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Nicholas Tonks

Zhe Qian

By Daniel Dunaief

Addition and subtraction aren’t just important during elementary school math class or to help prepare tax returns.

As it turns out, they are also important in the molecular biological world of healthy or diseased cells.

Some diseases add or subtract methyl groups, with a chemical formula of CH3, or phosphate groups, which has a phosphorous molecule attached to four oxygen molecules.

Nicholas Tonks. Photo courtesy of CSHL

Adding or taking away these groups can contribute to the progression of a disease that can mean the difference between sitting comfortably and watching a child’s performance of The Wizard of Oz or sitting in a hospital oncology unit, waiting for treatment for cancer.

Given the importance of these units, which can affect the function of cells, researchers have spent considerable time studying enzymes such as kinases, which add phosphates to proteins.

Protein tyrosine phosphatases, which Professor Nicholas Tonks at Cold Spring Harbor Laboratory purified when he was a postdoctoral researcher, removes these phosphate groups.

Recent PhD graduate Zhe Qian, who conducted research for six years in Tonks’s lab while a student at Stony Brook University, published a paper in the journal Genes & Development demonstrating how an antibody that interferes with a specific type of protein tyrosine phosphatase called PTPRD alters the way breast cancer spreads in cell cultures.

“The PTPs are important regulators of the process of signal transduction — the mechanisms by which cells respond to changes in their environment,” explained Tonks. “Disruption of these signal transduction mechanisms frequently underlies human disease.”

To be sure, Tonks cautioned that the study, which provides a proof of concept for the use of antibodies to manipulate signaling output in a cancer cell, is a long way from providing another tool to combat the development or spread of breast cancer.

The research, which formed the basis for Qian’s PhD project, offers an encouraging start on which to add more information.

Blocking the receptor

Qian, who goes by the name “Changer,” suggested that developing a compound or small molecule to inhibit or target the receptor for this enzyme was difficult, which is “why we chose to use an antibody-based method,” he said.

By tying up a receptor on the outside of the cell membrane, the antibody also doesn’t need to enter the cell to reach its target.

The Antibody Shared Resource, led by Research Associate Professor Johannes Yeh, created antibodies to this particular receptor. Yeh created an antibody is shaped like a Y, with two arms with specific attachments for the PTPD receptor.

Once the antibody attaches, it grabs two of these receptors at the same time, causing a dimerization of the protein. Binding to these proteins causes them to lose their functionality and, ultimately, destroys them.

Cell cultures of breast cancer treated with this antibody became less invasive.

Limited presence

One of the potential complications of finding a new target for any treatment is the side effects from such an approach.

If, for example, these receptors also had normal metabolic functions in a healthy cell, inhibiting or killing those receptors could create problematic side effect.

In this case, however,  the targeted receptor is expressed in the spine and the brain. Antibodies normally don’t cross the blood-brain barrier.

Qian and Tonks don’t know if the antibody would affect the normal function of the brain. Further research would help address this and other questions.

Additionally, as with any possible treatment, future research would also need to address whether cancer cells developed resistance to such an approach.

In the time frame Qian explored, the cells in culture didn’t become resistant.

If the potential therapeutic use of this antibody becomes viable, future researchers and clinicians might combine several treatments to develop ways to contain breast cancer.

Eureka moment

In his research, Qian studied the effect of these antibodies on fixed cell, which are dead but still have the biochemical features of a living cell He also studied living cells.

When the antibody attaches to the receptor, it becomes visible through a staining process. Most antibody candidates stain living cells. Only the successful one showed loss-of-signal in living staining.

The antibody Qian used not only limited the ability of the receptor to send a signal, but also killed the receptor. The important moment in his research occurred when he discovered the antibody suppressed cancer cell invasion in cell culture.

Outside of the lab, Qian enjoys swimming, which he does between four and five times per week. Indeed, he combined his athletic and professional pursuits when he recently raised funds for Swim Across America.

“I not only want to do research, but I also want to call more attention to cancer research in the public,” said Qian.

The Swim Across America slogan suggests that each stroke is for someone who “couldn’t be with us” because of cancer. In the lab, Qian thinks each time he pipettes liquids during one of his many experiments it is for someone who couldn’t make it as well.

Qian, who currently lives in Hicksville, grew up in Suchow City, which is a village west of Shanghai and where Cold Spring Harbor Asia is located. 

Qian has been living on Long Island since he arrived in the United States. Qian graduated from Stony Brook University in October and is currently looking for a job in industry.

Looking back, Qian is pleased with the work he’s done and the contribution he’s made to breast cancer research. He believes the antibody approach offers a viable alternative or complement to searching for small molecules that could target or inhibit proteins or enzymes important in the development of cancer.

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Chelsea Coenraads photo from Monica Coenraads

Chelsea Coenraads speaks through her eyes. She shows her family how much she loves them with slight changes in her expression. Her family “tries to get her to smile all the time, because her smile can make the darkest situations be okay,” said her mother, Monica Coenraads.

At 18 years old, Chelsea, who lives with her parents in Trumbull, Connecticut, has spoken only one word, when she was a toddler, “duck.” Carrying a disorder that occurs in one out of every 10,000 live female births, Chelsea has Rett Syndrome. Under constant supervision, she has no hand function, spends her days in a wheelchair and is fed through a feeding tube.

But, “she’s so much more than her laundry list of symptoms,” her mother said.

Recently, Monica Coenraads, who cofounded the Rett Syndrome Research Trust, became aware of research at Cold Spring Harbor Laboratory. Professor Nicholas Tonks and his postdoctoral student, Navasona Krishnan, published a study in the Journal of Clinical Investigation in which they inhibited an enzyme Tonks called PTP1B, for protein tyrosine phosphatase.

Tonks and Krishnan demonstrated that male mice with a disorder that comes from an X-linked mutation in a gene called MECP2 lived 75 days, compared with the typical 50 days without the inhibitor. Meanwhile, female mice stopped doing paw gestures that are a model for hand gestures often encountered in patients with Rett.

“We now have a new tool for manipulating a molecular signaling pathway which we already know is deficient in mice models of Rett Syndrome and, we believe, in human patients as well,” said David Katz, a professor of Neuroscience and Psychiatry at Case Western Reserve University School of Medicine who has spent more than a decade studying Rett. Katz started collaborating with Tonks last month.

Professor Nicholas Tonks photo from CSHL
Professor Nicholas Tonks photo from CSHL

“We believe there are multiple pathways that make promising targets for drug therapy,” said Katz, who completed his Ph.D. at Stony Brook in 1981. By combining a series of treatments, scientists and doctors might be able to offer those with Rett Syndrome a drug cocktail, Katz suggested.

Tonks cautioned that the results are an encouraging step, but there is considerable work to do before this promising result can lead to a possible therapy.

“We are a long way from a treatment for the disease,” Tonks said “A lot more work needs to be done to define more precisely how inhibiting PTP1B would impact Rett patients.”

Tonks’ interest in Rett Syndrome started a few years ago, when Krishnan attended a lecture from another postdoc at Cold Spring Harbor Laboratory.

Krishnan “proposed the experiments in the first place,” Tonks said. “He is responsible for performing the studies.” Tonks credited the other co-authors on the paper for making important contributions, including Keerthi Krishnan, who gave the lecture several years ago that triggered Tonks’s interest. Keerthi and Navasona are not related.

The inhibitor used in these studies was something Tonks and his partners developed several years ago to treat diabetes and obesity at a company called CEPTYR Inc. that has since halted its operations.

As the first to purify protein tyrosine phosphatase, Tonks has generated interest in this family of about 100 proteins among other scientists.

“Before [Tonks’s] initial work, the nature of the enzymes that took phosphates off was obscure,” explained Dr. Benjamin Neel, director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center.

Neel, who described Tonks’ reputation as “stellar,” was a postdoc when Tonks purified the first member of this family. “When I saw that paper, I immediately decided this was going to be a major area and I needed to work on it.”

Tonks, who was born and raised in the United Kingdom, came to the United States to work with the pioneers in the signaling field, he said.

Tonks is married to Catriona Simpson, who also has a Ph.D. in biochemistry and works at Cold Spring Harbor Laboratory as an editor. The couple, who live in Huntington, have a 23-year old daughter, Clare, who is getting her master’s degree at Columbia University in English and History, a 19-year old son, Nicholas, who is interested in aviation management, and a 16-year old daughter, Caroline, who wants to become a ballet dancer.

Tonks expressed cautious optimism that he, Krishnan and his lab could help make a difference for the lives of people with Rett Syndrome.

Katz shared a quote from Andreas Rett, a physician from Vienna, Austria, who first recognized the disease.

“Their eyes are trying to tell me something,” Rett said. “I just don’t know what it is.” Katz said that is one of the factors that inspires him to search for effective treatments.

Those would like to learn more about Rett, or donate to research, can do so through www.rsrt.org.