Meet the man who combines science, technology and magic to understand proteins
Jun 18, 2024

Meet the man who combines science, technology and magic to understand proteins

Parag Mallick, founder and chief scientist of Nautilus Biotechnology, hopes his company’s solutions will unlock the secrets of proteins, the building blocks of biology. Being a magician as well, he says, "gives you a healthy disregard for the impossible."

Like many biotech companies, Nautilus Biotechnology calls California’s Silicon Valley home.

Marketplace’s Lily Jamali recently visited the company’s headquarters to meet with Parag Mallick, founder and chief scientist, who is also a magician and an associate professor at Stanford University.

Since 2016, Mallick and his team at Nautilus have been building a machine that they say will revolutionize biomedicine by helping scientists study proteins in detail and unlocking the secrets of the “dark proteome.” The vast majority of drugs approved by the Food and Drug Administration target proteins, after all.

The technology Nautilus has engineered for the task comes in the form of a sleek, dark box with electric blue flourishes. It will have its official debut later this year.

The following is an edited transcript of Jamali and Mallick’s conversation about the machine and the vision the company has for it.

Lily Jamali: All right, so you have to explain to me in as simple terms as possible, what is the proteome?

Parag Mallick: Let’s start with first, what are proteins? There are tens of thousands of different proteins, and they drive every aspect of biology. It is the actual material that drives life.

Jamali: So, those are proteins. Now, what is the proteome?

Mallick: The proteome is the collection of all the proteins in a system, so that can be a cell, that can be in your blood, that can be in bacteria. So, the proteome is the complete collection of all the proteins. How much is there? Where are they?

Jamali: Would mapping the proteome help treat certain diseases?

Mallick: Absolutely. Ninety-five percent of drugs target a protein. When proteins levels are off, that’s where disease comes from. And so, if we’re looking for the next great drug, really what we’re looking for is what is the target of that drug. What’s a protein that is numerous in the disease and rare in a healthy sample? So that’s your best drug target, something that really differentiates healthy from diseased. So right now, the first challenge we have is that we have never in a single experiment been able to measure the whole proteome. Our best draft version of the proteome has been collected over thousands and thousands of experiments by labs all over the world. And so even being able to know what the proteome is would be a tremendous step for biology. And then when we think about mapping them for helping disease, we just don’t know what proteins exist in your normal body when you’re healthy. We don’t know how they change over time. And if we don’t know that, how can we possibly know what happens when you’re sick? When you have cancer, we know that the proteome is changing, we don’t know how. And so, what we’re developing here is an entirely new technology to be able to measure the proteome easily, sensitively, routinely and in a way that any biologist can do it.

Jamali: So you’re a magician on the side.

Mallick: Yes.

Jamali: How has that helped you do your work here?

Mallick: It sounds ridiculous. It sounds like science —

Jamali: Are you the only Stanford professor who’s also a magician, by the way?

Mallick: Interestingly, not. But I think science and magic, if you go back in time 200 years or so, the best scientists in the world were also some of the best magicians. The communities really grew up together. Magicians were popularizers of science, and people would go to the theater to see shows of amusing physics where there were magicians talking about physical principles. And as it turns out, magicians are the world’s foremost experts in perception. And so when you think about things like cognitive biases, those cognitive biases change how we look at our data, they change how we interpret our science. And so being a magician brings you awareness of those things. It also gives you a healthy disregard for the impossible.

Jamali: That’s helpful, isn’t it?

Mallick: It is. So, when we were working on something that is incredibly challenging, something brand new, challenging the impossible, that little bit of magician in there helps you explore those places a little more comfortably.

Jamali: Let’s describe the prototype of the instrument we’re looking at. So, this is a black box that’s kind of the size of a freezer. How would you describe it?

Mallick: It’s maybe the size of a washing machine. And to be clear, it’s not a black box. It’s a black-and-blue box.

Jamali: I stand corrected.

Mallick: It does sit on a, sit on a standard lab bench. And our goal in developing this instrument was to make it incredibly easy, so that any biologist would be able to use this technology so any time they wanted a proteome, they could get a proteome. And so, you’ll see it’s pretty easy to use. We’re just going to walk through it.

Jamali: Yes tell me what this box does exactly.

Mallick: The main goal of this instrument is to be able to take a sample, whether that’s a drop of blood or a set of cancer cells, and to be able to report out on all the proteins that are present in there and how much. And with that information, we can say, OK, is this normal? Is this high in this? Is it low in that? So, for instance, PSA is a protein that many people are familiar with — prostate-specific antigen. It’s used to diagnose prostate cancer. And if it’s high, that tells you that you potentially have prostate cancer. And so somewhere, somebody had to do a study of a large number of patients and say, OK, here are people with prostate cancer, here are people who don’t. What proteins are different? And so, the goal of this instrument would be to enable those studies to happen very easily and quickly, and again, comprehensively, looking at the proteome at a level of depth and sensitivity that wasn’t previously possible.

And so the way we interact with the instrument is you just first walk up to the touchscreen and you turn it on, and it’ll wake itself up and say hello. And then it’ll ask you, what sort of a study are you interested in doing today? And it’ll then show you a little plate on how to load your samples. And so, it’s just saying, put your samples in this row here, this is what each sample is and where it belongs in this plate. And then you say, all right, let’s get started, let’s open up the instrument.

Jamali: This little flap is opening up.

Mallick: It has a very dramatic opening.

Jamali: I thought a Tesla was going to come out.

Mallick: No, just very special flow cells. So, what appears to be just a little bit of plastic and some glass, really what you’re looking at is a nano-fabricated chip inside each well of this, of this flow cell, holds over almost a billion protein molecules, one at a time. So, if you imagine this giant chessboard, we’re going to affix each individual protein molecule at one cell of this chessboard, which has a billion cells. And so, across the three flow cells, each has about four lanes. So, 12 lanes in total, you measure 10 billion protein molecules. And just for scale of reference, that’s about the number of molecules that’s in a single cell.

The endgame here is you drop your sample on, you put your flow cells in and it’s actually seated on a temperature-controlled stage to make sure that everything stays at a very well-controlled temperature. So, it shows you these green lights which say that the flow cells are all loaded properly. This is where our samples would go in, and so just insert those in there. And then in here is really part of the magic as well. So, these plates hold some very special reagents that we’ve built inside the company. These are a set of antibodies that recognize very short portions of proteins, and so those alongside the system inside and some machine-learning software are really the magic of how we’re able to identify proteins.

Jamali: I think the last thing I’ll ask you is, for somebody who’s listening, how do you hope this technology trickles down to members of the public?

Mallick: So, the place this is going to first trickle down to the public, ideally, is in the form of biomarkers that help us catch diseases early. There’s going to be a blood test that you’re going to go into a doctor’s office and it’s going to look for some new protein that no one’s ever thought of or seen or been able to see before because it was part of the dark proteome, things we just couldn’t measure, and now it’s going to be visible and it’s going to be routine, and that’s going to be part of your everyday life. The next place it’s going to hit is in bringing down the costs of therapeutics. So much of why therapeutics are expensive is because they fail very late, often because of toxicity. If we can prevent those failures or find better targets earlier, we will bring down the costs of medication.

Jamali: So, this is about bringing down costs, but also just giving people more treatments that aren’t there right now?

Mallick: That’s right. So right now, we just don’t know what to look for. We have diseases that are considered untargetable, and we have diseases that only affect what we would call a small number of people, these rare disorders that only affect tens of thousands of people. And so, because the costs of developing a drug are so high, we don’t even start to look for therapies for those diseases. They’re just off the table. So that’s the first place people are going to see this.

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