Happy Halloween! We’ve had enough horror lately. So, to commemorate the holiday, I’d like to share a not-so-scary story, the story of the often-feared field of biophysics.
I am enrolled in a graduate school with an umbrella program in biomedical science. My program has seven varying concentrations. I work alongside all sorts of scientists: chemists, geneticists, immunologists, microbiologists, even skeletal biologists. During seminars and poster presentations, it’s typical to overhear a non-biophysicist remark that biophysics is “overly complicated,” “over my head,” or “above my pay grade.”
What is biophysics?
Biophysics uses physical theories to explain, describe, and observe biological events. Biophysicists investigate the structure of biomolecules, the thermodynamics of biological reactions, enzyme kinetics, protein movement, and more! Ever used or heard of FRET, NMR, x-ray crystallography, cryo-EM, small-angle scattering, or isothermal titration calorimetry? Those are all biophysical techniques.
Note that biophysics, like all areas of science, overlaps considerably with other areas of expertise. So, if you’re a biologist, chemist, neuroscientist, or biochemist, you’ve likely been exposed to some level of biophysics.
What’s all the fuss?
Ok, let’s clear the air. Why are people afraid of biophysics?
1) Math. When I joined the biophysics department at my school, I was often told, “Well, I hope you’re good at math.” I’m ok at math, but most calculations I do are your typical molarity calculations. True, some biophysicists use a lot of math in their research, particularly those who work with method development, but many of us do a basic level of math expected of any scientist.
2) MIA undergrad biophysics courses. Biophysics courses aren’t required or offered for many science degrees. But just because you didn’t learn about biophysics in a classroom doesn’t mean the knowledge is unattainable now. In fact, I wasn’t introduced to biophysics until after undergrad.
3) Jargon. Plenty of biophysicists love jargon!! They have a fancy vocabulary and enjoy showing it off. So, if you attend a biophysics seminar, the speaker might scare you away with their esoteric knowledge. Don’t let them! Biophysics can be accessible if communicated in a clear, concise way.
4) Theory. As part of their training, biophysicists are expected to learn the techniques they use as well as the theory and equations behind them. If you don’t understand the theory or equations, don’t fret (pun intended)! You can benefit from biophysics if you understand why an experiment was conducted and what conclusions were made without acquiring a deep understanding of underlying theory.
Crossing over: Learning biophysics as a non-biophysicist.
The next time you come across a biophysics figure in a paper or have the opportunity to use a biophysical technique, don’t shy away.
1) Ask for help from your biophysical friends. When doing so, tell them when they are using big words and phrases you don’t understand. Likely, the jargon they are using isn’t necessary but comes second nature to them.
2) YouTube. YouTube is an excellent source for explaining biophysical techniques. Pro tip: click around until you come across a biophysicist who speaks at your level. Some videos are super theory-oriented, while others are made for practicality and accessibility.
3) Take your time. Learning about biophysical techniques is more time-consuming than learning how a western blot or a qPCR works. Begin by learning the basics of an experiment: what is done and what can be learned. Then, your knowledge can grow from there.
A message to my fellow biophysicists:
It’s cool to show off our impressive data sets, brag about our niche knowledge, and geek out over new techniques. But remember to be mindful of your audience. Yes, when we speak to each other, we have our own language. But when we speak to researchers out of our niche, we can explain our work in simple, understandable terms. Improving our communication can help our fellow researchers explore biophysics while bolstering the importance of biophysical funding and education in academia.
When I started graduate school, I was prepared for the classwork. I was even prepared for being a teaching assistant. I had been doing this type of work since high school.
I thought that I was prepared for research as well. I thought that my graduate school research would be similar to the research I had done in undergrad. Unfortunately, starting my research in graduate school was a wake-up call.
For the first time, working hard did not mean more success. I couldn’t just complete a set of requirements to succeed in my research. I was stuck at a point where I was willing to work hard, but I had no idea what I was doing. My time felt wasted when my results were a dead end.
Moving forward five years, I have earned my Ph.D., completed dozens of research projects, worked as a postdoc and research specialist, and published and presented many different research projects.
Here is a secret though! I am not special. I’m not a genius or some natural-born researcher. I am a person just like you who struggled with research, learned, failed, and became successful through the process.
Research isn’t hard.
The biggest myth I believed was that research is innately hard. If saying research isn’t hard makes you angry or want to stop reading, hear me out.
The reality is research doesn’t need to be a struggle, but the majority of us are self-taught researchers. Especially if you learned research in academia, you have likely never had any training in how to conduct research. Of course, you have received training in how to collect data in your field, but what about how to learn your field, develop ideas, analyze your data, or publish and present your findings?
Think about when you learned a task you now find simple. In my case, I think about tying my shoes. I was so frustrated that I couldn’t tie my shoes that I wore velcro shoes way past when I should have. Now imagine that you were never taught how to tie your shoes. How much more difficult would it be to tie your shoes? How many more times would you fail? How much longer would it take you to be comfortable?
The reason this is so important to realize is that many of us will put up with things for much longer than we need to because we believe this is just how research is.
If I told you something wasn’t supposed to be hard, would you ask for help sooner? Would you find a way to make it easier? Would you stop overthinking what you are doing when it feels too easy? Would you spend more time living your life instead of trying to feel productive?
I know I would. I know because I did! My research journey changed when I stopped focusing on the struggle and found ways to make my research easier. This included reaching out to others for help, creating systems to complete my research, and accepting that I was in a learning process.
Therefore, if you believe your research is supposed to be a struggle, start challenging this idea. Ask for help and find mentors that can help you.
Now, I want to share 5 important tips for your research journey that I have learned through my own journey.
5 Tips to Become More Successful At Research
While you may be on board about becoming an efficient worker, you may still wonder how to become more efficient. So let’s go step-by-step through a system that I created for myself, which has made me more productive while decreasing burnout.
Stop Pursuing the Sexy Idea
We all want to be the scientist that has the research ideas that win Nobel Prizes and inspire movies. Therefore, we will dismiss novel, feasible ideas because they are too easy or don’t feel new enough. The reality is that the sexy ideas movies are created after likely weren’t how those ideas started.
Most projects are making a one or two step gain to the field. Then, once you complete a few projects, you have created a truly novel discovery that you likely would have not thought of at the beginning of the first project.
So instead, take the research idea that you know how to complete and you know is novel in some aspect and run with it! Don’t dismiss an idea because it doesn’t feel novel enough!
Research Success Happens in Indistinguishable Steps
TV and movies always show research success as a montage of hard work followed by one groundbreaking discovery that happened just as it was needed! Think about the Imitation game, The Big Bang Theory, or A Beautiful Mind.
While we may understand that it is being dramatized for the story, we may also think that the best way to have research success is through late nights, writing on a whiteboard, and insane amounts of coffee.
I would love to have my life turned into a movie one day, but all of my research success would break this notion. My success in research came from completing one step after another.
But looking back, what mattered weren’t the long nights or the time spent staring at data or reading papers. It was the time that I spent doing the little things like collecting one set of data at a time, creating one graph and a time, and testing one failed idea after another.
Take joy from the process of completing your research knowing that every step you are taking will lead you to success.
Stop Expecting Answers from Raw Data
When I first started performing data analysis, I wanted to look at spectra and be able to create clear conclusions about my data. Unfortunately, I was severely disappointed when I had no idea what my raw data was telling me.
For the majority of fields, raw data will only give you an understanding of the quality of your data.
Once you have examined your raw data, many of us will feel lost about what we do next. In my case, I knew that I needed to complete more analysis, but I didn’t know where to go because I was expecting my raw data to tell me.
I learned to create a system where I did specific data analysis steps to visualize my raw data. This means that I created many different figures to determine what the conclusions of my data were before I started planning my research papers.
This makes it easy because I do not even start looking for conclusions until I have my data visualized. It’s just a simple, emotionless process of data analysis until I can actually start creating conclusions from my data.
Don’t Personalize Your Results
One of my labmates in grad school was down on their research for years, they kept questioning whether they even deserved a Ph.D.
They were down on themselves and wondered if their research was worth publishing. They had completed a massive amount of research, but the research had not yielded the results the advisor was expecting.
I couldn’t believe that they were questioning whether they deserved a Ph.D. or if their research should be published.
Then I asked a single question, “Do you think that your results are a reflection on you or your capability as a researcher?”
“Well, yeah…”, they answered.
It is so common to think that if we are a good enough researcher we will have life-changing data. You can’t take personally how the universe works. Your research is about discovering how the world works and our capabilities to manipulate it.
Therefore, your capabilities as a researcher are reflected only in how well, accurately, and ethically you made your discoveries, not in the discoveries themselves!
All Good Research Communication Starts with a Story
So once you have collected and analyzed your data, most of us will jump into trying to write our papers. Then, we get frustrated because we don’t know what we are writing!
The first time I tried to write a research article, I sat in a Starbucks for 8 hours trying to figure out how to write an introduction. After a full day, I had completed 1 paragraph. I spent most of my time looking at other papers, writing a sentence and then deleting it, and questioning whether I could actually do this.
Two years later, I was writing papers in a matter of hours. Not only could I write papers, I enjoyed writing them.
There were two tricks to developing scientific writing skills: (1) always start with a story and (2) understand the purpose of each section of your paper.
Once I complete my data analysis, the next step is to create a figure outline. A figure outline is just your figures that will be in your paper in the order that you will present them.
The key to this figure outline is that you should be able to explain your research story to another person by just looking at your figures. Once you can do this, all you need to do is write your story down to complete your research paper!
You can be successful in research. No, I don’t have to know who you are or your credentials for this statement to be true. I know you can, because if you are interested enough in research to get through this blog, you are interested enough to be successful.
Now, you may need to help along your journey, which is completely normal. You will have challenging and frustrating times in your journey. But you should challenge the beliefs that you just have to struggle through your research to be successful. You can make your research journey easier with these tips:
On the grain, competition between species reigns supreme. Many species appear to be capable of inhibiting L. kefiranofaciens, which keeps its abundance in check. Meanwhile, Lactococcus lactis, another member of the core community, produces toxins known as bacteriocins that target and strongly inhibit the growth of other members of the community.
Although the community on the grains remains stable throughout the fermentation process, the surrounding milk sees increases and declines in different members as the microbes move from a solid to a liquid environment. The researchers described the kefir grains as a "basecamp" from which the different microbes "colonize the milk in an orderly fashion." This migration happens in a set order of species, which appears to have a lot to do with the preferred diet of each group.
Next stop: Cooperation Station
Unlike the grain environment, the complex nutritional landscape of the milk pushes the microbes to cooperate rather than compete. First to colonize the milk is L. kefiranofaciens, which, as on the grain, is the most abundant species throughout the fermentation process. Surprisingly, despite its dominance, L. kefiranofaciens can't grow in milk on its own. Its growth has been suggested to be supported by rare species, many of which can grow in milk alone. These species break down proteins and sugars in the milk to produce smaller molecules, generally referred to as metabolites, that L. kefiranofaciens could use to grow.
The analysis of these metabolites, using several techniques collectively known as metabolomics, was crucial for resolving how and why all these microbes cooperate. By measuring the concentrations of key metabolites throughout the fermentation process, it became apparent that some of their patterns match the growth patterns of key kefir species. For example, the concentration of a key intermediate molecule that cells use to produce energy, called citrate, drops suddenly in the early stages of fermentation. This drop correlates with the growth of two kefir species, L. lactis, and Leuconostoc mesenteroides, which suggests that they could be using citrate to grow.
In the milk, cooperative interactions between species are far more common than competitive ones, indicating that there are benefits to be gleaned from the presence of others. For example, L. kefiranofaciens and L. mesenteroides share a mutually beneficial relationship in which the presence of one promotes the growth of the other. This partnership seems to be centered on cross-feeding between the two. L. kefiranofaciens breaks up proteins into amino acids that can be accessed by L. mesenteroides. In return, L. mesenteroides, now able to carry out fermentation, produces lactate which L. kefiranofaciens can consume.
The acid test
The production and accumulation of major fermentation products, including lactate and acetate, acidifies the milk and gives kefir its distinct, slightly sour taste. However, these products also play a role in regulating the growth of microbes in the process. They inhibit the growth of many species that are important in the early- to mid-stages of fermentation, including L. lactis, L. mesenteroides, and several rare species.
Meanwhile, other species appear to benefit from the accumulation of lactate and acetate. Metabolomics measurements reveal that different species of yeasts and Acetobacter bacteria begin to grow during a favorable window of lactate and acetate concentrations in the milk, indicating accumulation of these metabolites clear the way for late-growing species. Although, high concentrations of lactate and acetate would be unfavorable for everyone.
Like many of the other core species, Acetobacter fabarum cannot grow in milk on its own. Here, another beneficial cross-feeding interaction appears to be at play, with L. lactis, an earlier-growing species, providing lactate and specific amino acids for A. fabarum to consume. However, whether A. fabarum provides anything in return is not clear. In contrast to the mutualism between L. kefiranofaciens and L. mesenteroides, this interaction could be described as commensalism: one partner benefits, and the other is seemingly unaffected.
Studying interactions between microbes presents a near-limitless well of discovery, precisely because these interactions are everywhere and occur in many flavors: from cooperation to vicious competition, and everything in between. Humans also have the potential to leverage microbial communities for our benefit: for example, understanding how microbial communities associated with crop plants function could help us devise ways to increase hardiness and yields under environmental stress. One longer-term goal is to develop a comprehensive-enough understanding that we can build communities to perform specific tasks, whether that be degradation of pollutants in the environment, producing new chemical compounds, or improving our health.
Can we slow or even reverse aging? The good news is, slowing aging and gaining more than ten years is absolutely possible and doesn’t cost you anything except some discipline (yeah, I know, that’s the bad news here). However, to keep you reading, I’ll tell you a little later how that works. Whether it is possible to slow or even reverse aging is currently the topic of a lot of research.
But let’s start at the beginning. If you want to treat something, you first need to define it clearly. The most obvious definition for aging is chronological. However, changing the actual flow of time falls more into the realm of physics and is probably not very practical. What we want to influence is the biological age. To measure this, we use a lot of different methods, called “clocks,” and they work with blood parameters, heart rate variability, epigenetics, simple photos of your face, or other data. Clocks are all somewhat linked to chronological age but can generally tell you how one (or several) aspects of your biological age compare to the average person your age. So they tell you if you’re younger or older than you actually are.
The specific unpleasant cellular effects of aging are summed up as the 9 Hallmarks of Aging that you see above. I won't go into detail, but they are all interconnected and lead to what we recognize as aging, like wrinkles, grey hair, loss of muscle mass, frailty, dementia, decreasing bone density, and all the other stuff that you're not keen on having.
Reading this list, you might already guess why treating aging might have other perks than just living longer. The biggest deal, not only for the individual but also for society, would be increasing the so-called healthspan. It can be argued that while in the last 100 years we have already more than doubled the average life span, the healthspan, the time lived in good health, hasn't grown accordingly. Our current medicine has become very good at treating most of the countless ailments that old age brings; however, many are more managed than cured. So wouldn't it be better (and cheaper, by the way) to treat the underlying cause of most illnesses instead of each of them at a time? The results of healthspan research could revolutionize medicine and bring us from fixing what's broken to preventing the breaking.
But how far along are we? Will we still get old like our grandparents? That depends. To cite one of the leading minds in this field of science, Professor David Sinclair: "It's easy to expand your lifespan. […] If you do the right things, which is: Don't overeat, eat less often during the day, do some exercise, don't smoke, don't drink! That alone gives you, compared to people who don't do that, 14 extra years. So living longer isn't hard, it just takes some discipline." Well, I told you, it's not too easy, but it's doable. However, there is obviously more to aging research than the typical advice on living more healthy.
First of all, there are drugs and supplements that (at least in animal models) show a huge potential to give another few healthy years like Nicotinamide Mononucleotide (NMN), α-Ketoglutarate (AKG), Resveratrol, Metformin, and Rapamycin. I won’t go into detail on those now, but I’ll write some more articles about that on my blog soon.
Most of these, however, seem to work mainly as a prevention and not a cure. But there are other measures in the pipeline. An interesting idea is the so-called “Senolytics.” Instead of killing themselves as damaged cells normally do, some become senescent. Senescence occurs when cells sense an instability of their chromosomes after having divided a certain number of times or because of high stress (due to their Telomeres), so they permanently stop dividing. Senescent cells also secrete signals that lead to inflammation, changing the development of their surrounding cells and the extracellular matrix.
The more senescent cells in an organ, the less vital and functional the organ becomes. Senolytics like Dasatinib and Quercetin are substances that target and remove these senescent cells to rejuvenate the organ. There are ongoing clinical studies on human patients with these substances on several age-related diseases, and they show some promise, but there is still a lot of research to do.
The idea that sounds probably most impossible but has the potential to slow the clock and actually reverse aging is cellular reprogramming. Each cell in our body has basically the same genetic information, the same construction plans packed into our DNA organized in chromosomes. But how does a cell in your brain know that it’s not in your foot and has to behave differently? And, even more important, how does a cell know that it’s not supposed to copy itself as often as possible or try to build a new complete clone of you? The answer is epigenetics (mostly). Epigenetics is quite a young field that has made huge progress in the last 15 years. Epigenetics determines which of the genes of a cell’s genome are switched on and switched off by modifying the DNA or proteins associated with the DNA. These bookmarks make a cell behave as it does. They are changed by environmental influences like sunshine, smoking, food, no food, or a thousand other things. Most of these factors and time itself lead to an overall decrease in these bookmarks, although certain areas of the genome also acquire more of them with time. So the idea is to reset these bookmarks to a “younger” state.
In 2006 a set of four transcription factors (regulators for genes) were identified that can reset a differentiated cell into part of a certain tissue to a very similar state to that of the cells you find in an embryo. The cells treated with the transcription factors become stem cells and can be reprogrammed into almost any cell type within the body. These transcription factors are called Yamanaka Factors after one of the authors of this study from 2006. Using the Yamanaka Factors, there have been successful studies on animals. The aim is to reset the epigenetics of cells to young without dedifferentiating the cells, making the tissues they form fall apart. This technique is currently tested to restore vision in primates after successful tests on mice that have gone blind because of glaucoma. It is expected to be ready for human clinical trials next year. If this is successful, it would be a new hope for many blind people and be a proof of concept for rejuvenating a tissue by epigenetic reprogramming.
A possible future application of this could be to treat a patient's cells outside the body to become stem cells and then inject them to regenerate damaged tissue or to rejuvenate the patient as a whole.
Much is unclear about reversing aging. Many studies in the field show contradicting results, but what would have seemed impossible 20 years ago is rapidly evolving from promising basic research to clinical trials. Currently, you still need some discipline and changes to your lifestyle if you want to increase your lifespan and healthspan. However, the more life and health you win through your life choices, the closer scientists might be to real solutions to all the unpleasant effects of aging and maybe to aging itself.