Step One Toward an ML4 Cure: Infect a Mouse

A visit with National Institutes of Mental Health geneticist/rodentologist James Pickel

By Sara Rubin

Published August 25, 2006, issue of August 25, 2006.
  • Print
  • Share Share

To the untrained eye, the basement-level laboratory at the National Institutes of Mental Health, in Bethesda, Md., looks like a scene out of NASA. Scientists sport full-body plastic suits, hair nets and blue booties — all in an effort to keep the outside world’s contaminations at bay.

The lab’s sterility is interrupted only by Dr. James Pickel’s gregariousness. Pickel is the director of the Transgenic Core at NIMH, home to thousands of experimental mice. He is so enthusiastic, so good-humored, it’s sometimes difficult to tell that he is working on gravely serious illnesses.

Pickel spends 80% of his time doing research decided by the higher-ups at the National Institutes of Health, he said. Right now that means using bone-marrow cells to help heart attack patients redevelop heart muscle. The remaining 20% he can devote to projects of his own choosing. With this time Pickel tends to investigate rare diseases that typically receive limited funds for research, and at the forefront of his lab’s work today is creating a mouse model for mucolipidosis type IV (ML4), a disease characterized by the deficiency of a protein that plays a crucial role in psychomotor development. One in 100 Ashkenazic Jews is a carrier.

Pickel and the others in his lab work on the basic science of creating a genetic model. His task is to produce symptomatic mice. It will fall to others to develop a treatment. The process begins when Pickel’s team extracts embryonic stem cells — those that are still undifferentiated and can become any type of tissue — from a mouse uterus and allows them to multiply in petri dishes. The stem cells are coded with a protein that will look green under blue light, making them easier to track.

It is in these embryonic stem cells that the process of creating the transgene occurs. This has been Pickel’s major achievement with ML4; he has successfully cut and pasted to create recombined DNA that carries the ML4 gene.

The recombined stem cells are then injected into a mouse embryo (harvested from a donor female), giving them an environment in which they will ultimately multiply and specialize into tissues. The embryo containing the recombined DNA is called a chimera. Females are mated with vasectomized males. After copulation, female rodents, even if they do not become pregnant, behave as if they were; such females are called pseudopregnant. The chimeric cells are injected into the pseudopregnant female, who will act as a surrogate mother. This allows Pickel to eliminate interference from the male’s or surrogate mother’s genetic makeup, ensuring that the mice are chimeras, formed from the embryonic stem cells and host embryo.

The genome of the engineered mice can be seen when their tails are snipped off and put in vials to dissolve. From the dissolved tail the scientists can check for the presence of the ML4 gene.

Pickel looks at the mice using goggles that shine a blue light on them, and fluorescent green coloration appears in their ears, feet and tails (or everywhere in an albino mouse). This marker color shows that the targeted stem cells have incorporated themselves into the mouse’s body. The successful offspring — green on the inside, brown on the outside — are chimeras, and will be mated to produce a fleet of mice with the appropriate genetics for study, called “knockout” mice since the original gene is entirely absent.

Pickel took apparent pleasure in showing his lab to a recent visitor. In layman’s terms, he explained the function of each piece of equipment. Cell injectors, he said, cost about “a car apiece.” Of another gadget he said, “it used to look like scientific equipment; now it looks like something in your kitchen.”

In a way, Pickel’s mouse-making role resembles a step along an assembly line, but there is nothing impersonal about it. Some of the mice bred in the lab have gotten names over the years. And in the back of Pickel’s mind is the notion that the work he does could one day help someone.

“It gives me a good feeling,” he said, “that somebody is going to benefit from all this.”






Find us on Facebook!
  • The sign reads: “Dogs are allowed in this establishment but Zionists are not under any circumstances.”
  • Is Twitter Israel's new worst enemy?
  • More than 50 former Israeli soldiers have refused to serve in the current ground operation in #Gaza.
  • "My wife and I are both half-Jewish. Both of us very much felt and feel American first and Jewish second. We are currently debating whether we should send our daughter to a Jewish pre-K and kindergarten program or to a public one. Pros? Give her a Jewish community and identity that she could build on throughout her life. Cons? Costs a lot of money; She will enter school with the idea that being Jewish makes her different somehow instead of something that you do after or in addition to regular school. Maybe a Shabbat sing-along would be enough?"
  • Undeterred by the conflict, 24 Jews participated in the first ever Jewish National Fund— JDate singles trip to Israel. Translation: Jews age 30 to 45 travelled to Israel to get it on in the sun, with a side of hummus.
  • "It pains and shocks me to say this, but here goes: My father was right all along. He always told me, as I spouted liberal talking points at the Shabbos table and challenged his hawkish views on Israel and the Palestinians to his unending chagrin, that I would one day change my tune." Have you had a similar experience?
  • "'What’s this, mommy?' she asked, while pulling at the purple sleeve to unwrap this mysterious little gift mom keeps hidden in the inside pocket of her bag. Oh boy, how do I answer?"
  • "I fear that we are witnessing the end of politics in the Israeli-Palestinian conflict. I see no possibility for resolution right now. I look into the future and see only a void." What do you think?
  • Not a gazillionaire? Take the "poor door."
  • "We will do what we must to protect our people. We have that right. We are not less deserving of life and quiet than anyone else. No more apologies."
  • "Woody Allen should have quit while he was ahead." Ezra Glinter's review of "Magic in the Moonlight": http://jd.fo/f4Q1Q
  • Jon Stewart responds to his critics: “Look, obviously there are many strong opinions on this. But just merely mentioning Israel or questioning in any way the effectiveness or humanity of Israel’s policies is not the same thing as being pro-Hamas.”
  • "My bat mitzvah party took place in our living room. There were only a few Jewish kids there, and only one from my Sunday school class. She sat in the corner, wearing the right clothes, asking her mom when they could go." The latest in our Promised Lands series — what state should we visit next?
  • Former Israeli National Security Advisor Yaakov Amidror: “A cease-fire will mean that anytime Hamas wants to fight it can. Occupation of Gaza will bring longer-term quiet, but the price will be very high.” What do you think?
  • Should couples sign a pre-pregnancy contract, outlining how caring for the infant will be equally divided between the two parties involved? Just think of it as a ketubah for expectant parents:
  • from-cache

Would you like to receive updates about new stories?




















We will not share your e-mail address or other personal information.

Already subscribed? Manage your subscription.