A former clinical professor at UCLA, Dr. Hane Lee hopes to utilize state-of-the-art artificial intelligence (AI) to streamline the diagnostic processes for rare Mendelian diseases as 3billion's Chief Genomics Officer.

Dr. Lee spent a decade applying her expertise to help over 3,000 patients suffering from rare Mendelian disorders, within the UCLA Clinical Genomics Center.

Two decades after entering genetics, she is at the forefront of her field.

To gain more insight, we hit the ground running.

Scholarly Beginnings

Where did all of this start? What was the influence?

I was born here in Seoul but I spent a large portion of my childhood in the US while my father was doing his PhD program.

I grew up in graduate student housing throughout my childhood so my friends’ parents were pretty much all fellow students of my father within academia.

It was a very 'scholarly' environment, if you will. [laughs]

Your father's major was science-related?

His major was statistics, yes. I remember visiting his office, going to the campus where he was attending...

Looking back, that probably brought me into a vague mindset that this may be the path I'd like to take.

Sort of a natural progression of what you experienced in your childhood, growing up around that environment.

Exactly. Once my father got his doctorate degree, my family moved back to Korea.

My school years were all in Daejeon, a city famous for its sector called Daedeok Innopolis, which houses multiple universities and research institutes for science.

I guess the ‘scholarly’ environment continued. [laughs]

I think my parents’ dedicated educational ethics, my hard-working character, and the Korean 'educational culture,' so to speak, mingled pretty well and I became a high achiever - I liked getting good grades and I enjoyed excelling at school. I ended up going to a science high school which happened to be a boarding school.

However, honestly, I was not really into science that much at the time. I sometimes wonder that I may have been admitted to that high school because I got a good score in English and not Math or Science.

You were accepted into KAIST [Korea Advanced Institute of Science and Technology]. How did that feel?

I was happy.

Going from high school to KAIST wasn't such a huge change for me though. Even physically, the two campuses were across the street from each other so it was an easy move.

The switch from middle school into high school was much more significant for me. At a very young age, I learned that there was a much bigger world out there.

Expand on that a bit.

The first semester I attended high school, I spent a lot of time crying–it was a huge shock. It felt as if everyone was much smarter than me and I was in big trouble. It was a lot of pressure, and I did not think that I could ever get into a college.

However, I came to the realization that it’s okay to not be at the top of the class. It was a change of reality where I understood my place, and I was able to focus on my strengths. This is why the transition from high school to college was more of a natural progression.

At that time, most of the attendees at KAIST were also coming from such high schools that were specialized. Understandably perhaps, I was more accustomed to the atmosphere and process. It was another much bigger world but it wasn’t a shock anymore.

You had to decide a major out of high school right away, as well.

Right, so at that point, I was debating between computer science and biology. I know they sound like completely different fields and it was even more so at the time.

It probably tells that I didn’t really know what I wanted to do then.  I chose biology as I didn’t seem to enjoy programming as much as memorizing all the cell cycles and bid biology terminologies.

It was evident that Dr. Lee had dedicated ample time to studying. Her affinity for learning was nothing new though.

It was the summer of 2002 when the admittance letter to a PhD program arrived in her inbox. She had been approved to start her doctorate program at the David Geffen School of Medicine.

It was a bigger world that Dr. Lee stepped into and new questions came up as she started the program.

Was this doctorate program right for her?

Was this what she'd want to dedicate a significant portion of her life to?

The Big Move

Following your undergraduate degree completion at KAIST, you take a bold move and relocate to the United States, specifically UCLA, after being accepted to a PhD program.

Did you experience any culture shock with the move, or did you already have a basic understanding of how life was, due to exposure earlier in life?

I don’t think I had any culture shock; I remember it vividly from my first exposure to the American culture. Returning to the United States was a choice I made after considering my initial experience–a positive one–which I wanted to come back to. Being in Los Angeles where there are so many Asians and a huge Koreatown probably made things easier as well.

In terms of the graduate program though, it was not all a happy, joyful ride. After college I didn't do a master's program; I went straight to the United States for a PhD. I sometimes wonder if things would have been different if I did do a master's program in Korea.

I feel that if I had gone through a master's degree, and experienced what it was like being in the lab for what felt like 24 hours a day, things may have turned out different. In retrospect, I may not have elected to go for a PhD or I would have had a better idea which subspecialty within the broad biomedicine I wanted to study.

You enjoyed genetics at this time, though, right?

Not really. I didn’t really know what genetics was all about. Looking back though, I remember enjoying learning genetics in college and one clear reason I liked it was because it was more than simply memorizing everything.

It felt like it was a mixed bag of a little bit of math, statistics and biology. I probably have genes for statistics (laughs).

Genetics also deals more with humans in this context, opposed to raw numbers and no human connection, in a broad sense.

Yes, especially these days. Genetics/genomics is interplay of biology, statistics and informatics. I think it all worked out because I'm doing a lot of everything now, even a little bit of programming.

As you entered your PhD, you didn't study rare Mendelian disorders. It was a more broad scope, correct?

That's correct.

Diseases such as vertigo, migraine headaches, and such which is quite common amongst the general public. A lot of the actual work I did was more technology-driven as opposed to disease-focused. Running chromosomal microarray to do linkage analysis and association studies on pedigrees and cohorts, etc.

When I was about to graduate, my mentor, Dr. Stanley F. Nelson at UCLA bought one of the very first NGS (next-generation sequencing) machines. At 3billion, we currently use an Illumina NovaSeq6000. At that time, the brand was Solexa Technology, prior to Illumina acquiring it.

Give me some years.

This was the mid 2000's.

So, needless to say, I remained and did postdoc [post-doctoral] research in Dr. Nelson's lab and learned how to prep samples for the sequencer and how to use the sequencer. I also worked on developing a capture technique to capture a small portion of the human genome.

This is a technique routinely used today for exome sequencing.

This must have led to more collaboration opportunities.

Right.

This opened up a number of opportunities to collaborate with individuals studying various rare Mendelian disorders and led to discovering novel disease genes pertaining to such, as well.

Then, in 2011, Dr. Nelson, my mentor, decided he wanted to work with the Molecular Pathology laboratory at UCLA to start offering exome sequencing as a clinical test (i.e. Clinical Exome Sequencing test).

Since I knew the entire process from extracting genomic DNA from specimens, running the experiments and the bioinformatics pipeline to interpreting variants, he thought I'd be a strong fit.

Following the inception of this, I secured a position within the department of Pathology and Laboratory Medicine at UCLA.

By proxy, I was heavily involved with launching Clinical Exome Sequencing at UCLA, in the form of a dedicated sector.

That's when my career for rare diseases started, so to speak.

This sector at UCLA, it's a center for genetics, correct?

The Clinical Genomics Center at UCLA, yes.

It’s an enterprise co-founded and jointly run by three departments:

-Pathology and Laboratory Medicine
-Human Genetics
-Pediatrics

I think it nicely shows the significance of having people with different expertise and background join forces to solve difficult undiagnosed patient cases together.

Postgraduate Hane Lee was officially Dr. Lee now. As a clinical geneticist, she was not only an esteemed graduate of a premier graduate school, but also an important burgeoning figure within the landscape of rare Mendelian disorders.

None of this came as a surprise to those who took a look at her career trajectory thus far. It seemed natural. Expected, almost.

It would be roughly a decade between Dr. Lee's first accepted and published paper, and the day her work within the UCLA Clinical Genomics Center would be published in JAMA, a world-renowned journal noted in medicine as having cutthroat acceptance standards.

You have a lot of first and co-authored papers. That's quite an accomplishment; do such feats along the way help you maintain motivation? What was your first published paper?

Yes, of course it helped a lot.

The very first paper I published was while I was still in grad school. It was on performing a linkage analysis in a family and finding the disease causing variant. It was not in a novel gene but it was a new variant. A nice, small accomplishment for a student. A straightforward paper, per se.

One of the most important things I learned during the time I put that paper together is that regardless of the amount of work put into something, none of it matters unless a paper is published about it.

Another personal milestone was in 2014, soon after launching the Clinical Genomics Center at UCLA. I wrote a paper on the summary of our work. The paper was published in JAMA back-to-back with a paper from another institute that launched clinical exome sequencing about the same time UCLA did.

The two papers usually get cited together as the first papers describing how exome sequencing has started to change the diagnostic process in the field of medical genetics.

I felt very fortunate being in the position that I was at that time that I could be the first author of the paper, as publishing in JAMA is kind of a big deal.

Right place, right time.

Yes, almost a once-in-a-lifetime opportunity I guess.

You're published in JAMA, you're leading a huge effort at UCLA to bring more presence to your specialization of rare Mendelian conditions, a center is opened up... Is the culmination of these achievements validating your hard work up until that point, while you look in retrospect at your career?

I'd say so, yes. There were many obstacles, I’d say, along the way but I poured my heart into it to make things work.

I’ve also made friends with a lot of colleagues along the way from various departments and that alone was a huge achievement that paid by itself, in my opinion.

All the hard work you've put in up to this point. Are you satisfied?

I still have a lot to learn, and that will never end... I'm satisfied, though, yes.

Moral and Ethical Boundaries

So, why should anyone care at all about genetics?

Genetics is all around us.

When you stop and think about how many things in our everyday lives are connected to genetics, it's surprising. Our height, the way we act, our mannerisms, almost everything. It is very much who we are as people, as human beings.

We always talk about how we inherited a trait from our parents, grandparents and how we look alike with our siblings, etc. That’s all genetics.

Also, throughout studying genetics, it has made me more understanding and generous of others and accepting of the differences that I see in others. Genetics is what makes us different and unique. Also, perhaps someone has a certain type of personality which may seem brash or annoying on the surface; this may very well be due to their genetics. The way they were born. When I think this way, it makes me pause before blaming that person.

To expand further, it is the consideration of how one can act, even in my own personal life. Given a situation, I can choose to act humble, or braggadocious, in which case I choose the former. I was just born that way and I’m not nice or good at something because I am superior to someone else. I also know I happened to inherit a lot of 'bad' genes that make up my weakness. Of course, there are environmental factors that play a huge role as well but I think a lot are rooted to a degree, in genetics.

To come back to the question at hand, I think everyone should know about genetics to at least a basic degree especially these days as there are so many news articles and blogs about finding genetic risks, genetic ancestry, direct-consumer-tests, etc.

Unfortunately a lot of information get miscommunicated or mistranslated in/to the general public.

What are your thoughts about artificial intelligence (AI) being applied to genetics to refine various aspects? What should its boundaries be, if any?

My admittedly naïve concept about AI as I understand it, is that a machine can be trained to learn and replicate patterns, phenomenons, behaviors, etc.  

I’ve been thinking more often lately about how AI can help with my daily tasks–things I routinely do, processes pertaining to diagnosis, and other things.  

I think it’ll be possible for AI to make my life a bit more efficient. I expect it’ll take quite a long time to completely replace me. [laughs]

In a more broad sense, similar things may occur in the field of medicine or otherwise. A lot of things may eventually be replaced by AI but not completely, at least for a while.

Can AI be more creative than us? That, I'm not sure of. Maybe I don't understand AI well enough to make an informed judgement.

However, I don't think being creative comes from thin air–it comes from thoughts, which I build up in an order–which maybe a computer can learn and create formation out of.

What about things such as CRISPR/Cas9 and the moral or ethical debates which surround it? It creates a dichotomy.

For rare diseases, specifically treatments for rare diseases, I think there’s a potential for CRISPR/Cas9 to be used.

Most rare diseases are caused by a single variant in a single gene, it doesn't really matter what other genetic background you have although they could modify the main phenotype. So if CRISPR/Cas9 technology can somehow used to edit the genome, it may become a treatment option.

However, when the general public talks about 'playing God' and such, this is more related to creating a baby which has certain traits. Taller, smarter–these are complex phenotypes; multiple genes are involved. I'm not sure if it's even possible to achieve or there’s a need and worth even trying, so I try not to bring myself into such quarrels or debates.

That’s my very personal opinion and I may, again, be too naïve about the whole matter.

When it comes to morals or ethics, how do you think boundaries should be drawn?

It is evident that these technologies are powerful, especially when they can be used to improve someone's life... [pauses]

Yesterday I was speaking with our fellow geneticists about development of drugs for rare disease patients, for treatment, and challenges faced during clinical trials due to low amount of patients, resulting in delays or otherwise. The logic is, if a given treatment is not used for a patient with a specific disease, that patient will pass due to disease progression and lack of treatment.

It seems that anything may be better than this as an alternative in certain situations–however, it should be said that we need to consider each person's decision, and also take into account their personal judgement of their own quality of life.

I have seen many debilitating, often very severe rare diseases in my time as a clinical geneticist. With that being said, I'm more in favor of utilizing these very advanced, cutting-edge, often state-of-the-art technologies to improve the quality of life for these individuals.

As for making a baby potentially taller, smarter, or things like this, I'm not that interested in modifying genes to achieve such, at least at this point.

The Switch

Dr. Hane Lee, pictured top left next to Dr. Gohun Seo, poses for a picture with members of 3billion's sales, marketing, and design teams after our first webinar

The burning question–why would you leave a prestigious and world-renowned institution such as UCLA, while in a full-time position, to take the risk of working at a startup in Seoul, South Korea? What made you confident about that sort of switch?

I was not confident.

I’ll be honest–it was a large, inherent risk for my career I decided to take.

However, I always wanted to return to Korea, so I was looking for an opportunity to continue my career in rare diseases in Korea and I felt like I had a chance at 3billion.  

My circle of peers was questioning me of course, but I held my ground.

Another reason for the switch was just a change of scenery–at UCLA, our lab was an extremely small fragment of what was a larger hospital. There are both pros and cons to this.

Pros are that you get to work with some of the experts in each disease domain in the same building or just next door and have direct access to patient’s charts.

Cons are, there's a hospital-wide system, and at the end of the day, you're just a tiny lab in the grand scheme of things.

Restrictive, in some ways.

That, as well as the fear of losing funding if we are considered a financial loss even though I felt like the center was established  and was somewhat settled with a significant role.

At 3billion, there are near-50 people here with one goal - how to improve the diagnosis for rare diseases. This is wonderful.

The con to this is, I'm not able to directly interact with that aforementioned network of doctors or patients; it's a different system.

I've been in one system, so I wanted to take a risk and try out a different system–which is 3billion's.

We took a break and as our session wrapped up, spoke about what that word–passion–meant at a higher magnitude. During different phases, stages, and moments. Sometimes, seemingly a two-edged sword–it could both benefit and blind.

There was a theme with Dr. Lee's past thus far of transitioning often, be it to navigate academia or her own life in a better way. This could doubly apply to her passion.

Passion

You're someone who has become passionate about helping those who suffer from rare Mendelian conditions find diagnosis. Your passion has shifted in either direction, I assume.

Mhm, yeah, I think so–I'd say after receiving my doctorate I was unsure where I wanted to go and what I wanted to do.

I considered at one point completely changing my entire career path.

What to?

A nursery teacher; I love playing with babies and kids!

My parents were very good at coaxing me to stay a little more, however, and I’m glad they did.

Say two individuals have equivalent academic backgrounds. One with a deep passion [for something], one without. Is it possible for the individual who is void of any passion to perform at the same level as the other?

Having passion for something you do is significantly important.

However, I think that it's still possible for someone with ‘less’ passion to still build a career and perform well.

Throughout my career in genetics, I've known, met, and worked with people who would not be saddened to a high degree if they were not able to work on or study genetics again–this includes myself and I think there are more people who are like this in general.

Many people do not have specific dreams or passions, especially when they are in their 20s or 30s while deciding their career track; they exhibit adaptation and learn to enjoy it, which I feel is a more common path shown.

I do believe that it is almost impossible to outperform someone full of passion with equivalent ability though.

Backing up, we spoke on her journey thus far. Nearly two decades which Dr. Lee had devoted to relative causes–science, biology, genetics, rare diseases–and how at times, she considered pivoting or removing herself from academia.

It was all tied to that word–passion.

It is sometimes said that one should not follow their true passion as a means to an end, but rather, subscribe to a skill or ability they excel at to blend their passion in some way, through some parallel conduit.

Perhaps, at a deeper level, Dr. Lee's true passion is embedded in something more pragmatic and simple–helping humans–and the common thread throughout her journey has always been what makes us all human at a fundamental level–genetics.