Bonnie Bassler: Expert Q&A

[Editor's note: Bassler answered the following two related questions with one response.]

Q: As a young graduate investigator, what are some key starting points for achieving success in the research profession? Matthew E. Lundberg, University of California, San Diego Ph.D. program, La Jolla, California

Q: Do you have any advice or lessons you would like to share with first-year graduate students about to begin the long haul? Mathew, Houston, Texas

Bassler: Hello to both Matthews!
I think being open-minded about what Nature is trying to tell you is the key to being creative and successful. Often, as scientists, we get convinced about how a process must work or how an experiment should turn out, and then when an experiment yields something different, we either think the result is wrong or we get disappointed that things did not turn out the way we anticipated. Keeping your eyes open to "the answer," whatever it is, is the best course. I try to never be disappointed by a result. That way, I am often surprised, and I'm frequently challenged to change my thinking based on the findings instead of trying to fit the findings to my ideas. Also, I never let fear (not knowing a technique, having to do something I've never done before...) stop me from asking a scientific question. I force myself to learn whatever I need to know (no matter how painful) to do the best experiment I can.

Finally—and this will not be a surprise—you have to work really hard. Being creative and smart is not enough. Science is difficult and slow no matter who you are. The hours are long, and the glorious "aha" days come only very infrequently. You have to keep believing that if you put in the hours, those days will indeed come! Have fun. It is an amazing adventure. Work hard, and keep your eyes open to Nature's secrets.

Q: What do you think our high school students should be taught about all of this new information about bacteria, and should we make even more changes about how we use antibiotic substances? Helen Peterson, Hattiesburg, Mississippi

Bassler: Dear Helen,
I think interest in bacteria is increasing tremendously. Twenty years ago they were considered "solved," so their place in textbooks got old and dry. However, now we understand that bacteria exhibit all sorts of complicated behaviors (quorum sensing being only one of many). We also now know that bacteria are fabulous models for understanding human biology. I think students should be taught those things by learning how remarkably wonderful and sophisticated these little creatures are.

Regarding antibiotics, it is important that we understand how traditional antibiotics work, as there will always be a need for them in clinical settings. We also need to understand the perils of misuse and overuse of antibiotics and how resistance mechanisms evolve. We need to appreciate that antibiotics must be used judiciously so that they can remain effective for as long as possible.

Q: Is it possible that even when you make a drug to keep the bacteria from "talking" that the bacteria will work their way around the drug that's stopping them from communicating, just like they've worked around current antibiotics? Alexandra, 7th grade, Manchester, New Hampshire

Bassler: Hi Alexandra,
Absolutely. We know that bacteria will evolve mechanisms of resistance to anti-quorum-sensing therapies. The hope is that because anti-quorum-sensing strategies do not kill bacteria, only keep them from communicating, this is a less harsh treatment and a less stringent selection for resistance. Because of that, the hope is that resistance will develop more slowly than it does to traditional antibiotics. Thus anti-quorum-sensing therapies may have a "longer shelf life" than traditional antibiotics. Of course, we won't know if that is indeed the case until we make the drug and monitor its effectiveness.

Q: I have listened to many programs on TV in which scientists have said bacteria have been around for billions of years. If this is true, my question is: Has one particular strain of bacteria, say, been around for billions of years? Or has its descendants, continually breeding, been around for billions of years? Have they not evolved? Bill Klepsak, North Attleboro, Massachusetts

Bassler: Dear Bill,
The answer to your question is "both." Bacteria are constantly changing and evolving. We define a species or a strain of a species of bacteria based on its DNA content. Some strains and species have been around for long times because their offspring keep dividing and multiplying. However, occasionally a descendant acquires a fortuitous mutation in its DNA or it picks up a new gene or genes from somewhere. These processes make the descendant different from its parent. This is how new strains and species begin to evolve. This happens all the time, so indeed new strains/species are always arising.

Q: Dr. Bassler,
You have demonstrated that bacteria have the ability coordinate gene expression in response to population density. Does this suggest some form of altruistic and/or communal behavior amongst bacteria? Also, do these autoinducers simply communicate information to the neighboring cells (which the bacteria are free to respond to or ignore), or do the autoinducers actually bind to a receptor site, thus biochemically forcing other bacteria to comply? Thank you. Mark Hess and Honors Biology Classes, Chichester High School, Chichester, Pennsylvania

Bassler: Dear Mr. Hess and biology students of Chichester High,
I do not think bacteria are "altruistic." My opinion is that the coordination of activities through quorum sensing has evolved because it confers advantages to the group. When cells work together they can accomplish tasks and reap benefits that each bacterium could never manage as an individual. My belief is that each bacterium is "out for itself," but each member of the group has a better chance of survival if it acts in conjunction with the others.

Bacteria cannot "ignore" the information they are being supplied by their neighbors. The molecules indeed bind receptors, and that binding automatically causes biochemical and genetic changes inside the cell (i.e., the cell's response). I believe that this mechanism has evolved as a form of "policemanship," ensuring that all the members of the group participate. Otherwise, cheaters would arise; bacteria would produce the signals, ignore them, but force their neighbors to do the "work" (carry out the processes in response to the signals). Eventually, the majority of the bacteria would evolve to ignore the signals, and there would be no group effort. There are likely many molecular mechanisms embedded in bacterial communication relays that keep quorum-sensing systems functioning with high fidelity. We think about those mechanisms a lot and are trying to define them to understand how cheaters are kept in check.

Q: I was particularly fascinated with your NOVA segment tonight, as I have had a continuing on-and-off battle with the bacterium Clostridium difficile! What makes it keep returning? Does it turn on and off?! (I am 78 years old!!) Mrs. Delaine Heliotis, Somerville, New Jersey

Bassler: Dear Mrs. Heliotis,
First a disclaimer, I am not an expert on C. difficile, so this is a guess. In many recurring bacterial infections, there are bacteria called "persistors." What happens is that a person gets treated with an antibiotic, and the infection goes away ... almost. A small fraction of the infecting bacteria become "dormant" and escape the antibiotic treatment. After the person finishes the antibiotic treatment, since persistors remain, the person isn't fully cured. The bacteria regrow, and everything starts all over again, so the human suffers from a persistently recurring infection. Scientists are trying to understand persistors—how, given that bacteria are clones of one another, some bacteria can survive when others in the same infection are susceptible to the drug. Also, it is not understood why persistors only arise in some people and in some cases. These are hotly investigated topics, but unfortunately for now and for you, unsolved problems.

Q: Do bacteria use quorum sensing for a variety of purposes, e.g., fish form schools for protection, lions form prides to hunt? Also, do the same types of bacteria from different colonies communicate differently than the same types of bacteria from different colonies, i.e., do genetically related bacteria recognize each other aside from their being the same species? Paula, Washington, D.C.

Bassler: Dear Paula,
Quorum sensing is used to control hundreds of different group processes. In the cases we understand best, the processes controlled are ineffective when carried out by individual bacteria acting alone but become effective when carried out in synchrony by the group. Virulence is a good example of a quorum-sensing-controlled behavior. A few bacteria can't make us sick. Even if they release toxins or other harmful agents, we are HUGE compared to them, so each bacterium's measly few molecules of a toxin can't harm us. But, if the bacteria wait, count themselves with quorum-sensing molecules, and then all of the bacteria release their toxins simultaneously, they can overcome an enormous host. There are all kinds of examples of quorum-sensing-controlled group behaviors: bioluminescence, virulence, exchange of DNA, biofilm formation, symbiosis....

Bacteria have multiple chemical languages. We think each bacterial species has a molecule that is unique and represents its own species-specific language. Each unique molecule allows a particular species to know and communicate with its relatives (i.e., have a private conversation). We know there is a universal molecule, a sort of bacterial trade language that bacteria use to converse between species (i.e., a Bacterial Esperanto). There is mounting evidence that many additional molecules remain to be discovered, such as species non-specific molecules that say "who" the neighbor is. This field is only about 10 years old. So far we have only managed to identify a few molecules. We know that bacteria interpret a rich and complex chemical world, and we are working hard to define the complexity of the lexicon.

Q: Do you think viruses and prions communicate with each other, too? What about mitochondria, which have their own DNA? How many other "alternative" life-forms could be living within us? Pat Stauffer, Westminster, Maryland

Bassler: Dear Pat,
There is no evidence yet that viruses, prions, or mitochondria have a form of quorum sensing. To date, this phenomenon is only found in bacteria. However, this field is relatively young, and scientists are now beginning to study higher organisms for quorum sensing. Particularly interesting are yeast (fungi). Yeast are higher organisms, yet they are microbes, so they are not terribly different from bacteria. It might well be possible to discover an analogous, cell-cell communication system in yeast.

Regarding "alternative life-forms," we have thousands of different species of bacteria living in us and on as mutualists. These species protect us from harmful invading bacteria, help us digest our food, and perform other tasks that we require. I do not know about the numbers of other life-forms (viruses, prions...) that might routinely be in or on us.

Q: Is there any evidence that fungi cells may use communication techniques similar to those observed in bacteria? Ron Herzog, Cincinnati, Ohio

Bassler: Hi Ron,
As mentioned in the above answer, yes, the study of quorum sensing in yeast is a hot topic. A few reports have come out in the past few years demonstrating that different fungi have molecules that tune them in to their neighbors. It is not quite clear that these are bona fide quorum-sensing molecules, but it sure looks promising.

Q: Dear Dr. Bassler,
I saw your interview today, and I was so impressed with your discoveries.

I was diagnosed with an autoimmune disease, Rheumatoid Arthritis, almost 10 years ago. My deceased sister had Systemic Lupus Erythomatosis, and my mother has a type of rheumatic disease as well. RA has very significantly altered my life in a very negative way. During these past 10 years, my rheumatologist has treated my RA with Prednisone, Plaquenil, Remicaid infusions, Methotrexate, Humira, amongst other drugs. Unfortunately, in time, my immune system eventually renders these drugs ineffective as the disease seems to become "immune" to them. Consequently, in an effort to suppress my immune system, my rheumatologist prescribes yet another drug to replace the previous one. This is what I have to look forward to for the rest of my life.

I have read that scientists still don't know what causes rheumatic diseases, and while listening to your interview, I couldn't help but think that perhaps the immune system in autoimmune diseases is not responding to the body's cell structure or to the presence of another living organism like bacteria or viruses, but perhaps it reacts to their "communications," or as you call them "small quorum-sensing molecules." Perhaps not only do bacteria communicate amongst themselves, but somehow also directly or indirectly communicate with our immune systems. Or perhaps some immune systems just tend to be more sensitive to this communication, thus triggering an autoimmune attack and producing these dreadful diseases.

Perhaps your efforts to control infections by blocking this bacterial communication may also, in fact, CURE autoimmune diseases by blocking this inadvertent communication between the quorum-sensing molecules and the immune system. I realize, of course, that this is only a very far-fetched hypothesis, as your concept of "talking" bacteria once was perceived, but only research can shed some light on this, and I'm hoping you may someday lean in this direction as well.

Obviously, not being a scientist or a professional in any medical field myself, I have only a hunch regarding this, but in my despair, I hope that perhaps my silly idea could trigger some curiosity in you that would lead you to research this possibility. Or maybe my idea may serve as a brainstorming effort that would trigger in you yet another brilliant idea regarding the connection between talking bacteria or quorum-sensing molecules and autoimmune diseases.

Perhaps then I wouldn't have to live in eternal fatigue and severe pain, or be exposed to such potentially dangerous drugs. Maybe there is no hope for me in my lifetime, but perhaps your research could help any of my offspring who might inherit this type of autoimmune disease, along with hundreds of thousands of people in the world who suffer from autoimmune diseases.

I appreciate your contribution to humanity, and I wish you the very best. Maria de la Torre, Miami, Florida

Bassler: Dear Maria,
First, I am terribly sorry to hear about your RA and the suffering it causes you. I wish I could help you directly. Unfortunately, I can't, but at least I can respond to your comment. The idea that higher organisms are participating in the conversation with bacteria is a wonderful one, and one that is being actively investigated. Traditionally, microbial research has focused on bacteria and human disease, but shockingly little has been done to understand bacteria in human health. Not any more! There is an increasing awareness that the bacteria that live in us and on us are actively engaged in keeping us healthy and fending off invaders. It is also very possible that they play important roles in our behaviors and the diseases we do or do not get.

Much new research effort is being put into understanding the roles of our endogenous bacteria with the aim of developing methods to control, enhance, and exploit these bacteria to keep us ever healthier. The influence of quorum-sensing-mediated communication in this arena is being investigated, and certainly whether the conversation is two-way (i.e., whether our immune system or other systems talk back or listen in to the bacteria) is also being explored. Again, the idea is, if we can understand the molecular mechanisms underpinning the bacterial-human conversation, we can develop therapies to manipulate it to give us a better quality of life.

Q: Dear Bonnie,
Having coronary artery disease, I am fascinated with the Finnish researchers who have found evidence that nanobacteria may be the cause of the disease and are refining a treatment aimed at killing the bacteria and decalcifying the arteries. Do you know anything about this research? I understand that NASA is conducting laboratory tests on this concept. Any information that you could give me on this idea would be greatly appreciated, as I and millions of people could benefit if there is merit here.
Sincerely, Alan Lowich, Perth Amboy, New Jersey

Bassler: Dear Alan,
This sounds fascinating, but I'm afraid I have not heard of nanobacteria. Ummmm, I think you need a different expert!!! Sorry.

Q: Can you provide some thoughts on individuals with knee or hip implants and the biofilm some unfortunately develop and if there is hope for probiotics in this issue? [first name not given] Raunaque, LaCrosse, Wisconsin

Bassler: Dear Mr. or Ms. Raunaque,
Biofilms are communities of bacteria attached to surfaces (for example, as described in the NOVA piece, your teeth in the morning). Biofilms are a cause of constant concern for people with medical implants, heart valves, etc., because these medical devices provide a niche for bacteria to adhere to and thus cause infection. We know that quorum sensing is required for biofilm formation: If the bacteria can't talk, they can't make these large, interacting, adherent communities. The goal of many researchers' studies is to find methods to interfere with biofilm formation, and, of course, a key focus of study is on interrupting quorum sensing. One strategy is to make molecules that antagonize the natural quorum-sensing molecules to impede biofilm formation. Another strategy is the one you suggest, to develop probiotic quorum-sensing therapies that enhance the conversation among our commensal bacteria at the expense of the biofilm formers. Both these avenues are currently being explored.

Q: Do you think, with your current findings of intercellular communication, that such research could eventually lead to the prevention or help the cure of AIDS? Chris Casey, Phoenix, Arizona

Bassler: Dear Chris,
At present, there is no evidence that viruses use quorum-sensing mechanisms to communicate. My guess is that our studies will have little or no bearing on AIDS research. Luckily of course, many fantastic scientists are focused on that terrible disease and its prevention/cure.

Q: I was intrigued by your work with bacteria. Their ability to communicate is amazing. In respect to using your findings to fight disease (or, rather, bad bacteria), a thought came to mind. There was mention that bacteria do not activate their function until they detect that there are enough of them to do so safely. Can this be thwarted by making them "think" they are outnumbered by other good bacteria, perhaps? Is there some way to trick them to think it is not safe to activate their harmful function? Just a thought... William Hubbard, San Carlos, California

Bassler: Dear William,
This, too, is an excellent idea. Indeed, there are many possibilities all aimed at fooling the bacteria into not detecting that they have the appropriate number of cells or the correct species around them to launch their attacks. One possibility is to develop molecules that simply interfere with the bacteria detecting the real quorum-sensing molecules. This strategy would render the bacteria "thinking" they are alone when they are in fact a group, so they would not initiate virulence, giving one's immune system time to hunt them down and eliminate them. A second possibility is to develop molecules that trick the bacteria into "thinking" they are at high cell number when, in fact, they are not. This strategy would cause the bacteria to launch their attack prematurely, and it would be ineffective. Again, one's immune system would be alerted and function to eliminate the invading bacteria. A third possibility is the one you suggest, to develop molecules that confuse the bacteria about the composition of the neighborhood. Again, the bacteria would do the wrong thing at the wrong time. Too bad for them!

Q: No question here, just a comment. I don't think I have ever referred to a microbiologist as "charming" before, so this is a first. I was fascinated by your work on NOVA, but I am just as taken with what a winsome and engaging human being you are. No question your mom was proud and, if you "buy" Thomas Aquinas's philosophical view of existence, still is. You're an inspiration to more than just girls and young women. Phil Motta, Phoenix, Arizona

Bassler: Dear Phil,
Thank you very much for this touching comment. I'm very flattered. I am going to show this to my lab, because I am not so clear that they always find me "charming"!!!! Seriously, a heartfelt thanks for writing this to me.

Q: Not a question, just a comment. I just finished watching tonight's presentation of NOVA scienceNOW. Bonnie's story was so inspiring. What a wonderful and refreshing way to show a "scientist"—a great mind and undoubtedly a great heart. I was moved to tears when I heard her speak about her mother. Continue your amazing work, Bonnie!! Hooray for you and hooray for women!!! Mayra, Cuyahoga Falls, Ohio

Bassler: Dear Mayra,
Again, a very, very heartfelt thanks. I am so glad to hear that the piece came across to you in this way.

Q: Your face told the whole story. Your enthusiasm and energy was hard to contain. While talking about your Mom, your face cried. With all of your accomplishments, one of your strongest is your communication. Steve Sanchez, Wayne, New Jersey

Bassler: Hi Steve,
Thank you so much. This is very kind. For reasons that the NOVA program made clear, I DO NOT play poker!!!! I can't keep secrets either.

Q: I think you are really on to something very great, and I cannot believe you carried the ability and determination to not give up. I am so proud of your continued efforts in spite of personal setbacks. Keep trucking and, as you hope, you can do something that will definitely help mankind! Stephen Lanier, Deltona, Florida

Bassler: Dear Stephen,
This is also a very kind comment. I am lucky because I get to work with the smartest, most creative, and most devoted group of students and postdoctoral fellows imaginable. I am confident in their ability to keep going. They are fearless and tireless. They, in turn, always keep me going.

Q: Hi Bonnie,
I also want you to live a long time so that you can help others. Please wear a helmet when riding your bicycle. Paul Moskovitz, St. Louis, Missouri

Bassler: Hi Paul,
Sigh. I received a number of emails containing very well-deserved scoldings about the bike helmet. First, for the record, I was wearing a helmet in the NOVA piece. But, indeed, I was wearing it more like a beret than a helmet. I'm sorry! I confess to being vain for the filming. Silly, but true. I promise, from here forward, to wear my helmet as it was intended. I sincerely thank everyone who wrote these comments. You have shamed me! But, I'm touched that you care so much about me after only knowing me for nine minutes!!!

Q: You are so motivated. In 1961, Ellis Englesberg was my advisor, but the operon was not my passion. Forty-five years later, I'm still a clinical microbiologist. Thanks, Allan Coe, Palm Springs, California

Bassler: Dear Allan,
Thanks! I had the good fortune to not start science until it was very clear what genes are and do. I am happy to hear you are a clinical microbiologist. You are influencing the qualities of our lives right now. I only fantasize that I will somehow do that.

Q: I am a microbiology teacher who failed retirement. I am trying to bring some "cutting-edge" technology to the boonies here in New Mexico. I am still tutoring students in my home lab (complete with my own SEM). As a trained microbiologist, is there any way I could do even a tiny bit of research for you that would fill a tiny gap in your marvelous program? Pardon my presumption, but I would love to have a "piece of this action." Thanks. Bob Slusher (Howard Hughes Medical Institute graduate and former student of Prof. Malatesta at good old Princeton U.) Robert Slusher, Santa Fe, New Mexico

Bassler: Dear Robert,
Thank you for this kind note and the generous offer. I will tell Professor Malatesta I heard from you, and she'll be so proud to know about your excitement and enthusiasm. I will have to think about a possible way to transport some of our work to your "lab" in New Mexico. Hmmmm....

Q: I enjoyed the segment about you and your work on my local PBS station last night. Free TV, I call it. No cable, just free TV. What struck me in a timely fashion was how you spoke about your mother. Just turning 54 last Sunday, I am at a turning point in my life. After seeing how positive and touching your mother's words were to you, I compared it to my life's experience. My mother's last words to me were "No, talking." She died in 2004 after a long illness ending with years of dementia, silently leaving me one piece at a time, devastating me in the process. Her and my father's headstone arrived finally last spring, and I buried them together. I read aloud a letter written by both of them to each other in 1945 as I buried them. I had never read the letters, just picked them from their love-letter boxes, making sure that they were written on the same day in the 1940s. She was in Orlando, and he was in the war. They were each other's words to one another.

The past nine months have been spent doing a lot of nothing in response to years of doing too much. When I saw your work, your energy, and your story about your mother, I realized that I am truly on the upside of all my sadness. My natural Happy Camper is back. Thanks for sharing yourself and your work. I look forward to reading more about all the beautiful things in life that are in science and our world. As each day passes, I believe that we are closer to each other in the smallest ways and our influences are greater than we ever even dreamed. Have a wonderful day. Brenda, Orlando, Florida

Bassler: Dear Brenda,
Thank you so much for sharing this story with me. I was tremendously moved by it. I think reading the love letters is a wonderfully creative and loving way to pay tribute to your parents. It is delightful to hear that the NOVA piece made you realize you are indeed working through your sadness. I have come to terms with the idea that for the rest of my life, I will get very sad about my mom from time to time. I have realized, in fact, that I'm glad that will happen. It means I still love her and appreciate all that she did for me.