Mystery No More: Howard Hughes’ Legacy Advances Science

Mark Masselli (00:04)
How is the Howard Hughes Medical Institute leveraging artificial intelligence and other cutting edge
technologies to solve biology's deepest mysteries?

Nelson Spruston (00:13)
What we're trying to do at HHMI is to use the deep bench of talent to use a basketball analogy again, to come up
with ideas for problems. A question longstanding open questions in the biological sciences where the
opportunity to collect large, high quality data sets and combine that with artificial intelligence, which benefits
from these large data sets, can actually fuel new discoveries. And it's an H-H-M-I-W wide program. We're
engaging with all the scientists, across the HHMI community for ideas, and it will be operated out of the Janelia
Research Campus for practical reasons. This is a great place for us to do it.

Margaret Flinter (01:01)
Our guest is the Vice President and Executive Director of the Institute's Big Bet on research. Nelson Spruston
holds a PhD in neuroscience from the Baylor College of Medicine.

Nelson (01:11)
If you could record signals from the brain of a rat, that it might be able to actually use those signals to imagine
the path that it follows to collect a reward.

Margaret (01:24)
This is Conversations on Healthcare.

Mark (01:37)
Dr. Spruston, welcome to Conversations on Healthcare.

Nelson (01:41)
Thanks for having me.

Mark (01:42)
Yeah. You know, we hear a lot about the Howard Hughes Medical Institute. Let's start by asking you to give us
an overview of HHMI.

Nelson (01:51)
HHMI was established in 1953, and it's, was the vision of Howard Hughes. And, in 1985, the, trustees of HHMI
sold the Hughes Aircraft Company and established a, an endowment, which is now used to fund medical
research, and has been doing that for, 40 years since then. And many major discoveries have been made by
HHMI, investigators and other scientists in the HHMI network over, its history.

Margaret (02:27)
Well, we are really looking forward to learning more, about the work that you've been doing, but one thing,
Nelson I understand is that HHMI provides each one of its investigators with about a million dollars per year to
spend on their research projects. How does this support, and enhance your philosophy of people, not projects,
giving it to the researchers to decide on the projects?

Nelson (02:51)
Yeah, this is the really, the cornerstone of HHMI is people, not projects, and it's compliments the approach of
the National Institutes of Health, which is to really fund specific projects. Our approach instead is to identify
people who have a very strong track record of making important discoveries in biomedical research and letting
them pursue their best ideas without asking for our permission. And, we periodically review all of the HHMI
investigators and other HHMI scientists and, provided that they meet the very high bar that we set for them. We
keep funding them. And, at Janelia we do something very similar. The HHMI investigators are located at
universities around the country. The campus where I work is called the Janelia Research Campus. It's in
Northern Virginia, and we do things a little differently here. Everything that we do is supported by HHMI on
campus. It's the only, research campus owned by and operated by HHMI.

Mark (03:57)
Well, that's exciting to hear about the campus and the work that you're doing. Tell, tell me, are you out searching
all 50 states, or how are you identifying, those lead researchers? It sounds like, they win the lotto if they,
encounter you, but I'm sure they're looking out for you, but you're looking for them as well.

Nelson (04:17)
Yeah, we are. We are, we are definitely actively, pursuing scientists all over the country, even all over the
world. The investigators are all located at American universities and to Janelia campuses here in the United
States also. But we have researchers coming to us from all over the world, and, we really focus on excellence.
Excellence is a core, fo philosophy of HHMI is to pursue, pursue excellence every way we can. We're also
looking to find people who, have excellent skills and talents. Wherever we can find them, we sort of scour the
whole world and look, look for them wherever we can find them.

Mark (04:58)
Well, It's basketball season, Margaret. I'm wondering if they have a portal, that people can join or a draft to
draft. It can be drafted in HHMI. It sounds like. It's, it's well worth it.

Nelson (05:12)
Yeah. It's, it's a fantastic organization and, yeah, it's a real privilege to be part of it. It's, the, the history of HHMI
is extremely impressive. The philosophy of HHMI is to focus on fundamental basic research in the biomedical
sciences. And from the understanding of complex biological systems that flows from that philosophy, we often
see real treatments and cures for diseases following that understanding.

Margaret (05:46)
Well, we are really, delighted to have an opportunity to share with our audience, more about the institute and the
work that you're doing. So let me ask you a few more things about what's going, going on, and also about ai, at
the institute. You've launched the cell map segmentation challenge and are investing $500 million in AI driven
life sciences research. What are you trying to achieve with these initiatives? Is this broad across many
investigators or targeted teller audience more about that?

Nelson (06:17)
Yeah. The biggest program is called AI at HHMI, and that's the $500 million investment over 10 years. And
what we're seeking to do is to leverage this, you know, massive improvement in deep learning technologies to
accelerate discovery in biology. And we're seeing lots of organizations, do that around the world. And it's a
logical thing to do because it is one of the opportunities that exist for AI to have a real positive benefit on
mankind. What we're trying to do at HHMI is to use the deep bench of talent, to use a basketball analogy again,
to come up with ideas for problems, question longstanding open questions in the biological sciences where the
opportunity to collect large, high quality data sets and combine that with artificial intelligence, which benefits
from these large data sets, can actually fuel new discoveries. And it's an H-H-M-I-W wide program. We're
engaging with all the scientists, across the HHMI community for ideas, and it will be operated out of the Janelia
Research Campus for practical reasons. This is a great place for us to do it. And we're gonna hire a team of AI
scientists and AI engineers and data engineers, and a bunch of research scientists to do the work and collect
these big data sets to tackle problems ranging from things like neuroscience, immunology, and RNA biology to
name just a few.

Mark (07:55)
Oh, that's great. Margaret. I think we've had, in our last guest that so many of them talking about ai, some of the
excitement about a ai, but also some of the things that worries people about ai, and there are fears, that, it feeds
into the existing inequities in our healthcare system. There are also concerns that it's not secure because sharing
sensitive information with any AI chatbot carries some privacy risk. I'm wondering how HHMI addresses these
challenges?

Nelson (08:25)
Great question. I mean, because we don't deal with patient data specifically. We're doing fundamental basic
research. We don't have the confidentiality issue to contend with. And, but we are aware that AI systems can be
very, very powerful. And like any powerful tool, it can be used for good purposes, and it can be used for not so
good purposes. So we are going to establish an AI advisory committee that will advise us on safety and security
of any systems that we develop, and to ensure that the purposes of the AI systems we develop are aligned with,
what humans are designing them to be used for.

Margaret (09:09)
Well, there's, there's also the public's view, of course, on ai, and, we saw the Kaiser Family Foundation poll
mm-hmm. Mm-hmm. Recently that, said that most adults, including the majority of those who used ai, were not
confident that the health information provided by AI chatbots was accurate. I have to say that doesn't seem to be

stopping any of them from asking and going back and asking again. But we are, I think, it's safe to say living in
a time when there's, certainly some, mistrust, of science and of information. What's your view on the situation?

Nelson (09:45)
I think there's a, we should, draw a line between mistrust of science and mistrust of AI systems because they're
not exactly the same thing. I think that it's probably wise to be careful about getting health related information
from online AI systems. And personally, I would definitely recommend that people, stick to their doctor for
making their, you know, healthcare decisions. I think the, the question of trust of scientists and science and in
our society is an important one. And I think we, scientists all have a responsibility to do what we can to try to,
help people understand the very, very complex subjects that we deal with as scientists and how we do the work
that we do in a way that is rigorous and, where even we challenge ourselves all the time and evidence-based. So,
this is a, it's a good challenge for all of us as scientists and an important one to tackle.

Mark (10:47)
You know, I think that's such an important area to talk a little more about, which is the, I guess, post covid,
you'd say there's been a real, diminution of, of trust in, in science. And, you know, I think there's an individual
responsibility and there's a larger collective responsibility. What do you see happening with your colleagues
around the country as they try to address this really important issue? And it really re it's more than a one-on-one
conversation because it's, we, we have the larger country that we're concerned about. So any special initiatives
that the institute has been thinking about to challenge this in addition to your, portfolio of very important
scientific work, but without this type of support that may fall on deaf ears, right. Of all the great breakthroughs
that you, might, come up with.

Nelson (11:43)
Yeah, I think it's a very important point. We've been doing HHMI has been doing a number of things for a very
long time to try to, promote an interest and understanding of science throughout our communities. One example
is we have a program called Bio Interactive, which creates biology material teacher materials for teachers of
biology to use in high schools. And those are very, very widely adopted in high schools throughout the country.
Something like 75 or 80% of schools now use bio interactive materials in the biology classroom. So that's one
example of the kinds of things that we do at HHMI that go beyond just supporting and doing research and enter
into this realm of how do we educate, our communities about the importance of science and biology in
particular.

Margaret (12:37)
I'm glad you said that. 'cause I was thinking, as you were speaking earlier, of what a great opportunity to reach
into the next generation and the younger generation. And to do that by strengthening the science curriculum, in
the schools is wonderful. And I'm betting you probably host some of them at that campus in Virginia from time
to time as well. And we maybe can hear more about emerging, how you're looking at emerging scholars. But I
wanted to go back, if, if I could still to, sharing with our audience some of the specific, work of your impressive
record. I know you've, worked at identifying genes and molecular processes for immune system, function, as
one particular area. Can you share with us, any, work in that area where HHMI has really been in the discovery
process and how that might have led to any new therapeutic approaches?

Nelson (13:28)
Yeah. I think one of the most, compelling examples is the CRISPR story, which actually started as real basic
research outside of HHMI, into understanding the genomes of thermophilic bacteria. And this led to the
discovery of these, repeats that occur in the bacterial genomes. And these are have been evolved over time by
bacteria's defense against viruses. And, one Julia investigator, Jennifer Donna, adopted this technology or took
advantage of, of this technology that's been studied extensively to develop mechanisms for editing genomes and
editing genomes has become a key strategy now for developing treatments against genetic diseases. And one
HHMI, investigator Stewart Orkin, has recently, achieved a breakthrough in this area by using editing of a gene
called BCL 11 A, which is a suppressor of, fetal hemoglobin, and it's being used, quite successfully now as a
treatment for sickle cell disease.

Margaret (14:40)
Yes. Very exciting.

Nelson (14:42)
And the impressive aspect of this story is that the whole thing, you know, started as a, a very, basic biological
understanding of basic biological system that then turned into a technology that then turned into a treatment for
a disease.

Mark (14:57)
I don't think we had Jennifer on, but I remember we had, one of the lead people, on the CRISPR technology and
just thinking about, the importance CRISPR had, it was, at the time it came out, it was the AI for us, right. And
now we have ai right? Sort of the next generation. We haven't forgotten CRISPR because it's so fundamental to,
to, to, to research. What do you see out in the horizon past ai? What's, what's, what's lurking out there that might
also be something in five years that all of us will be talking about?

Nelson (15:29)
Oh, boy, that's a, it's difficult to think beyond AI these days. There's so much happening in this space. Yeah.
And the impact is gonna be so tremendous. I mean, one of the things obviously that has really shaken the world
of biology is alpha fold, which was developed by Google Deep Mind, and it's transforming the way, people
study cell biology, study molecular biology and the way that drugs are developed. So, the, the opportunities and
possibilities for AI and the impact it's going to have on our basic understanding of biology, as well as the way
we go about developing, treatments, therapies, and cures for diseases is, in my opinion, it's so profound that I, I
haven't spent much time thinking what happens after that.

Mark (16:17)
Actually, Margaret, I, I, I just read an article the other day that somebody who had a very rare disease had used a
database that had, off-label drugs, right. And it connected back to their, to their particular problem. And, and
actually they were in remission.

Margaret (16:33)
It's got Gotten a lot of attention, using old drugs and old data with the massive…

Nelson (16:38)
Yeah, I thought that article too, that sounded like a very cool, story. Very cool use of ai.

Margaret (16:44)
Well, I think, in a, in a lot of ways, you've, brought to the, the forefront of our conversations, an area that's just
incredibly positive, and in a moment where so much is in question, to look at science and look at what we might
be doing, to make life better for people is incredible. So I'm gonna just, pick out another piece of what we,
gleaned looking at the work that goes on there. Tell us about the research where rats were put into a virtual
reality arena and they had teleport powers.

Nelson (17:18)
Yeah, this is a very cool study. The lead author is Chongxi Lai, and it was, work that was done here at the
Janelia Research Campus in Albert Lee's lab, who's now at Beth Israel. Chongxi and Albert had this really
creative idea that if you could record signals from the brain of a rat, that it might be able to actually use those
signals to imagine the path that it follows to collect a reward. So they used a technology that was actually
developed at Janelia by, a, a group leader named Tim Harris and his team, and they worked with a, company in
Belgium that does, nano fabrication and for semiconductor products. And they adapted that to create tiny little
probes that can be inserted into the brains of animals like rats. They have hundreds of, tiny little probes that can
be used to record signals from neurons. And so what, Chongxi and Albert did is they recorded the signals from
rats as they learned to navigate in a virtual reality environment to find rewards. And then at some point, they,
trained the neural activity that was active during navigation to the rewards to actually act as a, a brain machine
interface, and allowed the animal to actually navigate to the reward without actually moving, but rather using its
mental, imagination and the neural signals that go along with that to navigate towards a reward. So there are a
few really important implications of this work. One of the implications is that even animals like rats likely have
the thing that we call imagination. We can all imagine, for example, being at home and what route we take to
drive from home to work. Rats seem to be able to do something comparable to that. And it also has implications
for, brain machine interfaces and understanding what kinds of signals can be effectively used, for people who
can't move their bodies to use their brain signals to control devices in the environment.

Mark (19:36)

It almost sounded like, and I don't want to use my Trekky knowledge, but a holodeck, that you were able to
create or somehow sort of moving in that direction.

Nelson (19:47)
Uh, well, I'm not familiar with that term, but hopefully,

Mark (19:50)
Oh, you gotta, you gotta, well, the Star Trek people will email you after, but, you know, at H-H-M-I, you also
oversee gene targeting and transgenics research. One sort of maybe describe what that is, and, tell us what
progress you've been making in that area.

Nelson (20:10)
Yeah. A really powerful method in animal research these days is to manipulate the genome, in ways that allow
us to understand the results of those manipulations. And I'll just give you, one example. So a huge advantage in
biology is to be able to see things that might otherwise be invisible. And neural activity is one of those things
that people like to be able to, neuroscientists in particular, like to be able to see it happening in an animal. And
so at Janelia, we, developed a technology called G camp, which is a protein that's, fluorescent and sensitive to
calcium. So when neurons are activated, calcium enters the cell, and if they have this protein inside them, the
cell gets a little bit brighter, and you can express these proteins, these calcium sensitive proteins in the cells of
animals like rats or mice using transgenic technologies. And it's basically inserting the gene for this engineered
protein that acts as a sensor for calcium into the genome of the animal, so that you can actually use this tool as a
way of revealing a physiological process in the animal that you otherwise wouldn't be able to see. So that's just
one example of how transgenics or gene targeting can be used in biological, in the biological sciences.

Margaret (21:42)
Fascinating. You know, we'd be remiss if we didn't ask you about your own lab, and your work, and I, I
understand you do a lot of work in exploring the role of the hippocampus and learning and memory. We'd love
to have you share some about your own work, that you're excited about.

Nelson (21:59)
Oh, thank you for the opportunity. I wanna say I work with an incredible group of people here at Janelia.
Everything that we do in the lab is teamwork and collaboration, and it flows really from the development of new
technologies that allow us to do things like, for example, imaging neural activity in the brain of a mouse. And
that's one of the things that we've done recently in the lab. A couple of brilliant scientists in my lab, Wayne s
and Johan Nus, led the work. They're both now off doing their own thing. The, the study that they did, in
collaboration with many others was to express these G camp proteins that I just mentioned in the brains of mice,
and to image neural activity in thousands of neurons in the hippocampus as mice were trained and learned to do
a task in a virtual reality environment. And the reason they were able to do this study is not only the
development of the GAMP sensor that I just mentioned, but also an incredibly powerful microscope with a
huge, wide field of view that allowed us to monitor the activity of thousands of neurons at the resolution of
individual cells. And we can monitor the same population of cells over the course of many days as the animals
learned to do a fairly complex task. And what we saw was really remarkable that you could see activity coming
from what was initially unstructured into a very, very structured representation of the task. And even sometimes
offline when the animal wasn't performing the task, we could say, see indications of the same, same kinds of
activity that happened while the animal was doing the task, indicating, as I mentioned in the study from Albert
Lee's lab, that maybe the animals are actually thinking about the task offline when they're, when they're not
actually, running to and, and looking for rewards in this virtual environment. So we've learned a lot from this
approach about how neural activity changes. And I think a very simple way of thinking about this, again, is that
if you wanna understand something like memory and what's happening at the cellular level and the synaptic
level as we form memories, it sure helps a lot to be able to see it happening in the cells.

Mark (24:22)
Yeah. That's great. So you've got a big, anniversary coming up for the Janelia Center, right? 20 20th
anniversaries right around the corner. That's gonna be next year. Next year. What, what are the plans? And
maybe tell us a little about, about the formation of the, of the campus. How, how did it get its name and, maybe
the size, you're, you're on a huge campus there, 700 acres, but tell us, tell us a little bit about what one might
say.

Nelson (24:52)

Yeah. We Have a, a, a big, a nice, beautiful campus, on the Potomac River here, about 45 minutes outside of
Washington dc HHMI purchased the land in the early two thousands with the goal of building the Janelia
Research Campus. And the purpose of Janelia is really to compliment the way research is done in other places,
mainly universities. And this is really the vision of the inaugural executive director, Jerry Rubin, who had this
idea that often what happens is people are trained as scientists to do science in the lab, and as soon as they get
good at it, they get asked to run a lab. And running a lab involves so many other things besides doing science.
They very quickly, they're not doing science anymore. So Jerry's vision was to create a place where people
could keep doing science for many, many years, after their training ended even. And so some of the principles
that make that possible are the labs are really small, compared to many labs at universities, and they're fully
funded by HHMI. We don't even allow our group leaders to apply for grants from other organizations. So the
absence of grant writing responsibility, we're not a university, so we don't have much in the way of teaching
responsibility. And the small labs all together make it possible for people to stay hands-on at the bench doing
science and in a very, very collaborative way, because the small lab thing also makes, makes for lots of time to
talk to your colleagues and to come up with and brainstorm new ideas for innovative technologies or new
approaches to tackle longstanding biological problems.

Mark (26:31)
Where where are you connected worldwide? Obviously you've got NIH is one area. What, what are the other
partners around the globe that, HHMI is working with?

Nelson (26:45)
Well, you know, in terms of, funding agencies that support the kind of research that we do in other countries,
there's the Welcome Trust, and the Max Blank Institute and, is in Germany. The Welcome Trust is in the uk.
Those are some other examples of, major funding agencies, for the biological sciences. And we, we partner
sometimes with scientists who are funded and supported by those organizations. But, we have a very broad
range of collaborations. We have something here at JANELIA called the Visiting Program, and we bring,
something like a hundred visitors a year to our campus to collaborate with our scientists.

Margaret (27:29)
Well, it sounds a little bit like Nirvana, though I know the tremendous, tremendous amount of hard work, but
the, the ability to focus on the work and not be in the constant next competitive cycle, for what's out there for the
funding…

Mark (27:41)
And the vision, somebody had to put this together

Margaret (27:42)
…and the vision is, is really impressive. I appreciate what you, said about the, the, folks that you bring. And I, I
wanna go back to my, illusion a little bit earlier to, younger people. Are you doing anything with mentoring at
the, college level, even the high school level, exposing people to the joys of bench science? Anything that you
have in your outreach, or is it really more focused on the work itself?

Nelson (28:12)
I wanna mention, that we have a variety of programs at HHMI supporting scientists at all career stages. I
mentioned bio interactive, that's, not so much supporting scientists, but actually supporting educators. That's at
the high school level. We also have summer undergraduate research programs. We have program, called the
Gilliam Fellows Program that supports graduate students. We have a Hannah Gray Fellows program that
supports people at the postdoctoral and early faculty phase of their career. And we have their Robowski
Scholars, which support people in universities in the early stages of their faculty position. Of course, we have
Janelia, we have the investigator program. So our programs really span a very, very broad range of career
stages, if you will, in terms of training scientists, again, with the focus of a two Shema being squarely on
excellence, but also really valuing the importance of creating an inclusive environment where people can be
recruited from all kinds of backgrounds, and given the opportunity to contribute with their talent and their skills
and their knowledge to the research enterprise. I think that's a tremendously helpful way of broadening the
participation of our communities, not just nationally, but even internationally. 'cause many, as I mentioned,
many people come from other countries, and it's a very, very powerful way for promoting the value of science
and of, you know, sort of promoting the health and of science, for many decades to come.

Margaret (29:54)

Well, I couldn't agree with you more, and I'm so glad we've had a chance to, talk with you and to get this
information. I, I am sure there are more than a few people taking furious notes, as they listen to this and watch
it, to learn more about those opportunities. So thank you Nelson, for joining us, and thanks as always to our
audience for being here. Just a reminder, be sure to subscribe to our videos on YouTube, find us on a, on
Facebook and x, and share your thoughts and comments about this program, as well as all of our other programs
take care and be well.

(30:30)
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