Chatting with Cong Le about Gene Editing: How Can Carbon-based Life Face the Challenges of Silicon-based Life?

When looking back at the major scientific breakthroughs in human civilization over the past century, Walter Isaacson, a renowned American biographer, proposed a "three - level" framework in The Code Breaker : The first level is the physics revolution based on atoms, which enabled humans to master nuclear energy and initiated the era of atomic bombs; the second level is the information revolution with 0 and 1 as its language, laying the foundation for the digital world and the Silicon Valley miracle; and the third level is the life - science revolution that is reshaping the future, especially gene - editing technology, which gives us the possibility of "programming life" for the first time.

Gene editing won the Nobel Prize in 2020, and the patent disputes still stir up waves in the academic and capital circles. But to trace the real milestone moment of gene - editing technology, many people would mention a paper published in Science in 2013 - Multiplex Genome Engineering Using CRISPR/Cas Systems . It was this paper that pushed CRISPR - Cas9 from a laboratory concept to applications in mammalian cells.

Image source: nobelprize.org

If compared with today's technology, that paper was like the "GPT moment" in life science. It not only brought gene editing into a new paradigm but also opened the door for later applications.

In this episode, we invited Cong Le, the first author of this paper and currently an assistant professor in the Department of Pathology and Genetics at Stanford University School of Medicine. He not only witnessed the scientific research transition from "reading genes" to "writing genes" but also saw how CRISPR evolved from a cutting - edge exploration to a world - changing force in just over a decade. This time, the podcast host Hong Jun and Cong Le reviewed the R & D story behind gene - editing technology, explored how it could open up new possibilities for the human future, and further envisioned the broad imagination space brought by the combination of gene editing and artificial intelligence.

The following is a selection of this dialogue:

01 The R & D Path of Gene Editing

Hong Jun: In this episode, I'm trying to break through my own capabilities. Let's talk about gene editing and the application of AI in the field of gene editing. Today, my guest is Cong Le, an assistant professor of pathology and genetics at Stanford University School of Medicine. Cong Le is the first author of the CRISPR - Cas9 paper published in Science in 2013. This paper is a milestone that pushed gene - editing technology from a laboratory concept to applications in mammalian cells. If compared with today's technological development, it can be called the GPT moment in the field of gene editing and is also one of the most influential and epoch - making studies in the history of life science.

This paper was jointly completed by you and your supervisor Feng Zhang. Could you tell me what position this paper held in the industry at that time? Why was it so crucial for the entire gene - editing industry?

Source: science.org

Cong Le: This paper, along with several other teams, was the first to prove that the CRISPR - Cas9 gene - editing tool could edit human DNA and perform genetic modification in living human cells. I think this is the key reason why it is an important milestone in scientific or technological development. Before that, the CRISPR - Cas9 system only existed in microorganisms, and the ability to edit the genome in human cells was first demonstrated in 2013.

Hong Jun: So, this can be said to be the pioneering work of the application of CRISPR - Cas9 in human and mammalian cells, and it also made gene editing a very convenient and easy - to - use technology in the future.

Cong Le: Yes, actually, there are three core points. First, it made everyone aware that we can modify the DNA of human cells. Second, we can reprogram using a very simple technology like CRISPR - Cas9. Previously, modifying a gene might cost a huge amount of money and time. But with a simple method of synthesizing a short RNA - carrying sequence called CRISPR - Cas9, we can edit any gene sequence. This is like suddenly going from walking to having a carriage, or even suddenly having a train or an airplane, which reduced the cost of gene editing by an order of magnitude and increased the scale. Third, this method proved to be safe for use in living cells. We can test the cells before and after editing a living cell and find that the cell state is normal, which also shows that it is not just an isolated case, not just a powerful but difficult - to - apply technology. Not only us, but also other research groups proved that we can safely and effectively perform CRISPR - mediated gene editing in living cells. I think these three points are very crucial to support the broader application of this technology.

Image source: Wikipedia

Hong Jun: Let's talk in detail about this paper and the technology later, including the Nobel Prize controversy in 2020 and the complex patent war in between. Before that, could you briefly introduce your own experience? I'm also curious about what made you focus on that field in 2013 and write such a paper.

Cong Le: Actually, I grew up in Zhongguancun and loved playing computer games since childhood. So, after the college entrance examination, my first major was electronic engineering. My goal at Tsinghua University was to become a game designer. But after studying electronics for a while, on the one hand, due to the health problems of my family members, and on the other hand, after reading some books related to biomedicine in the library, I was deeply touched. I felt that if I could design life and medical drugs, it would be a very valuable and interesting thing. Moreover, I found that there were still many basic things in that field that were not clearly understood. For example, why do some people get diabetes? Why do some families have genetic diseases? Why do some people get Alzheimer's disease during the aging process? There were no answers to such simple questions. So, I thought that compared with designing a circuit, an electronic product, or a software, designing life was more interesting, more challenging, and could better satisfy a person's curiosity. So, I later transferred to the biology department.

At first, I just wanted to understand how to better transform and design many biological problems. So, when I went to Harvard University for my Ph.D., I met my first supervisor, George Church. In George Church's laboratory, I met Feng Zhang, who was an independent research fellow at that time, equivalent to an independent research post - doctoral position. Since George Church was one of the earliest scientists to contact and propose gene - sequencing and gene - modification technologies, Feng Zhang and I were greatly influenced by him when we first met.

At that time, Feng Zhang told me that we should think about how to do gene editing, not just sequencing, because sequencing is just reading a book, not writing a book. If you really want to understand a system, as many famous physicists like Richard Feynman said, you can only truly understand it when you can create something. I really agreed with Feng Zhang's idea at that time. So, when Feng Zhang quickly got a faculty position at MIT, I became one of the earliest students to join Feng Zhang's laboratory and participated in the earliest CRISPR gene - editing work.

George Church. Image source: Isc official website

Hong Jun: Your two supervisors are both very outstanding. George Church was already very famous at Harvard University at that time and was a well - known heavyweight professor in the field of gene science. And you just mentioned that when you first met Feng Zhang, he was just transitioning from a post - doctoral fellow to an assistant professor and was even still looking for a faculty position. But you firmly chose to cooperate with this young scholar because you thought his direction was more suitable for you. This actually requires a lot of courage.

Cong Le: Yes, I also think I'm very lucky. The biggest common point between George Church and Feng Zhang is that they both have very good vision and judgment. I think this is extremely important when doing original and disruptive research. Many times, you can't fully understand something at the beginning, but if you can realize that this direction is worth pursuing one step ahead, it is more crucial than execution itself.

Hong Jun: Yes, I think entrepreneurs also need to have this quality. You just mentioned that when you started doing CRISPR - related research in 2009, you found that it wasn't just you who discovered this. Who else discovered this? And did you start competing in the speed of paper publication?

Cong Le: Yes. I remember that Jennifer Doudna's biography also mentioned that when we started in 2009 and 2010, we initially set it as a high - risk, high - reward long - term project over several years and weren't in a hurry because scientific research is an exploration. But it was really stupid. I later realized that time and speed were also very important.

In 2012, we had achieved good results and were planning to polish and write the paper as perfectly as possible. But in June of that year, we suddenly saw a paper published by the Doudna laboratory in Science . Although they only conducted in vitro experiments, they had precisely proved that the CRISPR system could be programmed with a simple guide RNA to edit any DNA sequence. When someone achieved it in vitro, we realized two things: First, we weren't the only ones who thought of this direction; second, since it had been achieved in vitro, the application in human cells was just a matter of time, and other teams would soon follow up to do gene editing in human cells. So, we immediately accelerated the submission of the paper and no longer pursued the "perfection" of the paper. I think there is a general perfectionist complex in the academic circle, but at critical moments, speed is also important.

Hong Jun: But when your paper was finally published, it still looked very well - written.

Cong Le: It's because we had been brewing it for a long time. In fact, an earlier and simpler version would have been enough for publication.

Hong Jun: Actually, you could have published it in stages instead of waiting to accumulate a big one at once.

Cong Le: Of course, I think everyone's early papers are very good. But in our first paper, we not only showed the destruction and cutting of a gene but also how to precisely repair a gene. That is, at that time, we had not only started precise repair and replacement but also performed simultaneous editing of multiple targets. In fact, we did steps 1, 2, and 3 in the early stage, but maybe only step 1 or 1 and 2 could have been published earlier. But it doesn't matter. This is just the tuition fee at the early stage of my career.

Hong Jun: The price was missing the Nobel Prize.

Cong Le: It's hard to say. I think the Nobel Prize itself is somewhat subjective. In fact, any award is similar. Even if we had published earlier, we might not have won the prize. After all, our work was more about applying the technology, and from the perspective of theory and basic experiments, the scientists who first proposed and verified the core principles might be more worthy of praise. How the Nobel Prize selects among different ideas and methods is determined by people. However, I do think that if we had been faster, at least there wouldn't have been such a big controversy over the patent later.

Professor Feng Zhang. Image source: mit.edu

Hong Jun: I remember that during that period, besides your paper, Feng Zhang's laboratory also published a large number of gene - editing - related results. What were the main directions?

Cong Le: When you have a breakthrough in underlying technology, it's like if I create the iPhone platform for smartphones, I can develop countless application scenarios on it. After we developed CRISPR, we started to expand in two dimensions. One dimension is vertical expansion, delving into the applications of specific diseases and specific treatment methods. The other is horizontal expansion of different possibilities, such as DNA editing, RNA editing, epigenetic editing, and splicing editing. So, horizontally, we expand different possibilities and different editing paradigms, and vertically, for example, we also did gene editing for liver diseases, gene editing for genetic eye diseases, and gene editing for target discovery through large - scale gene screening for immune tumors. So, once we have such a core platform technology, we can expand both vertically and horizontally. Of course, many of these works are also done in cooperation with others.

Hong Jun: So, actually, if there is a breakthrough in the underlying technology, many applications can be developed on it. So, that crucial step is very important.

Cong Le: I think it's the same as AI, right? You can expand horizontally or vertically into a specific application scenario.

Hong Jun: If I remember correctly, on the same day you published your paper, your other supervisor, George Church, also published a paper on gene editing. Is this a coincidence?

Cong Le: It's not a coincidence. Although scientific journals are good platforms for disseminating research results, their timeliness is often not fast. Usually, journals will wait for multiple papers in a related field to be submitted and reviewed, and then publish them together to form a special series. So, the simultaneous publication is more of an arrangement by the editorial department. On the other hand, at that time, many research teams were independently promoting the advancement of this technology.

Image source: nature.com

Hong Jun: Can you tell me how you registered the gene - editing patent? I remember this