Young padawans mentoring, you seek: How I did research with 10 undergraduate students

Doing research is a lot of fun! 🙂 You can do things that no one has ever done before. It is like fulfilling your childish curiosities by playing around with nature, unraveling its mysterious principles, and sometimes finding useful applications for things that were previously considered to be purely fundamental. With time your experience grows – you finish your Ph.D., and at some point, you realize that you can hardly find time to check all of your ideas alone. Through this experience, I understood that I definitely need support. The support of undergraduate students! 🙂

In this post, I would like to share some thoughts and realizations I learned from working with undergrads. While reading, try to focus on what could be learned from my experience and not on my particular situation. Most likely, a lot of the things I describe cannot be applied to every postdoc or graduate student. However, I believe that experience I have obtained can be extremely valuable for other Jedi masters looking to mentor their padawans!

Take-home messages:

  • Undergraduate students can be extremely motivated and capable of solving complex problems
  • A mentor needs to take into account different personalities when working with undergraduates and assign tasks based on this
  • Working in groups can be fun but can diminish the sense of individual accomplishment
  • Undergraduate students are willing to learn (even if it takes more time to accomplish their goals)
  • Focus. Having one or two motivated students can be better than having a big group of unmotivated individuals
  • Undergrads are not small graduate students: they have a limited schedule and, usually, need step-by-step instructions to successfully complete tasks

My journey of mentoring 10 undergraduate students

“Always two there are, no more, no less. A master and apprentice.”

In October 2016, I was invited to work at the Pines Lab. It is hard to explain how excited I was! When I learned that I had the privilege of working under Alex Pines – an absolute legend, mentor, and leader in the field of magnetic resonance – I was over the moon. I was also thrilled by the atmosphere of UC Berkeley, where the concentration of IQ per square meter is mind-blowing. Although there were a lot of advantages related to my new position, I was also faced with some challenges in the new lab. One of which was the different dynamics amongst my lab associates. In previous labs, the associates consisted primarily of graduate students and postdocs. However, in Pines Lab, we have a different approach. As a well-accomplished scientist, Alex now believes that funding is best spent on postdocs and therefore, only a few of us are now working in the lab. However, we can’t accomplish everything alone and needed to reach out to others for help. Thankfully,  UC Berkeley provides a win-win solution for this challenge: postdocs are open to mentoring students and the campus is full of bright and motivated undergrads eager to do research!

I started a quest for my Jedi padawans by sending an E-mail to the chemical engineering undergraduate academic advisor requesting to advertise “the opening” for summer positions in the Pines Lab. Maybe my ad was just too good to refuse, or the UC Berkley students were absolutely eager for work, but in only two days I received more than thirty (thirty!) E-mails from students who were willing to work in the Lab! The hardest part was choosing only a small fraction of them.  Long story short, this is how I ended up having 10 students… Yes, believe me, I could not take any less as they were all extremely motivated, knowledgeable, and willing to learn more at the same time! This being said, be sure that you take the right amount of students required for the project that you have in mind.

Today, after more than a year of working with my students, teaching and mentoring them, finishing papers together and working on new ones, I feel happy and satisfied with my selection and decisions. My experience allowed me not only to learn a lot about how undergraduate students think and about what motivates them and what can boost their productivity, but it also allowed me to find the mentoring/teaching style that I feel most comfortable with.

The best students

“Truly wonderful, the mind of a child is.”

I found that, surprisingly, resumes of undergrads do not always correlate directly with their performance in the lab. However, it does not mean that you should completely disregard their scholarly performance when you are looking for them. The successful student should (1) have enough knowledge to be able to quickly grasp the ideas and concepts you work with but at the same time (2) have enough curiosity to learn more about things they don’t know about. Unfortunately, NMR as a research topic requires at least a basic understanding of quantum mechanics, therefore making it an overall challenging subject for freshmen and sophomore students (however, there could be exceptions!). Therefore, in my opinion, the best way to find a prospective student is to talk to them in person, ask about their interests/hobbies, what type of work they like and what they don’t like. From my conversations with potential undergrads, I realized that those who like a more structured way of working and need a lot of supervising would not be the best match for me.

I found that for me, the most important students’ qualities are:

  • Ability to work independently
  • Responsibility
  • Enthusiasm about doing research
  • Personality matching (see below)

The last point, personality matching, is the main lesson I gained from my experience. Personality matters much more than anything else in research with undergrads, and I feel that this can be even truer for higher levels of graduate school in which professor-student interactions play a crucial role in a lab’s success!

Personality matters

“Good relations with the Wookiees, I have.”

Have you ever heard about the Myers-Briggs 16 personality types? If not, you should learn about it as soon as possible. Basically, this “theory” allows you to rationalize your own behavior and better understand the motivations of different types of people. It also explains why some individuals are naturally stronger in certain tasks and others are better at different ones. Therefore, when managing undergraduate research, you can always find a fulfilling and interesting problem for a student if you identify his/her personality type and look at things creatively.

Find the right problem for the right people. If you think the people are not right for the problems you post, chances are, it is not the right problem for the people you have.

For example, I suggested two of my students work on the project of using Earth-field MRI combined with SABRE hyperpolarization. It soon became very clear to me that one of the students was more interested in studying the basics of MRI and the way the Earth-field imaging instrument works than the other.  At one point I caught myself thinking that the second student was just lazier than the first one and much less motivated about going to the lab in general… However, purely by accident, I learned that the second student was interested in 3D modeling. We had another project in the lab that required machining a chemical reactor. Therefore, I asked him to make a 3D modeling of the reactor and found that he loved it. Ever since then, he was an absolutely different person – working hard and passionately while finishing the task much earlier than I expected. It was not the laziness of the student but rather my misunderstanding of his interests that did not allow him to be as motivated as he can be at the beginning of our work.

Take-home message – find the right problem for the right people. If you think the people are not right for the problems you post, chances are, it is not the right problem for the people you have. This is especially true for doing research with undergrads: they are volunteering their time to help you and it is your fault if are not motivated!

Finding the right project

“Already know you that which you need.”

I found that it is very important for students to work on problems that have clearly posted goals. For example, when choosing between two projects, one of which is very cool but relatively abstract and the second one which is less intellectually complicated but more practical, students often choose the second one. They want to see the immediate outcome of their research even though it is sometimes hard to get enough results given the limits of their residence in the lab. The most compelling project for undergrads is one that to them, makes an observable difference in the world!

The most compelling project for undergrads is one that to them, makes an observable difference in the world!

One of these application-oriented projects was the building of the para-H2-based polarizer. I explained to my students that I want to make a device that can automatically produce boluses of hyperpolarized liquids (for example, aqueous solutions of 13C-hyperpolarized metabolites such as pyruvate or lactate). Once produced, these boluses can be injected into animals and their metabolism can be monitored in vivo using NMR/MRI.

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Nick and Lucia conducting SABRE experiments.

This idea is not new and many researchers work on different aspects of this problem. However, one of the biggest issues preventing the widespread applicability of para-H2-based techniques is the presence of platinum-group metals in solutions with hyperpolarized molecules. Obviously, injecting even trace quantities of the metals in vivo should be avoided.

Therefore, we decided to focus on this part of the problem and at the same time started building para-H2-based polarizer. Two of my students were working on the testing of different scavengers’ performance by means of inductively coupled plasma atomic emission spectroscopy (ICP-AES) and three of the students were helping to build a so-called “hyper-cart”, a transportable cart containing all of the components necessary for producing hyperpolarized compounds.

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Elizabeth, Lucia, and Nevin are working on building the parahydrogen “hyper-cart”.

After performing a lot of tests, we were able to identify the nature of two commercially available metal scavengers that can efficiently and very quickly clear the hyperpolarized solutions from the trace metal quantities. Since the result was important, we decided to submit a paper describing the metal scavenging process to the Journal of Physical Chemistry Letters and it was successfully published there. It was a pleasure to see the students’ motivation when, even during their midterm exams, they were still able to find time to stay at work late to finish the figures and tables for the paper! Overall, despite challenges, this was a good research project for undergrads: a simple and clear idea resulting in a measurable advancement to the field.

Managing vs. Mentoring

“Always pass on what you have learned.”

One of the biggest realizations that occurred to me while working with my students was understanding of the difference between managing and mentoring.

Managing is about organizing, making plans, setting up goals, splitting them into micro-goals, setting up the deadlines and so on. In other words, all the stuff that I hate… Mentoring, on the other hand, is giving padawans the opportunity to learn by doing their own work, providing resources and support, discussing the best ways to achieve the goals (as opposed to stating them), referring to the resources with useful information and troubleshooting when things don’t work. Through my experience, I found that mentoring is something I truly enjoy. You can clearly see the growth of students who are willing to learn!

Let’s take the previous example of the para-H2 cart. One of my chemical engineering students, Vincent, told me during his interview that he likes automation and programming. Since we needed automatically actuated valves to run gases and liquids, I suggested that he build an Arduino-based setup to control the valves. I did not have the background to teach him everything about Arduino, but I knew where he could find information about how to do it. Eventually, he created a very good setup that was extremely helpful. Check out this video created by him explaining all the components of his setup:

This is why personality matching is important. Some students would require more of a managing advisor while my approach leaned towards mentoring and allowing the student to figure out the details by himself. Not everyone would be able to do what Vincent has done, but his desire to learn, coupled with his desire to make a significant contribution to the project led to a successful outcome.

Journal Clubs

“Powerful you have become, the dark side I sense in you.”

I also found another valuable tool for mentoring students – Journal Clubs. I first learned about this type of meetings looking at Mark Does’ lab at the Vanderbilt Institute of Imaging Science. In Mark’s lab, students and postdocs meet once a week (in addition to weekly group meetings) and discuss a paper they want to learn more about. Mark does not even show up there – it is the students’ task to meet and study together.

My journal clubs were slightly different than the ones at Vanderbilt. Since my students are only undergrads, letting them learn completely by themselves would not be the most productive option. Therefore, a schedule of students was created before each semester. For each journal club, one of the students had to choose a paper of interest. Ideally, it should be a paper related to our research but this was not necessary. After choosing a topic of interest, a student would send his paper for the rest of the group in advance to read it and prepare for the discussion. When arriving at the journal club, the student would first make a short presentation about the paper and then discuss it with the rest of the group. I would then show up after 30-40 mins and work together to answer any questions the students had. We also discussed NMR-related and general scientific questions after I arrived.

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Joseph is explaining approaches to study chemical kinetics by NMR.

Based on the students’ reviews, they liked the journal clubs a lot. It helps them understand the research process and how to work with each other without a lot of guidance. I originally realized that students were not as eager to ask each other questions while I was in the room. This is why I decided to let them have 30-40 minutes on their own: this way I always entered a room full of discussion and exploration. They didn’t need my micro-management and ultimately worked together to facilitate ideas and find the answers to unknown questions.

Conclusions

“Do or do not. There is no try.”

Here is the biggest realization. Undergraduate students are not small graduate students. While graduate students have the time and ability to focus on projects, undergraduates have other responsibilities to classes, college activities, and simply navigating their busy university life. Therefore, they need to be treated differently than graduate students. Although optimism is great, do not be discouraged if you undergraduate students have other time commitments and responsibilities that interfere with their projects. They are not smaller, younger graduate students but rather have unique requirements and standards of learning all of their own.

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Hyun, Nick, James, Lucia, Nevin, and Dario making a birthday gift for me.

I want to express gratitude and say thanks to all undergraduate students I had a pleasure to mentor: Patricia Buenbrazo, Nevin Widarman, Hubert Situ, James (Xingyang) Li, Dario Gelevski, Vincent Stevenson, Lucia Ke, Elizabeth Chyn, Nick (Hao) Zhang, Hyun Park, Sean Littleton. Some of them have already graduated, some of them are still working on exciting projects and I hope to have a chance to mentor many more! 🙂 I also want to say a lot of thanks to Jessica Andrews who helped me to write this post and suggested the Master Yoda quotes idea. Check out her website: she writes about TV and movies and she is very passionate about it!

And of course, let the force be with you.

And with your undergraduate students! 🙂

Monday Morning Effect

Friday evening. While his friends had already met in the Pub on Shattuck Avenue to celebrate a happy hour, UC Berkeley’s Ph.D. student Henry Bryndza was still in the Lab. He wanted to finish preparation of his samples so that he could come over on Monday morning to focus on the NMR measurements, not worrying about sample preparations. In order to suppress chemical reactions which could have started in his samples over the weekend, Henry put them in the liquid nitrogen dewar (T=-196oC).

Henry was working in the Laboratory of Robert Bergman, a renowned UC Berkeley professor who has made a significant contribution to the organic and metallorganic chemistry. Bergman and Bryndza were studying Fischer–Tropsch reactions using exemplary Cobalt and Iridium catalysts [1].

When he came back on Monday, Henry started to observe very interesting phenomena. 1H NMR spectra of the samples he took in the morning showed very weird “negative” NMR peaks (Figure 1). Moreover, the intensity of these peaks decreased day after day during the week when Henry tried to repeat the experiments and completely disappeared by the end of the week [2]. Henry was confused and decided to repeat his measurements. Surprisingly, this phenomenon was not observed every single time but was definitely the strongest on Mondays. Bergman and Bryndza decided to jestingly call this a “Monday phenomenon”; this was the beginning of what was known later as Parahydrogen-Induced Polarization (PHIP).

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Figure 1. “Pseudo-CIDNP” observed in 1H NMR spectra during hydrogenolysis reactions of Cobalt alkylidyne complexes. Adapted from [3].

Bryndza and Bergman asked for help from many NMR specialists, including NMR expert Professor Alex Pines from UC Berkeley and Professor Joachim Bargon from the University of Bonn [2]. The last one was known for the discovery of so-called chemically-induced dynamic nuclear polarization (CIDNP). The CIDNP effect is usually manifested as positive and negative NMR signals (very similar to those observed in Henry’s experiments) for the reactions taking place via radical intermediates. After contacting Bargon and other CIDNP specialists, weird results were interpreted as “pseudo-CIDNP” in hydrogenation reactions [3]. However, it was clear that CIDNP-based explanation was at least not complete, first, because of the very unusual suggestion of radical pairs in the studied hydrogenation reactions and, second, because of the lack of convincing simulations supporting the observed phenomena. Moreover, it by no means explained why the effect was the strongest on Mondays and why it was only observed in the laboratory of Robert Bergman.

This “Monday morning” puzzle remained unresolved until the International Society of Magnetic Resonance meeting in Rio de Janeiro in June 1986. There, during an evening session, Professor Daniel Weitekamp from Caltech presented his “thought experiment” of using parahydrogen (para-H2) as a source of enhancing NMR signals. The concept and the expected results were immediately published in Physical Review Letters [4]. The experimental demonstration conducted by a Weitekamp’s Ph.D. student Russ Bowers followed in July, and brilliantly supported all theoretical predictions (Figure 2) [5].

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Figure 2. First experimental demonstration of a PASADENA experiment. The characteristic PHIP multiplets are seen on the right. Adapted from [5].
Bowers and Weitekamp called their experiment PASADENA (Parahydrogen And Synthesis Allow Dramatically Enhanced Nuclear Alignment) to glorify the location of their institute (Caltech is located in Pasadena, CA). After their publication, it immediately became obvious that PASADENA is, in fact, a correct explanation of “Monday phenomenon” of Bryndza and Bergman. Indeed, the low-temperature storage of NMR tubes over the weekend partially converted normal hydrogen into para-H2. The conversion was not complete, but it was enough to observe antiphase lines in 1H NMR spectra (Figure 1). The PASADENA effect and discovered later effect ALTADENA (Adiabatic Longitudinal Transport After Dissociation Engenders Net Alignment) were collectively given the name PHIP (Parahydrogen-Induced Polarization) [6].

Now let’s talk about physical principles of this effect. As we discussed before, due to the absence of a net nuclear magnetic moment, para-H2 itself does not produce an NMR signal. However, this single nuclear spin state implies that, in a sense, it is cold. Indeed, a comparable degree of spin ordering is obtainable at equilibrium only at temperatures of a few mK and magnetic fields of several Tesla [7]. The brilliance of Wetekamp’s idea was to introduce magnetic inequivalence to release this potential signal by connecting the singlet to the triplet states. This would require chemistry, but simple bond cleavage would not suffice. A singlet state of two protons is a relationship of one spin relative to the other and this order would be dissipated if the pair were split and mixed with an ensemble of other such products. Rather, it is necessary that the pair have a special relationship even after being distinguished by magnetic inequivalence. This is called a “pairwise” hydrogen addition and can be realized in hydrogenation reactions in the presence of homogeneous catalysts. To see how it works, let’s take as an example the simplest situation and imagine that a chemical reaction leads to the association of para-H2 with a molecule not containing magnetic nuclei.

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Figure 3. Schematic diagram of the PASADENA experiment: parahydrogen (para-H2) reacts with an unsaturated molecule forming a reaction product where two nascent para-H2 atoms occupy chemically inequivalent positions. Energy level diagrams and corresponding 1H NMR spectra are shown in the bottom. Thick blue rectangles indicate overpopulated energy levels.

The two-spin system of the hydrogen molecule gives rise to four nuclear spin energy levels. As we described before, three of these energy levels correspond to orthohydrogen, the state with total nuclear spin 1 (triplet state), whereas the remaining fourth energy level corresponds to parahydrogen (singlet state), the state with zero total nuclear spin (Figure 3). Transitions between singlet and triplet spin states are forbidden by symmetry and the spin 0 parahydrogen is NMR-silent.

Now, the incorporation of para-H2 into an asymmetric molecule breaks the symmetry of the singlet spin state. For simplicity, I will consider only the PASADENA experiment, the case where hydrogenation reaction is performed at a high magnetic field (wherein the chemical shift difference between the two para-H2-nascent protons is much greater than the spin-spin coupling J between them). In this situation, the population of the singlet spin state αββα (numerical factor is omitted) of para-H2 is immediately transferred to the population of spin states αβ and βα of the formed spin system.

This can be understood as follows. Because of the chemical reaction, two H atoms from para-H2 suddenly end up in a different molecular environment. This leads to a collapse of the nuclear spin wavefunction αββα into one of the two states, αβ or βα, each with 50% probability. Next, it is easy to deduce from the energy level diagram that the NMR spectrum of the produced in such a manner molecule will contain four peaks grouped in two antiphase multiplets (Figure 3), exactly what was observed in the experiments of Bryndza (Figure 1) and Bowers (Figure 2). The key requirement is that both hydrogen protons from the para-H2 molecule are added together without significant competition from exchange reactions. This is a property of many, but not all, hydrogenations.

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Figure 4. Hydride region of PHIP-enhanced 1H NMR spectra showing
negative-positive multiplets for products formed when RhI(CO)(PMe3)2 reacts with para-H2 in the absence (a) and presence (b) of styrene [8].
The assignment of the peaks to particular transitions depends on the sign of the J-coupling between the para-H2-nascent hydrogens. When J-coupling is positive, PASADENA multiplets are positive-negative; if J-coupling is negative, the spectral appearance is opposite. This feature is very useful for studying hydrogenation reaction intermediates. Normally, organic molecules possess positive J-couplings between protons; and J-couplings between them are negative in case of metal hydrides. Therefore, in a complex reaction involving many intermediates, it becomes possible to distinguish low-concentration hydrides (possessing negative-positive multiplets) from organic reaction products (Figure 4).

It is also important to realize that PHIP can lead to 100% nuclear spin polarization of the reaction product. In the case of PASADENA experiment, 100% population of para-H2 is split into just two energy levels, making transitions from these levels enhanced by orders of magnitude compared to the thermal case. Theoretically, if all para-H2 molecules are transferred to products in a pairwise manner and relaxation loses are minimized, the reaction product can acquire 100% spin polarization. This would, of course, require an additional step to transfer spin order from αβ and βα into the state αα but this can be readily realized using a simple RF pulse sequence.

Enormous NMR signal enhancements and unique spectroscopic signatures made PHIP a very useful tool in chemistry for more than 25 years to elucidate hydrogenation reaction mechanisms, study metalorganic hydride complexes, and catalysis [6]. However, PHIP can be also used in a very different context. Imagine a suitable molecular precursor which can become a naturally occurring metabolite after hydrogenation. This metabolite can be produced in seconds, with a very high level of nuclear polarization, injected into a living organism and a metabolism of that organism can be monitored by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI). Today PHIP, and its sister technology SABRE (Signal Amplification By Reversible Exchange) allow to efficiently hyperpolarize dozens of biologically relevant molecules on nuclei such as 1H, 13C, 15N, 19F, 29Si, 31P, 119Sn etc. But this is a story for a separate blog post! 🙂

It is important to emphasize that only the connection between nuclear spin and rotational degrees of freedom allows this unique situation to take place. Indeed, the fact that the nuclear spin state can be overpopulated simply by cooling is a remarkable quality inherent only to the small hydrogen molecule. Indeed, even though other molecules can have the similar connection between rotational and nuclear spin states (N2, F2 etc.), larger moments of inertia will make overpopulating these states much more challenging task (because of the lower temperature requirements). Moreover, it is very challenging to keep these molecules in the gas state at low temperatures, and the simple rule of making a total wavefunction be a product of individual wavefunctions will no longer hold true. So, it is more likely that hydrogen molecule is the only example when the rules of spin statistics and Pauli’s principle can lead to the nuclear spin hyperpolarization.

What excites me about this story is how a purely thought experiment, on the one hand, and a weird experimental phenomenon, on the other hand, emerged into a new discipline and a remarkable tool to study chemical reactions. Moreover, more exciting applications of the para-H2-based hyperpolarization techniques are expected to emerge in biomedicine. I really wish there were more Monday morning effects in science! Who knows but maybe someone today has come to a lab to look at a weird result which will form a new field of study tomorrow.

 

References

[1] J. Bargon. Chance Discoveries of Hyperpolarization Phenomena. eMagRes, 2007.

[2] Private conversations with Robert Bergman and Alex Pines.

[3] P. F. Seidler, H. E. Bryndza, J. E. Frommer, L. S. Stuhi, R. G. Bergman. Synthesis of Trinuclear Alkylidyne Complexes from Dinuclear Alkyne Complexes and Metal Hydrides. CIDNP Evidence for Vinyl Radical Intermediates In the Hydrogenolysis of These Clusters. Organometallics, 1983, 2 (11), 1701-1705.

[4] C. R. Bowers, D. P. Weitekamp. Transformation of Symmetrization Order to Nuclear-Spin Magnetization by Chemical Reaction and Nuclear Magnetic Resonance. Phys. Rev. Lett., 1986, 57 (21), 2645-2648.

[5] C. R. Bowers, D. P. Weitekamp. Parahydrogen and Synthesis Allow Dramatically Enhanced Nuclear Alignment. J. Am. Chem. Soc., 1987, 109 (18), 5541-5542.

[6] J. Natterer, J. Bargon. Parahydrogen-Induced Polarization. Prog. Nucl. Magn. Reson. Spect. 1997, 31, 293-315.

[7] D. Weitekamp. Sensitivity Enhancement Through Spin Statistics. Encyclopedia of Magnetic Resonance, 2007.

[8] S. Colebrooke, S. Duckett, J. Lohman, R. Eisenberg. Hydrogenation studies involving halobis(phosphine)-rhodium(I) dimers: Use of parahydrogen-induced polarisation to detect species present at low concentration. Chem. Eur. J., 2004, 10, 2459–2474.