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Li-An Yeh Discusses Drug Discovery from an Academic Perspective

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At A Glance

Name: Li-An Yeh

Position:Director for Lead Discovery, Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair

Background: Postdoc, Department of Biochemistry and Molecular Biology, Harvard University — 1981-1984; PhD, biochemistry, Purdue University — 1980; MS, chemistry, Kent State University — 1976

Having served as a postdoc at Harvard University’s department of biochemistry and molecular biology, Li-An Yeh moved on to commercial drug discovery, spending over 15 years in various high-ranking scientific positions at companies such as Pfizer, OsteoArthritis Sciences and Phytera. In 2001, however, Yeh proved that you can come home again, as she became the director of lead discovery for Harvard’s newly established Laboratory for Drug Discovery in Neurodegeneration. Recently, Inside Bioassays spoke with Yeh about the LDDN and her experiences in commercial and academic drug discovery.

Tell me a little about the history of your lab at Harvard, the Laboratory for Drug Discovery in Neurodegeneration?

The [LDDN] was initiated about three years ago when there was a very generous donor — one person from a huge corporation that wanted to remain unknown. And that person donated $37 million to Harvard with the mission that Harvard should use that money within 3 or 4 years to make contributions to drug discovery, and to search for cures for all those neurodegenerative [diseases] such as Alzheimer’s, Parkinson’s, ALS, and MS. So Harvard used the money to establish HCNR, which stands for the Harvard Center for Neurodegeneration and Repair. Within the HCNR, there are five core facilities, dealing with translational [research], microarrays, bioinformatics, imaging, and we are core “D,” drug discovery. With that mission in mind, about three years ago, my boss Ross Stein was hired, and he recruited [me] and my colleague, Dr. Gregory Cuny. All three of us came from industry backgrounds, so we tried to establish this laboratory — a very aggressive drug-discovery engine. [The LDDN] has one biology component, which is assay development, high-throughput screening, database management, compound library management, and lead discovery. My job is to discover leads in the early stage, and give them to [Greg Cuny], my counterpart within the chemistry department, to further optimize the lead and eventually make it into a drug.

So that provides the flow of how we do things. But our organization is very small. As you can see on the website, we only have 15 permanent employees — about half biologists and half chemists. But our projects are coming from the Harvard community — the neurology community. Our collaboration partners include the Children’s Hospital, Dana-Farber, Mass General, et cetera. We collaborate with all the hospitals affiliated with Harvard, so we don’t just limit ourselves to working with Brigham and Women’s or Mass General alone. Right now, we don’t even limit ourselves to neurodegeneration. We would also be interested in collaborating in other therapeutic areas if they really have an exciting project and really need our help.

What are some of the major projects that you are involved in currently?

I’m pretty much involved in all the projects on the biology side. Right now, we have a couple of projects [in the area of] Alzheimer’s, Parkinson’s, ALS, MS, and Huntington’s disease. So I’m currently involved in five projects or therapeutic indications. But within these five indications, in terms of active, ongoing projects, we have around 15 projects this year, but have had similar numbers in previous years that have already been completed. So totally, we have more or less worked on about 30 projects that we have received or collaborated on.

So working more in lead discovery yourself, do you find yourself more involved with biochemical screening than high-content cell-based screening?

I don’t think so. We can’t just tell the faculty: “Your assays or interests have to be limited to biochemical screens.” Of course, there are a million technologies you can apply to one screen, or to solve a problem or test an interesting hypothesis. So you can design pretty much anything for them. Our screening portfolio contains both biochemical and cell-based screening. Roughly 30 percent are cell based and 70 percent involve a molecular approach, including enzymatic assays, receptor-binding assays, protein-protein interactions, or hydrolase assays — all different aspects.

Do you see the role for cell-based assays increasing or remaining steady in drug discovery?

I think the role of cell-based assays is very important, but in primary screens, I think most of the drug companies still prefer a more clean-cut, molecular mechanism. If you screen with a cell-based assay, it is very likely that you will come across something very interesting and very exciting, but you don’t know the molecular mechanism of it. And then if you take a compound like that for further development, the major pharmaceutical companies have some concerns about it. They’re thinking that for FDA submission or for an IND or NDA, you need to definitively tell the FDA: “This is doing this by binding to this target or inhibiting that enzyme.” If you can’t do that, very likely you cannot explain your side effects. So I think molecular targets are vital for defining the target, but cell-based assays will give you enriched information in terms of the screening. So, I would say they’re important, but further elucidation of the molecular mechanism is equally important. In a lot of our assays, we started with cells, but the faculty member eventually is going to work out what exactly is happening in my cell. That’s the most exciting part: Target elucidation.

Having worked in both commercial and academic drug discovery, can you highlight some of the major differences between the two? I’m sure you could talk for a while about that, but I’m curious about your perspective here.

The first thing that is dramatically different is that the mission is different. Our mission is not to compete with other major pharmaceutical companies. So the targets we have do not necessarily have a large patient population. We don’t have to do an analysis about how much [money] the drug is going to make when we develop it. We are interested in just the other side ... that is, if [a drug company] doesn’t have an interest in looking at a drug in the particular area, [it’s something] we’ll be interested in. Often, diseases such as MS or ALS ... have populations that will not warrant a drug company to actively pursue a drug-discovery program because the market size is very small. For us, it’s one of our major interests to go after those diseases — of course, somebody has to be interested, either the government or academics. So our targets might not be the most popular or the best sellers that everybody is going after.

Second, a lot of our targets we do discovery for may not be related to any disease whatsoever, but it may just be linked to a very interesting pathway that eventually leads to a drug target. So it’s kind of in the early research stage. We could take an interesting target for lead discovery, but have nothing to do with it later on. We do a lot of lead-discovery chemogenomics, if you will — about [half] of our screens are related to that.

And the third difference is that in industry, you have loaded resources, but in academics, you have a very defined budget.

How do those budget constraints impact how you go about drug screening?

You have to be very creative. You evaluate all the platforms, and say: “Which platform will accomplish the same mission, but with less dollar attached to it?” So we have to do some creative thinking in that way. We should be able to save more money and do the same job that industry can do.

Why did you end up switching back to the academic side?

I think the most intriguing part for me is to be able to work with the famous researchers at Harvard Medical School. That’s the major factor that attracted me here. In terms of the compensation, we didn’t really have to step down, because this organization is kind of like a biotech of Harvard.

Are there any new initiatives coming from the lab or any notable progress in your drug discovery recently?

We have many interesting targets at this point in Huntington’s disease and ALS, and we also have a very exciting neuroprotectant, or anti-necrotic compound, that has already proven to be efficacious in animal models. So we’re very excited about those findings.

A big advantage at Harvard is that we have so many collaborations going on, that when you have something interesting in vitro, you can always find another partner or collaborator who has an appropriate animal model to test those discoveries for you.

I would also like to note that although we are working in academics, the LDDN goal is not necessarily just for publication. We also are very actively pursuing intellectual property, and gaining IP protection, so that would not be that different from industry. Of course, we could not take a compound all the way to clinical trials. We still want to be able to collaborate with a bigger biotech or pharma to go through the development stage. Our mission is just in the discovery stage, and after we’ve got an optimal candidate or lead, we’d like to partner with industry in clinical trials and the IND — it’s almost impossible for an organization like ours to take something through all the way to that stage.

 

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