A Mexican surgeon made media history in 1987 by transplantinghuman fetal neurons into the brains of patients with Parkinson'sdisease. His rationale was to insert those still-undifferentiatedprogenitors of dopamine-producing cells into the cerebral regionwhere Parkinson's patients' dopaminergic cells die off.

That first-ever attempt yielded clinically controversial results, but theapproach caught on. In November 1988, neurosurgeon Curt Freed atthe University of Colorado performed the first fetal dopamine cellimplant into an American Parkinson's patient.

Seven years later, in November 1994, Freed could tell the 24thannual meeting of the Society for Neuroscience that he hadtransplanted human fetal tissue into the brains of another 17 patients.Summing up this experience, he told the meeting that "fetalmesencephalic dopamine cells survive transplantation, grow into hostbrain, and relieve signs of advanced Parkinson's disease."

Part of the fetal nerve cells' presumed magic resides in a geneimprobably named hedgehog, hh for short. A leading fruit flygeneticist, Christianne Nsslein-Volhard, at the Max-Planck Institutein Tbingen, Germany, found hh 15 years ago in the genome of hermodel insects, Drosophila melanogaster. It owes its quirky name tothe spiky appearance of fly larva expressing the hedgehog gene.

Since then, developmental biologists have located vertebratehomologs of hh in birds, mice and lately in human embryos. Now, anine-month-old biotechnology company in Cambridge, Mass. namedOntogeny Inc. is betting its seed money on the potent properties thathh possesses, and to which it holds proprietary rights.

The word "ontogeny" describes the origin anddevelopment of an individual organism from embryo to adult. It's abasic Ontogeny doctrine that hh acts through development, which hasparallels in the adult. The protein acts on cells, which thendifferentiate, and redifferentiate, also under the influence of hh.

`Hedgehog' Conducts Neuroembryonic Orchestra

As stem and progenitor cells in the gestating nervous systemdifferentiate into central nervous system and spinal motor neurons,the molecule that induces their choice of fates is none other thanhedgehog, more specifically a gene encoding a cell-surface receptorvariant. Researchers refer to as "Sonic hedgehog (Shh).

Ontogeny has taken as its mission educating hh to induce cell types toorder, starting with dopaminergic neurons for treating Parkinson'sdisease. This tall order is a little like hiding a needle in a precisethree-dimensional site within a haystack.

Two members of the company's scientific advisory board describetwo recently acquired handles on this mission impossible:concentration and location. Developmental neurobiologist ThomasJessell of the Howard Hughes Medical Institute at ColumbiaUniversity, New York, has just showed that the progeny-cell choicesthat Shh makes depend upon the protein's concentration gradient.

Jessell reports this finding in the latest issue of Cell, dated June 2,under the title: "Sonic Hedgehog induces the differentiation ofventral forebrain neurons."

Last week in Nature, dated May 25, his rival and fellow Ontogenyboard member, Harvard University cell biologist Andrew McMahon,proposed that "Shh acts as a morphogen [determining earlyembryonic form and structure] to induce ventral cell types in thevertebrate central nervous system."

Jessell has a separate paper in this month's Current Biology (June1995) explaining how Shh induction of motor neurons can beindependent of its induction of differentiation in the floor plate, anearly embryonic precursor tissue of the future central nervous system.

"So what this does," Jessell told BioWorld Today, "is in a senseprovide a unifying theme that all ventral neuronal cell typesgenerated within the nervous system are probably induced by a singleinductive signal, which is Shh."

"If you think about it," Ontogeny's chief operating officer, medicalphysicist Heidi Wyle, told BioWorld Today, "God could have madethe biology so that at each differentiation stage, you could have adifferent inducing molecule. But," she explained, "that's not the wayit works. We think there are very few inducing molecules, such asShh, and they act by concentration gradients _ very simple andelegant."

Matching Therapy To CNS Anterior-Posterior Topography

Despite its futuristic feel, hedgehog is not biotechnology's firstpractical inducing molecule. "The best example," Wyle observed, isEPO _ recombinant erythropoietin. It induces the hemopoieticsystem, and it looks to us as if Shh does the same thing for the centralnervous system."

In charting its future research and development program, hercompany's point of departure is a conceptual cross-section of theearly embryonic central nervous system, from front to back, fromforebrain to midbrain to hindbrain to spinal cord:

* basal forebrain neurons are their target to treat Alzheimer'sdisease;

* striatal forebrain neurons for Huntington's;

* dopaminergic midbrain neurons for Parkinson's;

* spinal motor neurons for amyotrophic lateral sclerosis.

Getting specific, she added: "Thus, the cell has to have the rightprogram to become a basal forebrain neuron or a dopaminergicneuron. So when the cell `sees' hh, it becomes what it's supposed tobe."

Ex Vivo Cell Replacement

Applying hedgehog therapy to Parkinson's and other diseases, Wylesaid, "will come in two waves, or phases: ex vivo cell replacement inthe near term, followed at some future time by in vivo site-specificcell differentiation.

"The first approach," she explained, is to use Shh in vitro to make theright cells for ex vivo transplantation. That's work in progress; webelieve it's easily do-able, because there are certain markers ondopaminergic neurons, so you can find where you are."

She said that, "Cell replacement will be quick; we expect to go intothe clinic within three or four years at most."

Developmental Biologist Douglas Melton of Howard HughesMedical Institute at Harvard University co-founded Ontogeny inSeptember 1994, in association with Jessell, McMahon and otherscientists. Venture capitalists J. H. Whitney, Greylock, Sutter Hilland Charles River grubstaked the new firm with $4.2 million.

Colorado's Curt Freed told BioWorld Today that because of thelimited availability of fetal tissues from legal abortions, "the searchfor an unlimited number of cells for transplant would be a verydesirable thing, both from a clinical and scientific point of view, aswell as totally separating this issue from the political aspects ofabortion."

He added that "The discovery of hedgehog by the Ontogeny foundinginvestigators was a very important discovery, especially for my fieldof neurotransplants. It's a wonderful insight into how the braindevelops. How one single growth factor or molecule can causedevelopment of a bunch of different types of neurons, dependingupon where it's expressed in the brain." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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