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Case Study SummaryHuman Genome makesmind-boggling readingGenetic researchers are lookingforward to medical miracles — andbackward into evolutionary historyBy Steve Sternberg

education.usatoday.com

Biotech and genetic research promises to yield huge benefits to patients ofthe future while becoming a multimillion-dollar industry. The three USATODAY articles in this case study present the scientific progress made andthe challenging questions it is generating. Technology has the potential toredefine the moral landscape. Will it? It is an important topic of discussionfor current and future leaders in business, government and communities.

DNA-rights defenders: Get off my genetic propertyMoney creates conflict of researchvs. privacyBy Elizabeth Neus

Thinkers: ‘Genes cannot explain’‘No evidence of 30,000 genesevolving over. . .tens of millions ofyears can tell the whole story.’By Greg Barrett

Case Study Expert: Janis SmithAdjunct Professor,

Brown University

Genetically altered food:Women more skeptical

Would eatsuch food

USA TODAY Snapshots®

By Lori Joseph, and Sam Ward, USA TODAY

Source: www.pulse.org

Would giveit to theirchildren

Willing topay more fornon-altered

food

Women

50%

71%

37%

59%47%

35%

Men

Human genome makesmind-boggling readingGenetic researchers are looking forward to medicalmiracles — and backward into evolutionary history

Cover story

By Steve SternbergUSA TODAY

The first close reading of the “TheBook of Life” — the 3 billion letters thatmake up the human genetic code —reveals that it’s packed with moremysteries and surprises than a pulpthriller.

Perhaps the biggest surprise since thecode was deciphered in June is that ittakes just 30,000 to 40,000 genes tomake, maintain and repair a human.That’s far fewer than the 140,000 genesthat some had predicted and not manymore than a worm or a common weed.

“If you’re judging the complexity ofan organism by the number of genes ithas, we’ve just taken a big hit in thepride department,” says the NationalGenome Research Institute’s director,Francis Collins, who also heads the U.S.arm of the international HumanGenome Project (HGP).

Twin analyses of the genome werereleased today by two leading journals,Nature and Science. Both issues also arepacked with reports looking at what thegenome tells us about ourselves and howwe differ from other organisms on Earth.

And the genome is the perfect placeto look. If ancient Greeks talked of the“Great Chain of Being,” the genome isit, and in a form that the ancients couldhardly have imagined — a spiralingchain of chemicals running throughevery living being. In humans, the chainis vast, “25 times larger than anypreviously studied genome and eighttimes larger than the sum of all suchgenomes,” Collins reports.

Among the findings: uMen, whose sperm cells divide

almost endlessly to boost opportunitiesfor fertilization, are twice as likely aswomen to generate abrupt geneticmutations. These altered sequencesmay mingle with those of the mother’sgenes after fertilization, shuffling wildcards into their child’s geneticinheritance. Some errors may make nodifference to the developing fetus, somemight be beneficial, and some might beharmful. What this means to humandevelopment is poorly understood. uProteins, the most complex large

molecules in nature, are much morecomplicated in humans than in animalsor plants.

Reprinted with permission. All rights reserved.

AS SEEN IN USA TODAY LIFE SECTION, MONDAY, FEBRUARY 12, 2001

Reprinted with permission. All rights reserved.

USA TODAY photo illustration: source/PhotoDisc

uHundreds of human genes appear to have come frombacteria millions of years ago. Whether the bacteria infectedhumans or they were carried by a virus is still unknown. uEvery human’s genome carries the residues of evolution,

a history stretching back millions of years. The journals discuss these things and many more. Nature

begins with a 68-page report by the genome project, apublicly funded consortium of 20 groups in the USA, UnitedKingdom, Japan, France, Germany and China. Science offers a48-page analysis by J. Craig Venter, CEO of Celera Genomics inRockville, Md., and an equally impressive who’s who ofcollaborators worldwide. Celera is the private company thatspurred the public-private race to solve the genome to itsphoto finish in June. Both groups have produced detailedsequences covering over 90% of the genome. And bothversions agree on the rough number of genes in the genome,the genome’s organization and other key features.

Multi-tasking genes

Probably the most intriguing question to emerge fromthese analyses is this: How do relatively few genes build andmaintain an organism as complex as a human, with 90,000 to300,000 proteins and 100 trillion highly specialized cells?

Venter, whose firm challenged the publicly fundedinternational sequencing project by exploiting a clever,automated technique called “whole genome shotgunsequencing,” says the answer promises to topple a hallowedprinciple of the gene world: “one gene (makes) one protein.”

The new analyses indicate that each gene makes on averagetwo proteins. Somehow — the how is still being explored —the cell’s machinery can order up the protein it needs at anygiven instant, researchers say.

When that occurs, enzymes within the cell swing intoaction. They splice together the genetic sequences that makethe needed protein, even when the sequences are in pieces,spread out along the chromosome.

This means that the human genome is anything but a staticalphabet. It’s a living text that continually edits and rewritesitself, spelling out biological messages necessary for survival.

“It’s a manuscript in flux,” says Eric Lander of theWhitehead Institute Center for Genomic Research inCambridge, Mass., a lead researcher in the HGP. “It’s a never-ending, constantly changing story.”

The substance of the manuscript is more astonishing yet, says

Venter. “It is a guidebook to the formation of our species.” The genome also will serve as a guide for researchers who

are trying to develop new ways of treating cancer and otherailments that have plagued humans. Knowing the identityand location of genes, for instance, enables researchers tostudy their patterns of expression — when they turn on andoff. These clues have already yielded useful information.

One report in Science, for instance, compares gene expressionin normal vs. cancerous tissue. Researchers found several genesthat were either “silenced” or over-active in breast and coloncancer. If doctors can figure out what triggers these abnormalgenetic patterns, researchers say, they may be that much closerto learning how to block them.

Putting the genome in order

Sequencing the genome involved placing in their preciseorder the seemingly endless strings of nucleic acids thatmake up therungs of the twisted, 6-foot ladder of DNA insideevery living cell. The nucleic acids are adenine, thymine,cytosine and guanine. They are represented in the genomesequence by the letters A, T, C and G.

Over half of the genome is rich in segments called repeats,bits of sequence that appear over and over again, which offera remarkable window into evolutionary history.

“We can look at your DNA or mine,” says Kathy Hudson,assistant director of the National Genome Research Institute,“and see a history going back 800 million years.”

In the genome, says Douglas Wallace, director of molecularmedicine at Emory University in Atlanta, evolution is plain tosee.

Wallace says two lines of evolution converged in humans.One is a set of genes from the first bacteria capable of living inan oxygen-rich atmosphere, he says. The second set comesfrom the single-celled organisms that gobbled up the bacteriaand co-opted their ability to turn oxygen into energy.

Genes from those bacteria still reside in the human genome,the new analysis shows. Says Wallace: “We have the fusion oftwo different lines of evolution into the same genome.”

When researchers speak of the genome, they’re reallytalking about the sum of genetic sequences that make up the23 pairs of chromosomes in each human cell, half of each pairdonated by a parent. But the new research indicates that thisgenetic information isn’t evenly divided on thechromosomes. Lander describes the genome as a

Book of life: A detail from a diagram of Chromosome 19 shows the complexity of the human genome.

“remarkably uneven landscape.” “Some chromosomes are chockablock with genes, (and)

others are virtually devoid of genes,” Lander says. “The weirdestchromosome in the genome is (number) 19. It’s chockablock fullof genes and other functional elements, far beyond what you’dexpect, given its measly size. It’s a mighty little chromosomethere. Given its size, it has grand aspirations.”

In contrast, he says, “chromosomes 4 and 8 barely pulltheir weight.”

What genes lurk on chromosome 19? Among others: theApo-E gene, linked to Alzheimer’s disease; the LDL receptorgene, linked to bad cholesterol and heart disease; and theEpO gene, needed to form oxygen-carrying red blood cells.There’s even a gene that has been linked to a sometimesfatal, inherited reaction to anesthesia.

No one fully understands the laws that govern genomefunction or how to manipulate the genes to treat humandisease. But genomics and biotech firms, often partnered withmajor pharmaceutical firms, are determined to change that.

A biotech boom

Such research promises to yield huge benefits to patientsof the future — and possibly Nobel prizes to scientists whodevelopnew treatments or even cures. They’ll have plentyto work with.

Researchers have already identified 1,100 genes with atleast one mutation that has been linked to disease. Biotechfirms are uniquely positioned to plunge into such research.

A biotech industry analysis, released late last month byLehman Brothers, asserts that the genomics revolutionwill double biotech revenues to $4 billion annually by2005. The best investments, it says, will be in newlydeveloping technologies.

One of those is the new multimillion-dollar industry that hassprung up to catalogue what some call the human “proteome,”the complete roster of proteins in the human body.

Proteins by the tens of thousands serve as workhorses in

every cell, performing functions necessary for life. Not surprisingly, plenty of scientists and businessmen

want to get in on the action, despite market ambivalenceabout many other high-tech enterprises.

“You only have to whisper the word proteomics,” saysJosh LaBaer of Harvard University’s Institute for Proteomics,“and venture capitalists come knocking at your door.”

Other firms have begun collecting genetic informationfrom human volunteers — twins, if possible — so thatresearchers can study how genes and proteins function inboth healthy people and those with deadly diseases. Thisholds great promise.

“What will come out of this is a complete redefinition ofhuman biology,” says Paul Kelly, CEO of Gemini Genetics inCambridge, England.

Kelly’s firm has forged an agreement with Celera to helpthe genomics firm look for common disease genes, such asthose for osteoporosis and diabetes. Where? In Gemini’spopulations of twins and other research cohorts in Canada,the United Kingdom, New Zealand and Australia.

Celera also has begun moving into proteomics. Celera’s sistercompany, Applied Biosystems (both are divisions of AppleraCorp.) has matched its breakthrough gene-sequencing devicewith one that can speedily sequence proteins.

“Celera is making the biggest play in proteomics ofanybody,” says Venter. “We have $1.1 billion in cash in thebank, and we’re building a facility where we can sequence amillion proteins a day.

“That’s driving our program for the discovery of newdiagnostics and therapeutics — particularly in cancer. We’rebetting that we can actually do something about cancer.”

“We are made of and by protein,” says Harvard’s LaBaer,whose institute plans to obtain physical copies of everyhuman gene and to use those genes to create the hundredsof thousands of proteins.

“Virtually every pharmaceutical today, from aspirin tochemotherapy, works by affecting protein function,” LaBaersays. “This is where the future of biology, and medicine, resides.”

By Elizabeth NeusGannett News Service

WASHINGTON — Who owns your DNA? The answer might not be you. In an era when the map of the human genome can

be accessed by any professor with an Internetconnection, the question becomes more crucialevery day. Courts and lawyers and legislatureswrestle with it; people who joined medical studieswonder just what their participation means.

Courts have ruled that people who donate actualtissue — pieces of organs, tumors or blood, forexample — have no right to financial compensationif a drug or treatment is developed from researchdone on that tissue.

But DNA, which contains thegenetic blueprint from which youwere built, seems morepersonal, something whose fateyou and you alone should havethe right to control.

Oregon is the site of the mostrecent battle over the rights toDNA. The state’s 1995 geneticprivacy law, one of the first inthe nation, gives a personproperty rights to his or her ownDNA. A proposed change to the lawlast year would have taken those rightsaway. An advisory committee is expected to offerrecommendations to the Legislature and the

Money createsconflict of researchvs. privacy

DNA-rights defenders:Get off my genetic property

AS SEEN IN USA TODAY LIFE SECTION, MONDAY, SEPTEMBER 25, 2000

Health and Science

governor next month on how to proceed. “There are many competing agendas here,” says Gregory

Fowler, executive director of Geneforum.org, anorganization founded to educate people about gene-relatedissues. He also is a member of Oregon’s advisory committee.

Experts have tried to sort out those agendas for years.This year the federal government strengthened itsregulations protecting human research subjects, hoping tomake more explicit the process by which patients are toldwhat a study will entail.

The National Bioethics Advisory Commission report onwhich some of those recommendations were based notedthe difficulty in protecting subjects no longer physicallyinvolved in a study.

“Researchers are often unclear whether research onhuman tissue makes the people from whom it came ‘humansubjects,’ ” the commissionwrote President Clinton.

In some cases, those whodonated the original tissue orDNA are dead, leaving wideopen the question of whethernew research can be donewith that material — and whohas rights to it.

For example, 4,000 of the10,000 people who havetaken part in the 52-year-oldFramingham Heart Studyhave died, and coordinatorsof that study don’t know whocan give consent to use theinformation from the deadvolunteers if the studybecomes a commercialventure, as planned. They aretrying to work that out.

“We certainly feel we’reblazing a trail here,” saysSusan Paris, vice president foruniversity relations at BostonUniversity, which runs the Framingham study.

The usual concerns also come into play when the issue isgenetics. Researchers make every effort to disconnect theDNA samples from the identities of their donors, butexperts still worry.

“No genetic sample can be totally anonymous,” says LoriAndrews of the Institute for Science, Law and Technology atthe Illinois Institute of Technology. “We use DNA in forensicsto identify people. I could always figure out who it is.”

Complicating the issue further is money — lots of it. Biotech and genomics companies have been hot in recent

years in the stock market, and even academic researchers, onceseen as above the financial fray, often have start-up companies.

The federal government is balking at Framingham’s plansto go commercial; Washington underwrites the famousstudy, which provided the base line for nearly everythingwe know about heart disease. Some of the 6,000 livingparticipants are nervous about how their data — which

includes health histories, blood, tissue samples and DNA —will be used.

“A lot of time and commitment and love have beenpoured into this (by the volunteers), and they’re concernedthat the data isn’t exploited,” Paris says. “But we have to getover the fact that companies may make money (from thedata). How do you do (research) without money?”

John Kilyk Jr., managing partner with a Chicago law firmspecializing in intellectual property, says that those whobelieve volunteers should get a cut of any proceeds fail tounderstand how much money goes into the researchupfront, compared with what’s earned at the other end.

“There is a lot of money at stake, or at least there’s perceivedto be a lot more money at stake,” he says. “But there’s noguarantee that (researchers are) going to find something …What (laypeople) don’t appreciate is the time and money

involved in getting to thatpoint, and the number ofwinners and losers.”

Andrews rejects thatargument.

“It’s an unnecessary windfall,”she says. “They’re beingrewarded disproportionately towhat they do. It’s a trick on thepublic. It’s like patenting thealphabet and charging peopleevery time they speak.”

Some companies have founda way to compensate thosewho volunteer DNA withoutgoing into dollars and cents. Acompany called DNA Sciences,which wants to find gene-based tests and treatments forcommon illnesses, is building alarge database of DNA fromscratch by asking volunteers todonate. If a relevant test ortreatment is found, anyvolunteer who participated in

that study will be offered the test or treatment free, sayschief business officer Steven Lehrer. “The whole concept ofpaying people for (taking part in) research is very negative,”he says. “It looks like you coerced them.”

With the trend toward the creation and use of extremelylarge databases such as Framingham and DNA Sciences’Gene Trust, “the property value of any individual genomegets smaller,” says Gillian Woollett, associate vice presidentfor biologics and biotechnology at the PharmaceuticalResearch and Manufacturers of America, a drug industrytrade group.

Besides, she says, what portion of your DNA is yours? Thelarge part of the genome we share with chimpanzees? Thepart you share with an identical twin?

“Do you own what is unique to you,” she asks, “even ifyou don’t know what’s unique to you?”

Click here uwww.geneforum.org —

Geneforum

uwww.framingham.com/heart —Framingham Heart Study

uwww.bioethics.gov — NationalBioethics Advisory Commission.Click on “Reports” to find “ResearchInvolving Human BiologicalMaterials: Ethical Issues and Policy.”

uwww.dna.com — Gene Trust

By Greg BarrettGannett News Service

The philosopher, the theologian, the biologist and theauthor of spirituality are in basic agreement on this:Revelations released today about the human genome areabout as significant to our understanding of metaphysics aswalking on the moon is to our understanding of theuniverse. A boundary we still cannot fathom.

That is to say, this evolving map of our genes is not likelyto sway matters of the spirit. Never mind the project’sfindings that seem to support Darwinism and free will overcreationism and determinism.

No evidence of 30,000 genes evolving over the course oftens of millions of years can tell the whole story. Science canclaim to connect the dots of biology, not sketch the soul.

Philosopher: “If there were an omnipotent, omniscientand perfectly benevolent god, then I think his or herpurposes are actually incomprehensible,” says ColumbiaUniversity professor Philip Kitcher. “The idea that 30,000genes can explain or not explain anything is kind of absurd.”

Theologian: “Genes cannot explain the entire humanphenomenon,” says William May of Washington’s John PaulII Institute. “Is thinking a function of genes? I think not.”

Biologist: “I don’t need to provide for you how many

ounces a soul weighs or how many base pairs it is coded byin the DNA . . . to know that hope is worthwhile and hope isreal,” says scientist Robert Pollack, director of Columbia’sCenter for the Study of Science and Religion. “It is the realityof hope that matters, not the physicality of the soul.”

Author: “It is not possible to step on God’s toes,” saysNeale Donald Walsch, whose four Conversations With Godbooks have been best sellers. “I think God chuckles at ourastonishment at these rather primitive revelations, verymuch as we smile at a child’s first mastery ofmultiplication tables.”

Proof of whether mankind was slow in the making or wascreated in an instant is not likely to dissuade belief one wayor the other. Either version can be supported by the OldTestament, embraced as sacred text by Christianity, Judaismand Islam. And there are perhaps as many interpretations ofreligious doctrine as there are mutations of a cell. Both areuncountable. Similarly, there will be any number of waysbelievers and non-believers will read the discoveries of thehuman genome.

“The more we learn and the more we know,” Pollack says,“the more we are aware of the boundaries set upon us bythe two facts of our lives: our free will on the one hand, ourmortality on the other.”

Two themes constant in religion and science.

Thinkers: ‘Genescannot explain’

AS SEEN IN USA TODAY LIFE SECTION, MONDAY, FEBRUARY 12, 2001

Behind the Story: A Reporter’s Notebook

Steve Sternberg, Medical reporter, Life

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