Academia 2.01

Are you a student working on your way to obtaining PhD or a postdoc who wants to become a professor? In this post I want to share some ideas I have ‘extracted’ from my journey in academia. This journey has been relatively short (about 10 years) but I believe during this time I still learned something important that can be of value for the people interested in science and those who want to pursue academic path (and beyond).

Fight Your Procrastination

A lot of times in academia you float toward the path of minimal resistance. By the time you obtain your PhD, you often become acquainted with some topic/discipline and you keep staying there because (i) you feel expertise in this area (and it feels good to be an expert in something), (ii) it feels scary to go toward unexplored area (and you may think you don’t have enough brains/time to go through it anymore), and (iii) you may have more contacts/connections in the field of your current research (which makes it more probable to stay in the same ‘bubble’).

I meet different people. And I see a clear troubling trend in academia (it cannot be applied to everyone and there are many amazing creative and smart people) but the trend is definitively there: scientists become more and more incremental in their approaches, ideas, results. Richard Feynman only published about 37 papers (I need to find an exact number but this is about right) during his career but, oh boy, what papers are these papers! True brilliants. Feynman did not waste his time on doing incremental things, he did what he wanted in areas that interested him. Today the urge of publishing consistently new knowledge with high productivity (otherwise what? you are not smart/talented/hardworking-enough?) brings many people in academia – including PhD students, postdocs, and professors – to the brink of mental health crisis. And fighting the symptoms will not help to treat the disease: the pressure of socially accepted norms does not let us truly develop as society. This not only leads to the ‘natural selection’ of bad science (the one which is shiny, easy to swallow, extremely promising yet not very well thought-through) leaving many really talented people off the boat of modern academia.

Who are these leftover people? Very often these are truly talented individuals who embrace their curiosity across the boundaries of disciplines. And very often they are less competitive for the academic market compared to their ‘productive’ brothers. And the reason is simple – PROCRASTINATION. These people may very well may be extremely talented but because they have a hard time focusing on one topic – they jump from one idea to another, spend hours talking to their friends about science or new paper – they do not make enough of the ‘formal product’. This low ‘formal productivity’ such as low number of papers published in peer-reviewed journals limits their chances for success in classical academia (here by success I mean landing a professor position; in reality, ‘success’ is a much deeper topic that requires individual definition and separate discussion).

There is nothing wrong with you, it is the system that is outdated!

My long-term vision is to change classical academic approaches to education and science (because science is a derivative of education) (i) by making it more affordable to wider audiences and (ii) by focusing on empowering these ‘procrastinating’ people. There is nothing wrong with you, it is the system that is outdated! For these reason, I came up with 3 short tips which I explain in my short 3-video series. I will repeat them here for consistency.

Tip 1. Don’t be afraid to look stupid

You are already very smart (OF COURSE YOU ARE if you are reading this and especially if you gave me your E-mail in exchange for this type of content 😉). Starting from this moment, you should STOP worrying about how you may look if you ask (e.g., in the classroom) a question which may sounds ‘silly’. I do not encourage you to become a ‘douchebag’ and start annoying people with constant argumentation and unnecessary questions, but I advise you to let go the feeling of being ‘not smart enough’ from within you. Once you do that, learning becomes easy. Interactions in the classroom become enjoyable. Yes, it will still require a lot of work to accomplish your goals and to understand complicated subjects but the foundation is there. This simple understanding – of the fact that you are smart enough to comprehend everything we know so far in physics or chemistry (or, in general, in science) given enough time and dedication – will set you up to a very good mental platform to accomplish whatever you desire.

…you are SMART ENOUGH to comprehend EVERYTHING we know so far in physics or chemistry (or, in general, in SCIENCE) given enough TIME and DEDICATION…

Once you have let this fear of looking stupid go – keep working. Always challenge yourself to do interdisciplinary learning and collaborate with people of different opinions. For example, read papers on things that you don’t know and pay attention to connections that arise in different branches of science. Also – don’t be afraid to fail (more about it later). Bridging the gap between disciplines is not easy but it will definitely develop your brain further. In fact, science has no borders, there is no physics or chemistry in nature – these are simply words, a product of our imagination. However, nature can be understood using logic and common sense and by practicing ‘good thinking skills’.

Tip 2. Aim for the top but not for the perfection

I learned this from James Watson, a man who discovered DNA (or even stole this discovery from Rosalind Franklin 🙉, this does not matter as long as I talk about his ideas and not his personality). He said: “Never work to become number ten – work to become number one. But this way even if you end up 2nd – it’s a still great achievement!”. This concept resonates with me. Working to become number one in whatever you do is a great way of being THAT BEST best version of yourself. It is also important to work on your subconscious beliefs (more about it later) and rewriting bad programming. Your subconscious (also often called reptilian) brain remembers/learns from seeing/hearing repetitive messages and this is why things like affirmations work – you program yourself toward positivity and accomplishment.

We all can do USEFUL things for the WORLD and useful things for OURSELVES at the SAME TIME!

I personally struggle with trying to be perfect and this is how I procrastinate. I start thinking that what I am doing is not the best version of it and everything can be improved. It is not yet ready to be shown to the World… BAD IDEA! Show it to the World as long as it is more or less presentable! The solution is simple – set up deadlines and finish things at whatever cost. I am happy to say that at the digital age, this problem can be solved in many creative ways. Take, for example, this blog. I decided to write it not only to help you and give some advise but also to push myself toward writing. We all can do useful things for the World and useful things for ourselves at the same time! Stop procrastinating, just start doing what you always wanted to do no matter how ugly your ‘product’ may look like at the beginning. Aim for the top but not for the perfection!

Tip 3. Go toward uncomfortable

If you feel too comfortable, chances are  – you are not growing anymore… Feeling uncomfortable is GOOD and you need to embrace it. I came from Russia to Tennessee, spend there 2 years, then came to the Bay Area for 3 years and I going to Germany in a few months. Not only do I make my personal life uncomfortable – I make it uncomfortable everywhere – language, documents, predictability 🙉! I actually don’t think this type of life is suited for everyone and even don’t encourage you to embrace this view. But I do think that feeling uncomfortable MEANS moving toward revealing your full potential and shows the direction of maximal personal growth.

Life is not a zero-sum game! Everyone wins from the scientific progress and collaborations that have solid foundations, i.e., mutual benefit and looking for truth.

Going toward uncomfortable will undoubtedly lead you to interact/collaborate with people you disagree. This, in turn, will open your mind to more opportunities for growth since you will learn things from many angles and points of view. By interacting with people you will also learn that life is not a zero-sum game! Everyone wins from the scientific progress and collaborations that have solid foundations, i.e., mutual benefit and looking for truth.

How do I stay on top of the game? How do I learn? What do I do every day? Subscribe to my E-mail list to get updates and learn about new products! Let’s crunch the granite of science* together!

*Crunch the granite of science is a good old Russian phrase meaning hard studying

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).

Untitled-2-01
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].

2-01
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.

Figure_PASADENA-01
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-Hsuddenly 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.

Duckett_obsor-01.jpg
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-His 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-Hmolecules 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.