Yale Professor Aims To Control Master Switch

The Hartford Courant

Growing up in China, Jun Lu might have pursued a career in math if his father, a mathematician, hadn't advised against it.

His reasoning: Math can be done with little more than a pen, paper and your mind. For 2,000 years, thinkers have had those tools to contemplate the questions of mathematics. "Any questions left behind by them are probably very hard to address," Lu said.

But biology, his father said, capitalized on advances in technology. His son could have the chance to explore a new frontier.

Lu followed his father's advice and has found himself at the cutting edge of science, grappling with questions that might have been unimaginable a generation ago. At the moment, he's studying tiny but powerful molecules that have given researchers a new understanding of biology and could lead scientists to better make sense of cancer - possibly even cure it.

A professor of genetics at Yale University, Lu is one of dozens of Connecticut scientists exploring stem cells, unspecialized cells with unique regenerative abilities. Stem cell research is an emerging field that scientists believe may hold the key to curing a host of diseases.

With federal funding for most stem cell research limited until earlier this year, Connecticut leaders tried to give the state a leg up by funding millions of dollars in research grants since 2006. Scientists at Yale, UConn and Wesleyan University are now at work on projects aimed at repairing damaged bones, creating neurons to treat epilepsy, helping the body repair itself after a heart attack and a range of other innovations.

Lu is among the scientists pursuing another promising area of stem cell research, exploring the links between stem cells and cancer.


Scientists' understanding of cancer has changed in the past few decades, but the way it is treated has largely followed the same premise: kill as many cancer cells as possible.

Haifan Lin, the director of the Yale Stem Cell Center, describes one of the major forms of treatment this way: If the cancer cells are terrorists scattered around a city, chemotherapy tries to eliminate them by bombing the whole city.

But what if you could weed them out systematically, separating dangerous people - or cancer cells - from the others and targeting only those that cause harm?

Hope for that method of treatment is related to a relatively new premise, that maybe not all tumor cells are the same. Instead, in some cancers, a smaller group of the cancer cells control the action, creating new tumor cells and acting like generals commanding an army.The bulk of the cancer cells do the work of soldiers, but getting rid of them won't end the attack.

That idea came from work on acute myeloid leukemia, a fast-progressing cancer of the blood and bone marrow. Researchers found that the cancer cells could be divided into two types. One group of cells produced leukemia when injected into a mouse. Cells from the other group generally could not. Researchers have found similar characteristics in other cancers, including breast cancer.

That suggests that the key to treating those cancers wouldn't be to kill every cancer cell. It would be to target the specific controlling cells - called cancer stem cells - as if pulling out a weed by its roots.

Lu has long been convinced of the link between cancer and stem cells. Both cancer cells and stem cells are capable of replicating themselves, and he believes understanding the similarities and differences between stem cells and cancer cells could offer insights into cancer, maybe even a window to exploit to kill it.


Lu's work lies at the intersection of cancer and another major change in scientific thinking involving tiny molecules that play a major role in regulating our genetics - and possibly cancer, too.

The regulators are called micro RNA, molecules that are tiny but immensely powerful, performing vital work in human bodies. It has only been in the past decade that scientists recognized how important they are.

Before that, it was widely known that the blueprint for human life exists in our DNA, which expresses itself through our genes. Many scientists believed decoding the human genome would reveal all the genes that control us - perhaps 100,000 key genes.

But after the project was completed in 2003, scientists were startled to discover that we seem to have just 30,000 or fewer key genes, far fewer than researchers had believed and barely more than a roundworm, a species that is dramatically less complex than we are. How could that be?

The answer: There is more to controlling us than just those genes. That's where micro RNA comes in. It decides which genes are turned on and which are not, which of our genetic blueprints get built and which ones stay rolled up on the shelf. Lin calls micro RNA molecules "the masters of the masters." So, if the genes are the masters of a person's development, micro RNA molecules are the master switches to a person's genetics.

And Lu thinks they may be the master switches for cancer, too. He is examining the theory that cancer is caused by something going wrong with micro RNA molecules, the master switches that control our genes.

Here's how it might work: We all have genes called tumor suppressor genes, which stop cells from dividing and do other things to stop cancer formation. We also have genes that, when mutated, can turn normal cells into cancer cells.

But what if the micro RNA that keeps the cancer cell-causing genes in check mutates and stops working? Or if the micro RNA that turns on the tumor-stopping genes malfunctions or gets deleted? If something goes wrong with the things meant to regulate cancer, the theory goes, cancer could take advantage of it and develop.

Studies seem to support that idea. Micro RNA appears in samples taken from both cancerous and noncancerous tissue, but it appears differently. In some cases, there might be higher levels of micro RNA in the cancer tissue - the result, perhaps, of a mutation that causes too many micro RNA molecules to show up - but lower levels in normal tissue.

Other times the micro RNA might be absent in the cancer tissue but present in normal tissue.

Understanding the role micro RNA plays in cancer could point scientists to ways to combat it. If they can determine that mutations of a specific micro RNA leads certain genes to be turned on abnormally and lead to cancer, they could develop therapies aimed at stopping the mutated micro RNA from acting, preventing it from spurring the gene that produces cancer.

That means they must learn which genes could lead to cancer, and which micro RNA molecules control them. Lu's lab is exploring those questions in a number of ways. The researchers put different genes into mouse bone marrow cells, then implant them into mice and see if tumors or leukemia develop. It is far too early to consider the work on humans, but they are planning to try a similar experiment using human cells and a special breed of mice that can tolerate human cells.

The ultimate goal of Lu's work, like much of stem cell research, is likely years away. But as he works, Lu is proving his father's advice, addressing questions that could not have even been fathomed a generation, much less thousands of years, ago.

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