By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Back in 1921, a Dutch physician named J.L.A. Peutz reported a rare, multi-faceted, inherited disease ¿ now known as Peutz-Jeghers syndrome (PJS). Then in 1944, Harold Jeghers, also Dutch, described PJS in greater detail.

To this day, guesstimates of the syndrome¿s rarity range widely from prevalence of 1 in 25,000 to 1 in 100,000 individuals affected. PJS features two separate hallmarks ¿ freckling of certain skin areas, and infestation of the gastrointestinal tract with astronomical numbers of benign polyps, called hamartomas.

The brownish to bluish freckles dot the lips, mouth, fingers and feet, as first hint that a toddler may have PJS. The tiny blemishes fade in adult years. The hamartomas cause severe abdominal complications throughout life. One earmark of PJS is a marked tendency to contract cancer ¿ often of the breast in women and testicles in men.

In January 1998, Finnish scientists at the University of Helsinki tracked the PJS tumor suppressor gene to the small arm of human chromosome 19, and gave it the acronym Lkb1. Mutations in that gene cause the syndrome. The Finns are also authors of a paper in the current issue of Science, dated Aug. 17, 2001. Its title: ¿Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice.¿ The article¿s co-senior authors are molecular biologist Tomi Mdkeld in Helsinki, and developmental biologist Mark Henkemeyer at the University of Texas Southwestern Medical Center, in Dallas.

¿We¿re studying this Lkb1 gene,¿ Henkemeyer told BioWorld Today, ¿and our main finding is that when we knock out the Lkb1 gene and its protein product from mice, the animals cannot survive embryonic development. When we looked to see what happened to the embryo, we saw that the heart and blood vessels ¿ its cardiovascular system ¿ failed to form. The whole reason why we studied this protein was because it¿s associated with the Poetz-Jeghers syndrome. The reason why I¿m involved in this Science paper is that my laboratory has expertise in making mouse mutants ¿ in this case an animal model for PJS. The gene might also aid development of a clinical PJS predictive test.

¿The first thing that the Lkb1-minus mouse told us,¿ Henkemeyer said, ¿is that it is an essential gene. Those KO mice succumbed to mid-gestation lethality, associated with abnormalities connected to formation of the embryo¿s vascular system. That implicates the vascular endothelial growth factor, or VEGF.

¿If you look at a VEGF-minus animal,¿ Henkemeyer said, ¿you can see that the early development of the heart and the blood vessels are intimately associated with each other. If the blood vessels aren¿t developing right, the heart isn¿t going to develop right. Many of the cells that make up the early embryonic heart are endothelial cells. So in a way this is before epithelial heart muscle is forming.

¿People with [PJS] do have an increased risk for developing certain types of tumors,¿ Henkemeyer observed. ¿We¿re only hypothesizing at this point as to that particular cancer connection, because there¿s no experimental proof. But presumably, one reason why [PJS] patients are prone to development of specific cancers could be abnormal regulation of VEGF production in such predisposed tissues. And that could lead to the altered recruitment of blood vessels. We know from the role of angiogenesis in tumor growth and metastasis that the only way a solid tumor can take off is to encourage blood vessels to grow into it.

¿Most important,¿ Henkemeyer concluded, ¿our results provide a rationale for the increased risk of cancer incidence in Peutz-Jeghers patients by demonstrating that loss of Lkb1 confers an increased angiogenic potential in certain cell types by up-regulation of VEGF.¿

Saline Injection Rivaled Real Parkinson¿s Drug Release In PET-Controlled Placebo Effect In Brain

A clinical trial patient¿s stoutest ally is the placebo. This dummy drug or injection is supposed to mask identity of the active remedy being tested, to shield the participant from heightened expectation of benefit. Placebo-controlled studies were designed precisely to control for such an effect. (The word ¿placebo¿ means ¿I shall please.¿) It¿s a potential confounding factor in assessing the efficacy of any therapeutic intervention. The dummy substance is sometimes suspected of triggering a psychosomatic effect in the brain, bringing on improvement in the patient¿s medical condition. But experimental proof of this supposed neurological mechanism has been lacking.

Now there¿s reinforcement. A research paper in Science dated Aug. 10, 2001, carries the title: ¿Expectation and dopamine release: Mechanism of the placebo effect in Parkinson¿s disease.¿ Its authors are neuroscientists at the University of British Columbia, Vancouver. They point out that ¿in Parkinson¿s disease [PD] the placebo effect can be prominent.¿

For treating PD, the medication of choice is levodopa, a compound that is converted to dopamine, the neurotransmitter that dwindles as the disease progresses. The authors enrolled two groups of six PD patients and gave them injections of either apomorphine ¿ a shorter-acting anti-PD drug than levodopa, or of saline solution ¿ the placebo. They monitored neural responses in the brain to both regimens by positron emission tomography (PET). All participants and clinical staff were kept unaware of the double-blinded study¿s purpose.

The bottom-line result of the experiment was ¿in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo.¿ Moreover, ¿Release of dopamine was greater in patients who perceived placebo benefit than in those who did not.¿ Q.E.D.?