R. erythropolis (1).  These are bacteria which normally exist in our oral cavities, our nose, and our mouth, but sometimes end up growing in our gut.  We’ve talked in a previous post about how changes in your gut microbiome can affect your health.  Here, in this paper, we asked the question: what are different types of bacteria doing in your gut and could they actually be useful to us?

Gut bacteria produce all kinds of different molecules that act as signals to your body and towards other bacteria.  Your gut is almost like a Wild West of bacteria as well as fungi and viruses, all of which are fighting to survive.  When you have the right balance of these organisms you exist in a stable state or “homeostasis”.  How do some organisms end up tipping the balance and getting a foothold in the gut?  The answer likely comes from the molecules that they produce!  Certain types of bacteria might have a way of inhibiting the growth of other bacteria which allows them to overpopulate your gut.  We would want to study these bacteria in particular to see what they are doing to our normal homeostasis.

Many of these bacteria are finely tuned to survive in the environment that our bodies provide to them.  How can we understand what they are making if we can’t grow enough of them outside of our body?  This is where genetics comes in to the picture.  We’ve mentioned before one of the central dogmas of biology, that the DNA in a genome encodes for specific protein sequences.  Dr. Brady’s lab at Rockefeller looked at the DNA sequences in several portions of the Rhodococcus equi and R. erythropolis genome where we might anticipate active peptides to be encoded.  His lab then manually synthesized the peptides that those sequences encoded using synthetic chemistry and tested them against various bacteria and in combination with other drugs called beta lactams (this is the class of drugs that includes Penicillin).  They found two active drugs which they called, Humimycins.  When they studied these drugs in bacterial culture and when we studied them in mice we discovered that they seem to target a protein complex called a “Flippase”.  These Flippases, as the name suggests, have the ability to flip drugs like penicillin to the outside of the cell, thus rendering them ineffective.  If you are a bacteria that can inhibit Flippases you can confuse your neighbors and cause dysregulation and you can inhibit their growth.

While this all sounds very exciting there are a few questions that we need to ask about these Humimycins.  The first question is: if these drugs are active against specific types of gut bacteria, what effect would using them have on our normal gut microbiome?  You might eliminate MRSA for instance but would some other type of bacteria take over your gut?  Again this begs the question of what exactly is the “normal” situation in your gut?  This is a difficult question and it’s still an area of research that requires an enormous amount of research.  For now, because of how difficult beta-lactam resistant bacteria are to deal with, we might as well explore every option we have in our antibiotic arsenal.  Overall I think the most encouraging sign is that we are now considering how antibiotics and other drugs affect the microbiome and we are utilizing genetics to try to gain a better understanding of it.

Thanks for reading!  I’ve got a few of my own papers in the works so hopefully I’ll be able to discuss it more soon!  Cheers!

Sincerely,

GRW

 

 

1 Chu J et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nature Chem Bio. 2016. doi:10.1038/nchembio.2207

Conferences: A Scientist’s Vacation

Hello Everyone,

This time I wanted to write about my recent experience going to the American Chemical Society Meeting in Philly last month.  The title might be a little bit sarcastic; scientific conferences aren’t exactly vacations per say despite the fact that they are sometimes held in exotic locations.  For those of you who’ve never attended a conference, I thought I’d give a little bit of insight into what goes on during one of these events.  The general reasons that a scientist would go to a conference fall into two general categories: 1) To See and also 2) To Be Seen.  I hope that by the end I can convince you that no matter who you are, a young scientist or even a member of the general public, you can achieve both for yourself!

Scientific conferences provide an excellent opportunity to learn about current research in a given field or in many different fields.  The main bulk of time at a conference is spent attending sessions of lectures.  Generally these conferences run at least 4 or 5 days and each day will have at least 9-10 hours of lectures (from 8 AM to 6 PM usually).  The topics of these lectures can vary but will be focused on different subsections of the field that the conference represents.  For instance, this ACS conference was, as you might expect, centered on chemistry.  The impression that you might get from attending the ACS conference is that pretty much everyone does chemistry!  The theme of this one was “Chemistry by the People, of the People, and For the People”, a nice nod to Philly.  This meant that many of the talks would be about biochemistry and also chemistry related to human issues such as energy and the environment.  I attended a few very specific subsections on chemical biology and specifically related to DNA chemistry.  Even within this though we had a wide range of people come to present.  I saw talks by people in the industry, people in academia, and even a guy who was a virologist and Emory hospital!  Talks are also a great way to get to know the people in a field if you are not familiar with it.  For instance, I met a few people whose papers I read this past year. It was interesting to get to talk to them directly about their work.  The main piece I would give to someone going to a talk in a new field is:

 

DON’T be intimidated by anyone.

 

Everyone should be there to learn and to share their knowledge.  Anyone who would talk down to you or try to embarrass you because they know more about a topic than you do is a jerk.  And at any rate there’s always plenty more to see at a conference!

Everyone’s favorite thing to do at a conference is to go to the exhibitor stands.  This is usually held in the largest part of the building; a large conference hall or open area.  Here, companies of all different stripes come to present their wears and usually to give out free samples of different things.  Every company that is even remotely related to chemistry will show up to this thing.  We had people come from Dow, for Dupont, from Monsanto, from Gore, and the list goes on and on.  Some people are there to recruit people for jobs.  Other companies are actually trying to convince scientists to buy their equipment.  There were a huge number of glass blowing companies at the ACS meeting this time, more than I recall from the last one.  This makes sense since glassware is, by and large, essential to all fields of chemistry.  You also have different publishing companies from Elsevier to PloSONE.  Grad students love to go to this portion because you can get a lot of free samples, free food, and free T-shirts.  I have a closet full of T-shirts from various companies.  As a side note too, if the Big Bang Theory wanted to be more realistic, Sheldon and company would be wearing T-shirts from Sigma Aldrich and other company freebies not Marvel characters.

The second reason scientists go to a conference is to garner attention for their work and to get other people’s opinions on it.  This can be done in several ways such as presenting a poster, giving a talk, or participating in small group discussions.  Most young grad students (my future students included if you’re reading this) will only be allowed to go to a conference if they are at least presenting a poster.  Poster sessions usually run at the same time as the talks but usually you’d only present one poster; giving you time to do both.  Even though you might feel anxious about sharing your work in public, it’s often the most important thing part of being a scientist.  You’ll be in a room with several dozen other scientists sharing what you know and getting feedback on it.  I had a very productive poster session at this past conference; I spoke with a few people who knew more about aptamer work than me.  It really helped rejuvenate my enthusiasm for this particular project and helped me think of new places to take it.  I find the best time to give a poster is when you already have a lot of the project fleshed out and you’ve tested at least one hypothesis.  Some people believe that you should only present brand new data that you haven’t really finished exploring in order to maximize the benefits of the poster session.  I can see pros and cons to both ways of thinking.  Overall if you want to go to a conference you should be participating in the poster sessions.

Finally, perhaps the most prestigious part of going to a conference is giving an invited talk.  I’ve done this a few times but not at this conference.  It’s unclear to me exactly how you get yourself invited to give a talk.  To some extent, it’s whom you know.  To another extent it does really matter how well other people know your work.  Giving a talk can be stressful but it is ultimately extremely rewarding.  Aside from publishing a paper, a talk at a major scientific conference is the height of your work becoming an accepted part of the knowledge of the scientific community.  Again the question is whether or not you should show only new stuff or only stuff you have previously published.  The best talks, I find, have a little bit of both.  Speaking at a conference and open you up to a large audience and it can help you make a lot of new connections.  Graduate students should aim to give at least one talk during their time in grad school, if for nothing else but to get their feet wet.

Calls for talks aren’t really open to the general public but there are ways in which you can interact directly with members of the scientific community.  Many conferences also have small group discussions on specific topics or for professional developments.  I haven’t really gone to many of these but I know from having attended one or two that it can involve a discussion leader introducing a topic, say, “how do you get started working for the FDA”, and then opening it up to a panel or the audience.  People who are not scientists themselves can still go to these discussion and have their opinions heard.  Some of these discussions would benefit greatly from outside viewpoints.  There are a few I hope to go to in the next Biophysical Society Meeting that are about “science education”.  It would be very helpful to hear from students and from people who want to learn more about science about their experiences.  If you are motivated enough you can really make yourself be seen at a conference.

Many scientists find scientific conferences to be the highlight of their year.  In many ways they can be just that!  You get to interact with colleagues you haven’t seen in a while and also to meet new people and to make new connections.  You can also get a ton of free stuff; and who doesn’t like that?  Moreover it would be nice, in my opinion, to see non-scientists, non-industry people attend these conferences.  Unfortunately they can be quite expensive to attend.  The ACS meeting this year was actually $250 for a non-ACS member and it ends up being just about that much for the members when you factor in the membership fee.  I’d like to see a conference where, perhaps for one of the days, it was open to the general public for free.  The public would benefit greatly because they would get to learn a lot about science and scientists would also learn a lot about how to best communicate their work to the public.  ACS is huge, almost to an absurd point.  The one I went to in New Orleans had 20,000 visitors.  For this reason, they would be the perfect organization to be able to subsidize this “free public day”.  Or heck, just have an area outside the conference center sectioned off for the public to visit and have a few posters there one day.  Perhaps at the next conference that I attend I’ll try to convince a few of my colleagues and I to go to a park nearby and have an outside free public poster session with cookies or something!

Thanks for reading this time.  Please do let me know if this idea sounds intriguing and I will try to set it up.

 

Sincerely,

GRW

 

Link to ACS in case you would like to know about the next conference:

https://www.acs.org/content/acs/en.html

Ramachandran Plots: One of the best ways to describe Molecular Yoga

Hello Everyone,

 

It’s been just about a year since I started this blog.  Thank you to those of you who have kept interest and are reading it.  I thought for today I’d try to go back to the root of what I’m interested in, talking about molecular flexibility or “molecular yoga”.  I was reminded of one of the original parts of “Molecular Yoga” when reviewing a thesis presentation this past week: G. N. Ramachandran’s work on his “Ramachandran plots” from the 1960’s.  Ramachandran was a famous biophysicist who was interested in the structure of proteins, specifically how they are able to bend and twist to form interesting structures.  When we think of small molecules we sometimes have the tendency to assume to assume they are just small rigid shapes.  In reality, many molecules have the ability to undergo some “Molecular Yoga”.

Proteins are able to from shapes other than just being a linear, tangled mess.  I hope, in reading some of what I’ve wrote, you have gained insight into the fact that thermodynamic forces such as Entropy can drive molecules to wiggle about a little bit.  This is exemplified in proteins, as Ramachandran showed.  Take, for instance, a simple peptide formed from two amino acids bound together.  The carbon atoms that are held together by single bonds are able to rotate with respect to each other.

Rotations

This can allow them to move about and position, for instance, the R (random) groups in different places.  Ramachandran and colleagues looked at the rotations about those angles (Phi and Psi) for the natural occurring amino acids and whether or not they cause the atoms to crash into each other.  There are clustering regions on a Ramachandran plot where these angles are not causing crashing or to use a phrase we discussed earlier, are “Energetically Favorable”.  Interestingly, these are the angles in which secondary structures such as alpha helices and beta sheets can be found.  Thus, Ramachandran was able to provide a way for linking the favorability of bond angles to the secondary structures that occur in nature.

Alpha and Beta

Figure From Griffiths et al 2002

Ramachandran plots, though they may appear simplistic, provided scientists with the basis for developing much more complex ways of looking at molecular structures.  There are numerous groups working on computational modeling of proteins, and they use this type of information for their work.  I, personally, am interested in how these structures can be induced to change by target binding and by other phenomena.  You can see how it what my line of thinking is here as well.  For proteins you need to be able to add some energy into the system to make an angle rotate from its most favorable conformation to another conformation.  In my opinion, Molecular Yoga is about finding was to make this happen dynamically, not just for proteins but for many other types of molecules as well.

Thanks for reading this time.  I’ll be updating on my work soon!

Sincerely,

GRW

Original Paper:

Ramachandran, GN, Ramakrishana, C, Sasisekharan, V. J. Mol. Biol. (1963) 7,95-99

Equilibrium of Augmented Reality (AR) Games

Hi Everyone,

I wanted to post about an interesting current topic, the rise of Augmented Reality (AR) games.  These are games primarily supported on mobile platforms that require players to move about the world and find things (ex locations, small fictional creatures.)  Last week a very popular game was released and has boomed to millions of player almost overnight.  I think that there is some equilibrium that will be reached very shortly, however.  An equilibrium in chemistry, which I’ve talked about before, is essentially a situation where the potential of going from reaction state A to reaction state B, or the “driving forces” is equal (in most normal cases).  If we think about these AR games there are going to be numerous players who sign up in a short period of time because they are interested and the game is free.  There are driving forces against continuing to play, however.  The game will 1) eventually cost money and 2) become less interesting and more repetitive.  So eventually many players will drop out of the game.  There should be some equilibrium wherein the total number of players stays constant.  This could very well be only one person or it could be zero people!  You might very well think of many fads this way!

 

Just a quick post today as well!  Have a good day!

 

Sincerely,

 

GRW