A Wonderful Christmas with Mysterious Oscillations

It has been known for many decades that budding yeast cells can spontaneously synchronize their metabolism and cell division when grown in continuous cultures. This synchrony is most commonly and conveniently observed as oscillations in the oxygen consumption of the culture that can last over many weeks, as long as the culture is fed with fresh growth media. Yet the complexity of this mysterious phenomenon has resisted scientific curiosity for many decades and shifted it to the periphery of mainstream research.

My work on cell growth brought me to these mysterious oscillations, and I became fascinated by them and their challenge. At the time, it was suggested that their role is to separate DNA replication in time from the periods of intense oxygen consumption and reactive oxygen species production, and thus reduce the mutation rate. This sounded simple and intuitively appealing, so I did not pay much attention to the controversy in the literature. I just liked the appealing idea. Yet, when I started synchronizing yeast in the lab and looking at my own data, I could not reconcile them with restricting DNA to the low oxygen consumption phase. After checking meticulously everything in my experiments and not finding artifacts, I finally read carefully enough the published evidence and found that it was consistent with my data but could not convince me that DNA replication is sequestered away from the phase of high oxygen consumption. Now that made the whole phenomenon all that more mysterious and compelling to me. I really wanted to understand these oscillations!

I analyzed all my data and came up with my own hypothesis, but that was not enough; the complexity of the phenomenon could have misled me, so I needed a direct experimental test, ideally in a simple system that we understand well. It was very clear both from my data and data from many other labs published over 4-5 decades that the metabolic cycling in continuous cultures is correlated with partial cell division cycle synchrony. Thus, my idea was to simply synchronize cells with respect to their cell division cycle and measure oxygen consumption. Measurements of oxygen consumption during the division cycle were done in the 1960-1980s, but the data was from cells that mostly ferment (a very different growth condition) and not nearly as quantitative as what can be achieved nowadays. After considering all methods for synchronizing the cell division cycle of yeast, I decided to use a nutritional pulse as the most physiological method with the fewest artifacts. Instead of producing the intended cell division cycle synchrony, however, my experiments resulted in metabolic cycling without cell division cycling! At first, of course, that was a great surprise. Multiple repetitions of the experiment turned the observation into an exciting finding. Doing the sampling was time-consuming and demanding in the extreme, but I was so eager to know what was happening that I spent Christmas Day of 2010 collecting samples, the ones that ultimate were used for our article. It is still the longest, the happiest and the most exciting Christmas Day I have had in my life.

The results of the experiments gave an answer that I find very convincing. I felt we had learned something exciting, at least incredibly exciting for me, and I wanted to share it with colleagues who might be interested in it and incorporate their feedback before we submitted our article for review. I was shocked by the emotional responses that our work elicited, but that is a subject for another essay.

In retrospect, the work behind our PNAS article was a thrilling and rewarding journey. It certainly did not resolve the whole mystery but gave us insightful glimpses into the complexity of metabolic regulation and a delightfully memorable Christmas Day, one that I would love to repeat.

This paper essay was written for PubChase.

Slavov N. , Macinskas J., Caudy A., Botstein D. (2011)
Metabolic Cycling without Cell Division Cycling in Respiring Yeast
PNAS, vol. 108, 19090-19095

On the Wings of a Seagull

The time had stopped. Watching the chaotic ballet of ripples in the lake, I was thinking of the deep connections that unify seemingly disparate phenomena. The direction of the wind was fluctuating from second to second, switching the direction of the ripples almost in synchrony with my thoughts. In the Platonic tradition, I have always searched for and marveled at the deep unifying connections between different aspects of life and the world around me.

Still, I never suspected that the same fundamental ideas and symmetries that lie at the heart of nuclear physics, quantum chromodynamics and a huge variety of critical phenomena in physical systems would apply to biochemical networks, would govern the finely orchestrated regulation of tens of thousands of genes, would make the miracle of life possible. I wanted to savor the glory of the moment, not to be conscious of time.

Nonetheless, my thoughts were interrupted by a couple of seagulls soaring majestically in the air. The same fickle blows that caused the ripples to lurch back and forth were converted into a graceful flight. Through occasional adroit movements of their wings, the seagulls were gliding elegantly in the air. They were harnessing the erratic wind for their graceful ascent.

My immediate impulse was to emulate the seagulls, not only literally – because of my desire to glide through the air and soar toward the sky – but also figuratively, because of my desire to harness the power of the winds and storms in my life that I cannot even hope to control. I felt an irresistible urge to make the most of what I have with the grace and mastery of nature, with an insightful understanding of and respect for the deep principles shaping the universe. The seagulls went sky-high without controlling the wind, an example worth admiration! An example of gentleness and power synergistically united into a beautiful ascent.

Basking in the light of these thoughts, I sensed the blueprint of the erratic wind imprinted onto the random Hamiltonian matrices of atomic nuclei. Similarly to the seagulls, an elegant flap of wings (chiral symmetry) is enough to transform the randomness into a robust system-characteristic behavior. This is a recurrent, pervasive pattern that charms with uncanny, magnetic appeal: Complex systems transcending stochastisity and shaping randomness into exquisite creative dynamics. I know of nothing that can rival the grace and power of nature to leave freedom for creativity and still direct and orchestrate the large-scale dynamics. The world is a beautiful picture painted with gentle and adroit touches of the nature’s brush.

Beauty

I open my eyes and see beauty, a gratifying perception that inspires respect and reverence, that directs my actions and endows them with meaning and purpose. What is it? It is beyond me to verbally articulate it and yet I feel compelled to share the emotion and power that beauty engenders in me, even try to understand its essence; it is so easy to trivialize and so hard to capture the deep meaning of beauty with its multifarious forms, form a drop of dew and a falling autumn leaf to a majestic mountaintop, form a bird song to a symphony orchestra, from a snowdrop to a beautiful woman.

What is the unifying feature among all of these? Is it just a spatiotemporally organized neuronal activity, the response of my brain to fundamentally different stimuli or is it a multifaceted diamond presenting itself in hologramic mosaic of images. Is it the dynamic interplay of elegant simplicity creating astounding diversity, an intricate world that puzzles with its variety and charms with its few powerful unifying principles?

I can hardly approach these questions without biases! Being educated in the Western scientific tradition, I seek and marvel at the immutable forms from that sublime world that Plato called superlunary and Aristotle considered quintessential. Now we call it with different names but more often just tacitly assume that it exists; the implicit assumption that we can explain diverse phenomena in terms of universal principles is the very foundation behind much of modern science. It was the assumption that Newton made in inferring the laws of motion from astronomical observations of “the heavenly bodies” and then boldly generalized the principles to all terrestrial phenomena. We have indeed pursued this seductive assumption with a remarkable success and found common unifying principles behind ostensibly disparate phenomena.

I would go further and claim that even our ability to perceive the world testifies to its structure, to a set of statistical dependencies that consistently and reliably guide us through the dynamical interplay of thousands of variables; when I fail that is because my intuition cannot grasp the sharp turns in the enormous phase-space of my life, the high-order combinatorial nonlinearities that paint the dynamical portraits of life, portraits that often appear quite impressionistic while carrying their distinctive characters: Fractal portraits imprinted by stochastic influences and yet unmistakably reflecting their underlying intrinsic dynamics. I perceive and marvel and still cannot articulate the awe-inspiring grandeur that animates my life, the beauty that surrounds me — it is a feeling, a wonderfully gratifying perception!