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Rong Wang on Establishing a Proteomics Center at New York s Mt. Sinai

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At A Glance

Name: Rong Wang

Position: Associate professor, Mount Sinai School of Medicine’s Department of Human Genetics

Background: Research associate and associate professor, Rockefeller University’s Laboratory of Mass Spectrometry, 1992-2001.

PhD, Johns Hopkins University’s Department of Cellular and Molecular Biology, 1992.

 

How did you get into proteomics?

I got my PhD [at] Johns Hopkins. My thesis advisor was Bob Carter; he’s a professor in the pharmacology department working on mass spectrometry. We had the opportunity back then to explore mass spectrometry in biological applications. I worked on mass spectrometry back in 1984 in Beijing, working in the Beijing Medical Center. We got some kind of money from the World Bank and we imported a couple of mass spectrometers. Then we started working on peptides. Part of my mass spectrometry techniques I learned from Beijing, but most of the biochemistry applications [were] from when I did my PhD at Johns Hopkins from 1986 to 1992.

What did you study during your time with Carter?

What I did is, using mass spec, I developed methodologies to study phosphorylated molecules. And I was still very interested in biological applications to mass spec and that’s how I got into Alzheimer’s disease. Back then, working in the Johns Hopkins department of pathology, they carried out a lot of Alzheimer’s disease research, so one day we started talking. Back then, the people still didn’t know how APP, one of the proteins involved in Alzheimer’s disease, was processed. We said maybe we can use mass spec to solve this problem. So then I spent more time on that type of research rather than pure development of methodology. Bob Carter was a very good supervisor — he gave a lot of freedom to allow me to do this.

What did you do after you graduated from Hopkins?

After I graduated from Johns Hopkins, I decided to come to Brian Chait’s lab at Rockefeller University. That was back in 1992. I put aside Alzheimer’s disease during my postdoc. In Brian’s mind, we thought we should use the mass spec to sequence peptides rather than proteins. So then we together developed a technique called protein ladder sequencing. That work was published in Science. Since mass spec can give you very precise measurement for molecular weight, we looked for a way to create a peptide ladder. What we did is we modified the ion degradation chemistry to create sequential cleavage of peptides. Each one was different by one amino acid. So in this way, any of the peptides we have, we can create a mixture of peptides, one shorter than the other. Then we use the mass spec to measure the molecular weight. From the mass difference, we can identify the sequence of the protein and peptide. It’s quite different from what you do today because back then there was no database. We published the paper in 1994, a couple of years before the so-called proteomics approach came out.

After that, I was promoted as an assistant professor in 1994. Then I decided to come back to Alzheimer’s disease research. We focused on amyloid peptide degredation and also on characterizing all the isoforms of the amyloid peptide associated with other genetic mutations associated with Alzheimer’s disease. Later, in almost 1999 or 2000, we started to explore whether we can use a proteomics approach to study Alzheimer’s disease. We are still in the stage of finding better methodologies. I’m very interested in biomarker discovery, especially for early stages of Alzheimer’s disease, but this requires that we have reliable methodologies, especially for the so-called proteomics approach to study plasma. That’s why I participate in the HUPO Plasma Project, to try to find out a better methodology.

What have you found using mass spec to study Alzheimer’s disease?

On one side, we’re taking the approach to study protein-protein interaction using mass spec. So we started protein interaction studies to APP, the amyloid precursor protein. Last year we found one new protein that we only briefly reported in Science. We are now currently doing all the characterization to find out what is the function. This one we have not fully reported yet — it doesn’t have a name or a gene number. Based on the information we have now, it seems like the protein is associated with protein trafficking.

How did you find that protein?

We took the approach using the C-terminal fragment construct as a fish hook to see what protein is associated with the C-terminal fragment. When we isolate the protein complex on a gel, we cut out the band from the gel, then we identify by mass spec and database search.

Do you think it could be a diagnostic marker?

I don’t know yet. Really what we’re trying to do now is to understand the function.

How about the plasma project? How far along is the Alzheimer’s biomarker research?

I’m very happy with the plasma results. In terms of the HUPO project, the methodology that we used is quite reliable. The last time when we did the experiment, one of the proteins we found was in the picogram range. I’m very happy with the sensitivity and the detection dynamic range. I’ve already scheduled a meeting with Richard Mayeux — he’s the associate director of the Alzheimer’s Disease Research Center of Columbia University. We’re going to sit together and see how we can work together to analyze the plasma specimens he collected in his Alzheimer’s disease research.

What other things are you working on at the moment?

After I left Rockefeller back in 2001, I’m at Mount Sinai now, and we’re trying to establish a Sinai center on genomics and proteomics. We’re trying to work with a couple of departments together to make that happen at our university here. This center will include functional genomics, proteomics, and bioinformatics.

What are some of the problems the center is going to work on?

We’re trying to create two sides to the center. One side will be clinical, human disease-oriented research, so we’ll be looking at several diseases which is part of ongoing research at Mt. Sinai. The other side will focus on making the infrastructure to provide technology service to Mt. Sinai and perhaps other institutions. One thing that we have that’s ongoing is drug abuse. That’s a collaborative effort with another professor in Mt. Sinai. Basically we’re using animals to see how morphine treatment can cause long-term change in the brain. That’s using a proteomics approach. What we do is isolate a post-synaptic vesicle and a pre-synaptic vesicle and we see what is the protein change using quantitative methods, for example the ICAT or other reagents that are now available.

What other problems are you working on?

Another [study] we just published is on lipid droplet proteomics. We characterized lipid droplets isolated from an adipocyte under basal conditions and stimulated conditions. Then we characterized what is the protein change associated with the stimulated condition. Once your body needs to utilize energy, the a hormone will switch on the fat cell’s kinase and start a signal transduction cascade, and start the conversion of triglycerides. So during this process, the lipid droplet morphology also changes. They go from big to much smaller fragmented droplets. We think that we should be able to understand more once we characterize what are all the proteins involved in the lipid droplet at the [stimulated] stage. That work came out pretty good. Last month that paper was in the Journal of Biological Chemistry was the 13th most read paper.

Did you find some significant proteins that are involved in lipid metabolism?

We found a couple of them. One is called CGI-58 — this one is now under investigation by my collaborators at Rutgers University. That protein has been reported associated with a clinical dysfunction — patients that have a certain mutation have a lack of fat storage under the skin, and the skin becomes very dry. The name of the disease is Chanarin-Dorfman syndrome. People knew from the sequence that the disorder is probably with some kind of lipid hydrolysis activity, but they never knew what [the disorder entailed.] So we made this connection, which is pretty exciting. Also, there were a couple of other proteins.

What other things are you working on?

For cancer, we did a small piece of work — we tried to do some biomarker discovery. We looked at a bunch of plasma samples. There’s another professor at Mt. Sinai, John Roboz, and in his group he has a SELDI mass spectrometer. He first screened I don’t know how many tens of patient specimens, and he found that there was one peak that very specifically increased that was associated with colon cancer. But we didn’t know what it is. So we took the approach that we isolated the protein and identified what it is — it’s called Complimentary Factor 3 in a modified form. That protein is increased in patients with colon cancer.

Do you think that might be carried out into clinical studies?

We don’t know yet. It’s uncertain how specific that protein is. The Complimentary Factor 3 gene is associated with many diseases.

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