Jack A. Dunkle, PhD

Assoc. Professor of Chemistry and Biochemistry @UofAlabama | Structural biology | RNA biology | alumnus @UCBerkeley @UABNews

[Jack A. Dunkle, PhD @DunklePhd]

My department is searching for a tenure-track assistant professor of AI-enabled Chemistry or Biochemistry. Apply here: https://t.co/PIIaVJo5SG

[Michael Baym @baym]

@Burghoff Though it makes me wonder if the real future model isn't research labs becoming autonomous but many of the protocols and steps becoming sold as services by companies with a semiautonomous production floor. DNA sequencing and synthesis are already heading that way

[Jack A. Dunkle, PhD @DunklePhd]

Found this flash card on a sidewalk outside my building. Made my day.

[Michael 英泉 Eisen @mbeisen]

I know people think the Monty Hall problem is a game show trick or a silly math puzzle, but the fact that most people get the logic wrong can have real world consequences. I'll walk you through an example I teach in my undergraduate Human Genetics class.

[Jack A. Dunkle, PhD @DunklePhd]

Fe-S clusters are interesting and critical structures that make many biochemical pathways work. Ever wondered how they get assembled? In collaboration with the Frantom group of @UofAlabama, we are mapping this out in bacteria: https://t.co/UQnvYqch7j.

[Jack A. Dunkle, PhD @DunklePhd]

It's almost that time of year again...Southeast Enzyme Conference, May 2, 2026 (https://t.co/15s2kUqXWK). Bama crew from last year:

[Prachee Avasthi @PracheeAC]

At least for now, every aspect of biology we study suspends consideration of many layers of complexity we know exist (and many more we don’t). What about microenvironment, or gene regulation/epigenetics, or viscosity, or quantum effects?

We’ve undoubtedly learned some very interesting things. The problem is that this often drives massive efforts to measure and model particular dimensions of complexity as if they contain the decisive signal. We brute-force the next untapped layer, as if greater descriptive richness will necessarily or reliably give rise to causal understanding.

A pernicious threat here is that cost (given the high cost of next-generation, complexity-tapping technologies) and sheer volume of data (when all data are not of equal value) become proxies for greater insight.

Not to glorify things for which we had lower resolution and signal outlasted the noise, but in some ways I think our scientific predecessors had a lot of creativity with far less firepower than what we can currently deploy. They were forced to design truly elegant experiments and better identify where missing complexity had outsized value. As we continue to grapple with the step change afforded by our new capabilities, it seems just as important to recover that kind of judgment in deciding where and how frontier technologies are best deployed.

[Jack A. Dunkle, PhD @DunklePhd]

Congrats to @SarahKhweis:
Cas10 residues lining the target RNA binding channel regulate interference by distinguishing cognate target RNA from mismatched targets https://t.co/heuL0gp74c

[Jack A. Dunkle, PhD @DunklePhd]

Fun way to read a paper.

[Jack A. Dunkle, PhD @DunklePhd]

Gem of an interview…https://t.co/Waei7KsDeo

[Jack A. Dunkle, PhD @DunklePhd]

@gabepgomes AI interpretability

[Jack A. Dunkle, PhD @DunklePhd]

Christmas in July

[Jack A. Dunkle, PhD @DunklePhd]

Provocative

[Thomas Wolf @Thom_Wolf]

I shared a controversial take the other day at an event and I decided to write it down in a longer format: I’m afraid AI won't give us a "compressed 21st century".

The "compressed 21st century" comes from Dario's "Machine of Loving Grace" and if you haven’t read it, you probably should, it’s a noteworthy essay. In a nutshell the paper claims that, over a year or two, we’ll have a "country of Einsteins sitting in a data center”, and it will result in a compressed 21st century during which all the scientific discoveries of the 21st century will happen in the span of only 5-10 years.

I read this essay twice. The first time I was totally amazed: AI will change everything in science in 5 years, I thought! A few days later I came back to it and, re-reading it, I realized that much of it seemed like wishful thinking at best.

What we'll actually get, in my opinion, is “a country of yes-men on servers” (if we just continue on current trends). Let me explain the difference with a small part of my personal story.

I’ve always been a straight-A student. Coming from a small village, I joined the top French engineering school before getting accepted to MIT for PhD. School was always quite easy for me. I could just get where the professor was going, where the exam's creators were taking us and could predict the test questions beforehand.

That’s why, when I eventually became a researcher (more specifically a PhD student), I was completely shocked to discover that I was a pretty average, underwhelming, mediocre researcher. While many colleagues around me had interesting ideas, I was constantly hitting a wall. If something was not written in a book I could not invent it unless it was a rather useless variation of a known theory. More annoyingly, I found it very hard to challenge the status-quo, to question what I had learned. I was no Einstein, I was just very good at school. Or maybe even: I was no Einstein in part *because* I was good at school.

History is filled with geniuses struggling during their studies. Edison was called "addled" by his teacher. Barbara McClintock got criticized for "weird thinking" before winning a Nobel Prize. Einstein failed his first attempt at the ETH Zurich entrance exam. And the list goes on.

The main mistake people usually make is thinking Newton or Einstein were just scaled-up good students, that a genius comes to life when you linearly extrapolate a top-10% student.

This perspective misses the most crucial aspect of science: the skill to ask the right questions and to challenge even what one has learned. A real science breakthrough is Copernicus proposing, against all the knowledge of his days -in ML terms we would say “despite all his training dataset”-, that the earth may orbit the sun rather than the other way around.

To create an Einstein in a data center, we don't just need a system that knows all the answers, but rather one that can ask questions nobody else has thought of or dared to ask. One that writes 'What if everyone is wrong about this?' when all textbooks, experts, and common knowledge suggest otherwise.

Just consider the crazy paradigm shift of special relativity and the guts it took to formulate a first axiom like “let’s assume the speed of light is constant in all frames of reference” defying the common sense of these days (and even of today…)

Or take CRISPR, generally considered to be an adaptive bacterial immune system since the 80s until, 25 years after its discovery, Jennifer Doudna and Emmanuelle Charpentier proposed to use it for something much broader and general: gene editing, leading to a Nobel prize. This type of realization –"we've known XX does YY for years, but what if we've been wrong about it all along? Or what if we could apply it to the entirely different concept of ZZ instead?” is an example of out-side-of-knowledge thinking –or paradigm shift– which is essentially making the progress of science.

Such paradigm shifts happen rarely, maybe 1-2 times a year and are usually awarded Nobel prizes once everybody has taken stock of the impact. However rare they are, I agree with Dario in saying that they take the lion’s share in defining scientific progress over a given century while the rest is mostly noise.

Now let’s consider what we’re currently using to benchmark recent AI model intelligence improvement. Some of the most recent AI tests are for instance the grandiosely named "Humanity's Last Exam" or "Frontier Math". They consist of very difficult questions –usually written by PhDs– but with clear, closed-end, answers.

These are exactly the kinds of exams where I excelled in my field. These benchmarks test if AI models can find the right answers to a set of questions we already know the answer to.

However, real scientific breakthroughs will come not from answering known questions, but from asking challenging new questions and questioning common conceptions and previous ideas.

Remember Douglas Adams' Hitchhiker's Guide? The answer is apparently 42, but nobody knows the right question. That's research in a nutshell.

In my opinion this is one of the reasons LLMs, while they already have all of humanity's knowledge in memory, haven't generated any new knowledge by connecting previously unrelated facts. They're mostly doing "manifold filling" at the moment - filling in the interpolation gaps between what humans already know, somehow treating knowledge as an intangible fabric of reality.

We're currently building very obedient students, not revolutionaries. This is perfect for today’s main goal in the field of creating great assistants and overly compliant helpers. But until we find a way to incentivize them to question their knowledge and propose ideas that potentially go against past training data, they won't give us scientific revolutions yet.

If we want scientific breakthroughs, we should probably explore how we’re currently measuring the performance of AI models and move to a measure of knowledge and reasoning able to test if scientific AI models can for instance:
- Challenge their own training data knowledge
- Take bold counterfactual approaches
- Make general proposals based on tiny hints
- Ask non-obvious questions that lead to new research paths

We don't need an A+ student who can answer every question with general knowledge. We need a B student who sees and questions what everyone else missed.

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PS: You might be wondering what such a benchmark could look like. Evaluating it could involve testing a model on some recent discovery it should not know yet (a modern equivalent of special relativity) and explore how the model might start asking the right questions on a topic it has no exposure to the answers or conceptual framework of. This is challenging because most models are trained on virtually all human knowledge available today but it seems essential if we want to benchmark these behaviors. Overall this is really an open question and I’ll be happy to hear your insightful thoughts.

[Helen Willsey @goodfrognosis]

I can confirm the NIH is still working well enough to score my R01 terribly 😂🤪

[Jack A. Dunkle, PhD @DunklePhd]

We ❤️ the process.

[Jack A. Dunkle, PhD @DunklePhd]

This has also been seen recently in other RNA methyltransferases. Here's one example https://t.co/AmRGkqrJET

[Jack A. Dunkle, PhD @DunklePhd]

Happy to share the latest research from my group published in RNA: https://t.co/kFln85B6RC. We show a disordered-to-ordered transition of an N-terminal region upon binding RNA is important for activity in ribosomal RNA adenine dimethylase (RRAD) proteins.

[Israel Fernandez @IsraelF96135088]

Nice short/introductory review in all things ribosomes by pioneer Harry Noller in the special 50 years issue of Cell.

The ribosome comes to life: Cell https://t.co/iwPh7gyO0h

[Jack A. Dunkle, PhD @DunklePhd]

>mkdir AF_server_experiments

[Jack A. Dunkle, PhD @DunklePhd]

UA chem & UA Bio at #DiscoverBMB 2024 @mhigginslab @UofAlabama #rolltide