As reported by the Danbury News-Times, December 5, 2009.

Stem Cell Research Shows Promise in State

By John Burgeson

It happens a million times a minute in just about every animal species on the planet, from flatworms to humans.

Sperm meets egg. Cells divide. Soon, an embryo appears.

This process, common to all animal life, would stop dead in its tracks if it were not for stem cells, the cells that give rise to the millions of different types of cells that we're made out of. Muscle, nerve, skin and blood cells are a few of the major divisions, and there can be many subdivisions within each of those major tissue types.

In all, there are about 220 major cell types in the human body.

There are dozens of scientists in Connecticut who are part of a global effort to unlock the secrets of the stem cell, research that could lead to breakthroughs such as a vaccine for cancer and cures for other costly, debilitating diseases including Parkinson's, amyotrophic lateral sclerosis, spinal cord injury, burns, heart disease, diabetes and arthritis. In 2005, the state allocated $100 million over 10 years for the study of stem cells. Nearly all of this money has been, or will be, allocated to one of the three research centers: Yale University, the University of Connecticut and Wesleyan University.

In theory, every living cell in your body contains all of the genetic material needed to make a clone of yourself. (Humans, along with most other mammals, have about 25,000 genes. In humans, they're located on our 46 chromosomes, arranged in 23 pairs.)

But in practice, this can't be done, because once a cell becomes specialized, most of its genes are deactivated. That's where stem cells come in.

In Haifan Lin, Ph.D.'s lab on the third floor of Yale's Amistad building, most of the research is being carried out on the stem cells of fruit flies, Drosophila melanogaster. There are several reasons for this. For starters, humans, it turns out, have a lot in common with fruit flies, with a surprising amount of genetic material that's identical.

"Humans and flies are actually very, very similar --it's just that there's less of everything in a fly," Lin said, who's been researching stem cells since 1994.

Secondly, the flies are cheap and easy to care for, and their DNA is less complex than that of a mammal's. "We have 600 different fly mutants," Lin said, with some degree of pride.

Thirdly, there are few ethical issues attached to an insect with a life span of about a month, and which seems happy to live in the lab, feeding on yeast. Even with mice, researchers have to follow strict ethical protocols.

"Stem cells have two jobs," Lin said. "The first is to make a lot of specialized cells. The other is to maintain themselves."

To accomplish this, stem cells have to undergo asymmetrical division. "When stem cells divide, one copy is the specialized cell, and the other is an exact copy of itself."

Lin said that it's this asymmetrical division that's central to stem cell survival. To accomplish this, all stem cells -- whether human or fly -- have what is called piwi/Argonaute genes. "These genes are key to stem cell self-renewal," Lin said. "We also discovered that these genes also work in the neighboring stem cells, too. So, it's the micro-environment that provides instructive cues to the stem cells -- kind of like 'it takes a village to raise a child.' They listen to their neighboring cells, which are called niche cells."

Lin's latest research concerns piwi-interactive RNA, tiny snippets of stem cell RNA, or ribonucleic acid, that aren't involved in protein-building, unlike most RNA. Rather, they regulate the activity of the DNA.

"We discovered that there are 60,000 of the different types of piwi-interactive RNA that control the 'landscape' of the DNA. These little guys control where the mountains should be, where the rivers should be," Lin said. "And if you don't have a landscape, you're in trouble."

He said understanding these tiny bits of piwi-interactive RNA -- which are as small as any biological unit can possibly get -- will serve to solve "the puzzles we have in medicine -- such as what is the cause of cancer."

Once these puzzle are solved -- or even better-understood -- at the Drosophila level, then this knowledge will be applied to mice, and eventually to humans, Lin said.

As for the progress of Yale's research, Lin said that other universities are envious. "The University of Massachusetts says, 'We've spent $1 billion in this, and you've done more with $100 million."

At the University of Connecticut Health Center, Dr. Ren-He Xu is developing what is known as induced pluripotent human stem cells, or iPS cells, which behave just like blastocyst stem cells. These are the cells that give rise to all of the specialized cell in the body.

Xu has developed four human pluripotent stem cell lines, two of which have been submitted for approval to the National Institute of Health.

"If approved, they will be able to be used for any federally funded research project. This would be significant, because there are only two other existing stem cell lines available to federally funded researchers in the United States.

Xi's lab also trains both researchers and lab workers from other universities on the lab techniques required for stem cell research; 114 have been trained thus far, he said.

"Not all of this research will lead to cells that we can implant to cure, say spinal cord injuries," Xu said. "Some may be used to develop patient-specific drugs to treat heart problems, for example."

This is the future of medical treatment -- individual medicine, he said.

"In the future, you'll see your doctor with your entire genome on a flash drive," he said, "and the doctor will be able to see your diseased genes and also determine which drugs will work best."

The work can be frustrating, Xu said. "It's very easy for stem cells to differentiate, and when that happens, they're no longer stem cells. You have to keep weeding out the differentiated cells."

Xu shares lab space with Dr. Zihai Li, who is pursuing what might be the Holy Grail of medical research -- using stem cells to develop a vaccine against cancer.

"The idea of a vaccine for cancer is not new," he said. "For decades, people have considered the possibility that it's the body's immune system that's keeping the cancer in check. For years we knew that there are some people who smoked, but who never contracted lung cancer. The question is 'why?' "

He said that it's the same idea as vaccinating against the flu.

"Can this be true for cancer?" Li asked. "In the 1940s and '50s, people experimented with vaccine animals against cancer. The dream is that one day, you'll get a shot in your arm, and you'll forever be prevented from getting cancer. The question is: 'How we're going to do it?'"

He said that cancer cells and stem cells, it turns out, have a lot in common. Both undergo asymmetrical division. Both can grow indefinitely. Both can differentiate into other kinds of cells. And both can express what's known as embryonic molecules.

Human tests might be years away, but his experiments in mice look very encouraging. Li's team inoculated two mice with colon cancer tumor cells. One was then inoculated with the human stem cells and remained healthy. The other one developed a large tumor, and had to be euthanized.

"The results were quite astonishing," Li said. "We're still trying to figure out what the molecules are that trigger this immune response."

He added that human stem cells were used in the experiment because mouse and human stem cells are "virtually the same."

This turns out to be another great advantage in using stem cells in medical research ---- there's no reason why a singe stem cell line can't be used for the entire human race. "You don't have to develop a different stem cell line for each person," he said.