December 2016/January 2017

Michael Marks, PhD, Named AAAS Fellow for Organelle Assembly Insights

story3

A brightly painted ceramic cat waving a paw, a delicate starfish, and even a shrunken head are among an eclectic collection that fills the bookshelves of cell biologist Michael Marks, PhD. Many are souvenirs given to him by postdoc and undergrad researchers who have come from all over the world to work in his lab at Children’s Hospital of Philadelphia and appreciate his boundless curiosity and sense of humor.

Dr. Marks will soon have a new treasure to display: a rosette pin awarded to him by the American Association for the Advancement of Science (AAAS) in honor of his efforts to advance science and achievement of the AAAS Fellow distinction. The AAAS is the world’s largest general scientific society, including nearly 250 affiliated societies and academies of science.

Dr. Marks, who also is a professor in the department of Pathology and Lab Medicine, and the department of Physiology at the Perelman School of Medicine at the University of Pennsylvania, has devoted two decades to figuring out the intricacies of how melanosomes and other lysosome-related organelles form within cells.

“Broadly, I am interested in how stuff moves about inside of cells and how intracellular organelles actually form,” Dr. Marks said. “I study these strange, specific organelles that are only found in certain cell types in our bodies.”

These include melanosomes that make pigment in our skin, hair, and eyes; dense granules in platelets that regulate blood clot formation; organelles within dendritic cells that regulate our immune response; and lamellar bodies in lung epithelial type II cells that release pulmonary surfactant. Failure of some or all of these four organelles’ mechanisms due to genetic defects can lead to a rare disease called Hermanksy-Pudlak syndrome (HPS) that affects one in 500,000 to 1,000,000 individuals worldwide, especially in Puerto Rico. Dr. Marks and his collaborators have gained novel understanding about how each of these cell types is affected by the gene mutations that scientists have identified as causing 10 forms of HPS.

People with HPS have problems with blood clotting and abnormally light coloring of skin, hair, and eyes. Some forms of HPS also cause scar tissue formation in the lungs, called pulmonary fibrosis, which lead to breathing problems that can contribute to individuals’ shortened lifespans of about 40 to 50 years.

Dr. Marks’ lab so far has been most successful in establishing how melanosomes are built, and it is this work that the AAAS cited as worthy of the esteemed recognition of Fellow by his peers. The 10 genes that go awry in HPS encode subunits of four protein complexes, Dr. Marks explained. Three of those complexes take proteins from endosomes, which are intermediate compartments that act as sorting stations for proteins in cells, and then target them specifically for melanosomes.

The fourth complex, as Dr. Marks and his co-authors described in an August paper published in The Journal of Cell Biology, retrieves certain proteins back from the melanosomes and returns them to the endosomes that are then required again in that forward pathway. All four of these protein complexes function in a loop between early endosomes and melanosomes to deliver cargo to and from these maturing organelles. Dr. Marks’ dissection of how melanosomes are assembled within cells is valuable knowledge that can be applied to several fronts, from basic science to potential therapies.

“First of all, we might be able to figure out through interactions between these complexes and other proteins what other diseases may be caused by the same type of problem,” Dr. Marks said. “From a biological perspective, understanding how these organelles are adapted within these different cell types for these specialized functions is also important to understand. And eventually, knowing more about how they actually function will perhaps allow us to generate some kind of drugs to fix the basic problems these kids have. It would be a big deal if we could find a way to prolong their lives.”

The next step for Dr. Marks’ lab is to better understand how well the melanocyte system models the other organelle systems involved with the manifestations of HPS. Taking a closer look at the comparative anatomy of these different organelle systems in different cell types may help to potentially explain why some HPS patients get certain types of symptoms and not others.

Dr. Marks is quick to point out that his research projects are absolutely dependent on the connections he has made with collaborators at CHOP and elsewhere. “I don’t know how to do anything in my lab anymore,” he joked, giving credit to Mortimer Poncz, MD, chief of the Division of Hematology at CHOP, for his platelet expertise; Susan Guttentag, MD, formerly of CHOP who is now at Vanderbilt University School of Medicine, for her insights into lung epithelial cells; and Graca Raposo at the Institut Curie in Paris for her electron microscopy skills, to only name a few.

Another collaborator, Edward Behrens, MD, chief of the division of Rheumatology at CHOP, brought an intriguing question to Dr. Marks in 2015. They began talking about a symptom of HPS 1 (the most common form of HPS) that has received little attention: inflammatory bowel disease (IBD).

“It turns out that no one has ever studied it, although about one-third of this subset of patients get what some papers occasionally refer to as granulomatous colitis symptoms, and nobody has any clue why that happens,” Dr. Marks said. “But I had some insight from the work that we’ve been doing in dendritic cells in one of the other HPS forms that might be relevant toward this disorder.”

Drs. Marks and Behrens came up with a plan to test patients’ dendritic cells for their response to different stimulants in terms of the innate immune functions that they illicit. Their preliminary screen of patient sera seems to support the idea that some HPS patients overproduce certain inflammatory molecules. If the researchers are on the right track, then their findings could possibly lead to adapting treatments already being used in clinical trials for other disorders to better regulate this immune response.

Finding a way to reduce the IBD symptoms that children with HPS 1 experience could be one way to help improve their quality of life. Dr. Marks shared the example of family he was introduced to at a conference of the Hermansky-Pudlak Syndrome Network (HPS Network). Their child spent more than half her life — from the age of six months to 12 years — in and out of hospitals dealing with IBD and other complications related to HPS. The HPS Network awarded Drs. Mark and Behrens a grant this summer to develop a mouse model of HPS to further investigate immune function in the gut.

“I didn’t realize how bad inflammatory bowel symptoms could be for some HPS patients,” Dr. Marks said. “When you see kids who have these problems, it really motivates you to try to come up with something that is going to help them.”

The tradition of AAAS Fellows began in 1874, according to a press release in November announcing the 391 members who were awarded this honor in 2016. Dr. Marks will join this prestigious group at the AAAS Annual Meeting in Boston that will be held in February. They will be presented with official certificates and gold and blue rosette pins, representing science and engineering, respectively.

Share This

Print