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No Stone Unturned

To neuroscientist Dr. Gregory Petsko, Alzheimer's disease is nothing short of a looming national catastrophe. A renowned scientist who's dedicated the latter part of his career to investigating the disease's molecular underpinnings and devising new treatments for it, Dr. Petsko hopes to make even greater inroads against this devastating neurodegenerative condition as the new director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medical College. We sat down with Dr. Petsko to learn about his new role, how he envisions the institute leading the charge in Alzheimer's research, and why he's sounding the alarm about an impending disaster.

Dr. Gregory Petsko
All photos: Carlos Rene Perez

Q.: Congratulations on your new role as director of the Appel Alzheimer's Disease Research Institute. What attracted you to this position?

Dr. Petsko: Thank you. Steve Paul, the inaugural director who just stepped down, did a wonderful job establishing the institute and handed it over to me in great shape.

I have to confess: There are relatively few administrative-type jobs that I would take at this time in my life. But this one I couldn't refuse, not only because of my wanting to do something about this disease, but also because of the enormous respect and affection I have for Helen and Bob Appel.

I think this is a great opportunity, for two reasons. For one, it allows me to encourage a specific kind of research on Alzheimer's disease and other dementias that I think needs encouragement. And second, I hope to use it as a bully pulpit to alert the public to the enormous potential problem that we face with an aging population and a growth of neurodegenerative diseases in general and Alzheimer's disease in particular.

Q.: How is Alzheimer's disease, as you've described it, a comet hurtling toward Earth?

Dr. Petsko: There are more than 5 million people in the United States with Alzheimer's disease today. By 2050, that number will exceed the population of Illinois. The cost to the health care system alone will be a trillion dollars for this one disease, which will bankrupt it. For every one person with Alzheimer's disease, there are three caregivers, most of whom are family members, so the burden of disease is much greater than just the afflicted.

My father once said to me, 'You couldn't understand Russia in the Cold War until you understood that statistically, just about everybody in Russia lost a family member in World War II, and that colored their lives for the next generation and more.' Well, by the middle of this century, roughly every family in America will be affected, directly or indirectly, by Alzheimer's disease.

Q.: What are we doing to prevent this looming disaster?

Dr. Petsko: We're not doing enough. This disease is by some measures the third leading cause of death in this country — certainly one of the top five — and the only one of the top 10 for which there is no treatment. Given all those facts, you would think we'd be throwing every resource we have at it. Despite the fact that President Obama was smart and generous enough to increase the funding for Alzheimer's research, we're only spending about $500 million a year on this research. To make a dent in this disease, that spending needs to be four, maybe five times higher. That's the kind of funding that has made AIDS a disease you can live with, and that has led to finding cures for many different kinds of cancers.

The private sector has stepped up to the plate quite a bit, and the good news about the private sector — which includes donors like the Appels as well as foundations — is that they tend to fund riskier things, more outside-the-box approaches, and we need a lot more of that thinking on this disease and related forms of dementia.

Dr. Petsko

Q.: Why has it been so difficult to make inroads on Alzheimer's medically?

Dr. Petsko: For one thing, it's tough to get a good animal model for this disease; mice don't live 65 years. A second problem, believe it or not, is that it wasn't terribly clear until a few decades ago that this was really a disease. People were taught to just assume that you got senile when you get old, that it was inevitable. We now know from a variety of studies that there is a big difference between normal aging and Alzheimer's disease. And if it's a disease, that means it can be prevented and treated.

Q.: Is there anything the institute will do under your direction to better visualize Alzheimer's disease in lieu of animal models?

Dr. Petsko: I'm hoping we can lead a trend to develop better models by using human patient-derived neurons and not rely very much on animal models at all. Obviously, you can't just go into someone's brain and take out neurons. But what you can do — thanks to new technology developed a few years ago — is take a skin sample of someone with Alzheimer's disease, and by a series of elaborate steps, you can turn that into a neuron. We think these may be better models for understanding the disease, as well as for the initial development of targets and therapeutic approaches.

Q.: Your research focuses on the role of enzymes in the development of Alzheimer's disease. What are you learning and can you apply your research to new therapeutics?

Dr. Petsko: That's one focus, yes, though not the only one. It's pretty clear from human genetics that the processing of a protein called APP by a set of enzymes is important for the development of Alzheimer's disease. Exactly the role this processing plays is not clear. There are efforts on the way from pharmaceutical companies to block the action of those enzymes as a treatment for the disease. That might work — I hope it does for the sake of AD patients, but I have grave doubts — these enzymes have other important functions.

We took a different approach. With our collaborators, we asked, 'Where does this process occur? Where does APP encounter the enzymes that cut it?' The answer is that it happens in a very specific sub-compartment of the cell, which is called the endosome. The endosome is an organelle inside all the cells in your body. And endosomal dysfunction is a very early event in Alzheimer's disease. We have used this insight to develop a therapeutic strategy directed at fixing the problems with the endosome, so that APP processing will be reduced. Whether that will turn out to be therapeutic or not, I don't know. But what we do know is that this approach is potentially very powerful. It's not worrying about what the precise toxic species is that's leading to the death of neurons. It's asking: 'What's the cellular defect? And can we correct the cellular defect?'

I like that approach because it's not about inhibiting anything. That doesn't mean it'll work, but it shows that if you understand the processes taking place in the cell and what they do, it can give you ideas for therapy that you might not otherwise have.

Q.: Is that one of your goals at the institute, to foster a greater understanding of the fundamental cellular processes and translate results into new therapeutics?

Dr. Petsko: That's exactly what we're trying to do. I'd like to have faculty members in the institute who are gaining similar insights into Alzheimer's and other forms of dementia by trying to understand these things at a fundamental level, and then translating that fundamental understanding into new targets and new ideas for treatment.

Q.: You recently chaired the Appel Alzheimer's Disease Research Institute Symposium, and you'll give a plenary talk at the upcoming Leon Levy Neuroscience Symposium. Why are symposia like these important?

Dr. Petsko: There's no substitute for face-to-face interaction. You get ideas from just talking to people over coffee or dinner that you'd never get just reading their papers. The directors of our counterpart institutes — Scott Small at Columbia University College of Physicians & Surgeons and Sam Gandy at the Icahn School of Medicine at Mount Sinai — and I have all published papers together. We all know each other on a personal level. We should be able to take advantage of those kinds of relationships to make New York a central place for neurodegenerative disease research … and build cross-institute collaborations.

Q.: You've given a TED talk and are an outspoken proponent of the humanities as a means to better understand science. Why is it important to make science meaningful beyond academia?

 Dr. Petsko: Most of my best ideas have come about while I'm doing things that have nothing to do with science, and from insights that I've gotten from subjects far removed from science, like the humanities, the arts and occasionally the social sciences. It's by building analogies between things in those disciplines and what I'm trying to do in science that I've made my biggest creative leaps.

I think the humanities are really good for the creative imagination of a scientist. I think they also make a scientist a hell of a lot more interesting a human being. They facilitate your ability to communicate with lay people and having a more rounded life.

Q.: You come here from Boston. How are you finding New York City as a place to practice science?

Dr. Petsko: I'm taking a certain perverse delight in the struggle of New York sports teams — the element of Schadenfreude is not to be discounted [laughs]. But I do I think people from outside New York have a very clear, strong viewpoint about New York City: that it is a place where people are aggressive, rude and unfriendly. Nothing could be further from the truth. I have been astonished and delighted by how warm and friendly this place is. There's a camaraderie here, a feeling that we're all in this together and we need to look after each other and help each other.

That means that New York is a place where we can bring people together from different institutions and establish a powerhouse city for brain disease research. New York City is also the greatest center for private philanthropy in the world. In New York, we have the opportunity to be bold, to do stuff that's outside the box and to take big risks knowing that we can find people to help us do that.

Posted April 16, 2014 2:26 PM | Permalink to this post

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