Two rival biotechnology companies have simultaneously claimed, inrival scientific journals, discovery of the tubby gene in mice. Theseanimals mimic late-onset obesity in middle-aged humans.

In today's Nature, Sequana Therapeutics Inc., of La Jolla, Calif.,announces: "A candidate gene for the mouse mutation tubby."

Next week's Cell, dated April 19, 1996, will present a report by 27researchers at Millennium Pharmaceuticals Inc., of Cambridge,Mass., titled: "Identification and characterization of the mouseobesity gene, tubby: a member of a novel gene family."

Cell lifted its pre-publication embargo on the Millennium paper lateWednesday upon learning of the competing paper in Nature.Millennium put out an announcement, which stated: "Millennium'sdiscovery of the tub gene was originally reported in July 1995, inconnection with the announcement of the payment by Hoffmann-LaRoche Inc. [of Nutley, N.J.] to Millennium of a major milestone inthe two companies' research collaboration in obesity and Type IIdiabetes." (See BioWorld Today, July 27, 1995, p. 1.)

Sequana's announcement Wednesday observed: "Another researchgroup has purported to have cloned tub, but due to a lack ofpublished data the Sequana-Jackson group is unable to evaluate themerits of this information."

Principal author of the Sequana paper in Nature is mouse geneticistPatsy Nishina, a senior investigator at the Jackson Laboratory, in BarHarbor, Maine. That renowned animal breeding facility, now in its67th year, picked the spontaneously mutated tubby mouse out of alitter of normal mice in 1977. Tubby and its progeny became primearticles of commerce in research settings, but the animals' owngenetic underpinning remained unclear until now.

Tubby Mice Mimic Type II Diabetes

Unlike mice with the recently discovered obese (ob) and diabetes(db) mutations, the Nature paper points out, which grow fat soonafter birth, tubby (tub) mice begin putting on gross weight late in life,despite ingesting a normal amount of food for their size. As they age,that size doubles with obesity.

What's more, these fat mutants suffer from hyperinsulinemia andimpaired glucose tolerance, which presage non-insulin-dependentType II diabetes. This adult-onset version is the commonest form ofdiabetes mellitus in humans.

Besides putting on inordinate weight, such patients over time developother infirmities, most notably retinopathy, one of the principalcauses of blindness in the population at large. So do tubby mice.

"This mouse model," said Sequana's president and CEO, KevinKinsella, "displays retinal and axonal _ that is, neuronal _degeneration. The first leads to blindness; the second to breakdownin an area of the brain that has something to do with the satiety loop."

The just-discovered murine tub gene maps to mouse chromosome 7;its human homolog resides on chromosome 11.

"Sequana has probably the most extensive collection of humanpedigrees in the world, in which there's an obvious pattern ofextreme obesity," Kinsella said. "They number in excess of 400families, at the University of Pennsylvania and the Pasteur Institute inLille, France."

He added, "In the patients we have studied, we have no evidencewhatsoever that this tub gene on chromosome 11 is mutated or in anyway related to human obesity. Scientifically, it's very interesting, butcommercially, for drug discovery, it may be valueless."

Nevertheless, he told BioWorld Today, Sequana and Jackson LabsWednesday filed jointly for patent protection covering their tub genediscovery. Its principal inventor is Jackson's Patsy Nishina.

"The problem with the commercial value of this discovery," Kinsellasaid, "is that although it will be interesting to elucidate the pathwaywhere this may lead in humans, it's not the pot of gold. It's only asignpost that may lead to the pot of gold."

What the normal unmutated tub-encoded protein does in the humanbody is still "unclear," said molecular geneticist Michael North,Sequana's project leader for the tubby project, and a co-author of theNature paper.

"The tubby mouse," he told BioWorld Today, "is a good model forcertain aspects of late-onset obesity, which is the common form ofobesity in humans. Lessons learned from the regulation of bodyweight in adult tubby mice will potentially be relevant to theregulation of body weight in human adults."

North observed that adult-onset obesity "is a major risk factor forType II diabetes. And that risk increases exponentially as a person'sweight starts to exceed a body mass index [BMI] of 32."

For an obese individual 5.6 feet (1.6 meters) in height who weighs200 pounds (91 kilograms), BMI works out at 35.5.

Sequana's contribution to the collaboration with Jackson Labs, Northsummed up as "defining a minimal genetic interval containing thetubby gene, using cDNA selection, exon trapping, and genomicsequencing to identify genes in the minimal region. Then weevaluated each gene."

Surprisingly, North said, the homology between the tubby mouse andCaenorhabditis elegans, the nematode roundworm, turns out to be 59percent amino-acid identity. Tub also bears striking resemblance toDNA in the plant kingdom, notably rice and corn.

A Genetic Powerhouse

These examples of evolutionary conservation _ one sequence fits all_ suggests that the tub gene pathway is a genetic powerhouse, goingback toward the origins of life on earth. Sequana, North said, intendsto pursue that pathway.

One variant of the tub gene in tubby's brain, he observed, "has anopen reading frame of about 1.5 kilobases. The altered gene resultsfrom a point mutation, but at an intron splice site rather than a normalcoding region. Thus, tub differs radically from the mouse obesitygenes discovered in the recent past, notably ob and db, which encodeproteins such as leptin, seen as having potential therapeutic value.

But North sees otherwise: "I don't necessarily agree that the ob anddb pathway is going to be as close to producing a drug for humanobesity as some people might imagine. It's too early to speculatewhether leptin or the leptin receptor would be useful targets for adrug as well.

"And the problem with tub is that it's a very new kind of gene, lyingin a very novel pathway. It's still a little too early to speculatewhether or not this can lead to a blockbuster drug."

He concluded: "In all cases simply taking the first mutated gene thatyou find, and regarding that as your primary point of therapeuticintervention, is a little too simplistic." n

-- David N. Leff Science Editor

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