burgers, chips, and genes

8

Burgers, Chips, and Genes

JOSEPH L. GOLDSTEIN

Chair, Department of Molecular Genetics, and Paul J. Thomas Professor of Medicine and Genetics, University of Texas Southwestern Medical Center at Dallas,Dallas, Texas 75235-9046, USA

The opportunity to present this opening lecture in celebration of the 200th anniver-sary of the founding of Dartmouth Medical School caused me to reflect back on myown 35-year career in medicine. I am impressed by one dominant and recurringtheme—namely, how a few good ideas and the power of science can radically trans-form the way we live.

Thirty-five years ago, in September 1962, I began my first day of medical schoolat UT Southwestern Medical Center in Dallas. During my four years as a medicalstudent, therapeutic medicine was primitive by today’s standards. We had no H2blockers for treating ulcers, no calcium channel blockers or ACE inhibitors for highblood pressure, no statins for high cholesterol, no Prozac for depression, and no vac-cines for hepatitis or Hemophilus influenza. There were no bone marrow transplants,liver transplants, or heart transplants. Coronary bypass operations and coronary an-gioplasty did not exist. There were no CAT scans or MRIs. Alzheimer’s disease wasconsidered an extremely rare disorder, described briefly in Harrison’s Principles ofInternal Medicine (4th edition, 1962) and not even mentioned in Cecil-Loeb’s Text-book of Medicine (11th edition, 1963). AIDS did not exist, and sickle cell anemiawas the only inherited disease that had been studied at a molecular level. We had nopersonal computers, and there were only two Xerox machines in our entire medicalschool in 1962. But most amazing of all—there were no McDonald’s restaurants inDallas. Imagine medical students today without Big Macs!

And this brings me to the theme of this presentation: that the world in general andthe world of medicine in particular have been radically changed by three turns ofevents: burgers, chips, and genes. Let me explain.

BURGERS

First, the hamburger. I ate my first Big Mac in 1968 while I was a resident in med-icine at the Massachusetts General Hospital. McDonald’s had just opened its firstrestaurant in Boston. Since the early 1960s, McDonald’s has grown from several res-taurants in California to 23,000 restaurants in 101 countries throughout the world.Every day, 7% of the U.S. population eats in McDonald’s. McDonald’s serves 30million people in the world each day and sells 5 billion hamburgers each year. Mc-Donald’s owns more real estate than any other company or person in the world. Anew McDonald’s opens somewhere in the world every three hours, and each restau-rant is in the center of the four-minute universe, which means that in the next fewyears everyone in the world is going to be no more than a four-minute walk or drivefrom a McDonald’s.1,2

9GOLDSTEIN: BURGERS, CHIPS, AND GENES

If I had bought 100 shares of McDonald’s stock after I ate my first hamburger 29years ago, my investment of $2,000 would be worth about $2,000,000 today. In thosedays, $2,000 was one-half my annual salary as a medical resident. The genius of RayKroc, the founder of McDonald’s, was his discovery that people wanted to be servedin 60 seconds and his creativity in franchising fast food restaurants.3 Of all the re-markable things that have happened since I began medical school, McDonald’s is thebest example of how one good idea by one person can change the way we live. Or,as Woody Allen might say: This is an example of the transmutation of life—by alowly hamburger.

CHIPS

So much for burgers. Now for the chips, the second McDonald’s-like transmuta-tion that has occurred since I entered medical school 35 years ago. Burgers were notinvented in Dallas, but chips were, not by Frito-Lay, but by Texas Instruments. I amreferring to the silicon chips of the type that led to the revolution in microelectronicsand to the birth of the personal computer, the Internet, and the World Wide Web.

In 1959, Jack Kilby, an electronic engineer at Texas Instruments in Dallas, hit onthe ingenious idea of integrating all the transistors and other components of an elec-trical circuit on a single miniature flake of silicon.4,5 Each silicon chip was onlyabout a quarter-inch square in size, but it did the work of multiple transistors. Theidea of the integrated circuit solved the most important engineering problem of thiscentury: It was now possible to create a complex network of electrical circuits with-out having to wire together multiple transistors.

The first major practical application of the wireless chip came 30 years ago in1967, when Texas Instruments introduced the first pocket calculator, weighing only2.5 pounds and having all the electronic transistors squeezed onto a single siliconchip designed by Jack Kilby.5 At about the same time, Robert Noyce and GordonMoore founded Intel Corporation in the Palo Alto area with the then-daring idea thatthey could further miniaturize Kilby’s integrated circuit and produce a micropro-grammable computer on a chip that was about the size of the head of a pin—theso-called memory microchip.6 The rest is history.4

Without microchips, there would be no car phones, no cash cards, and no personalcomputers, not to mention the Internet. The typical American home contains 50 mi-crochips. There are microchips in your microwave, microchips in your doorbell, andmicrochips in your VCR. In the last five years, the production of microchips andcomputers accounted for 45% of U.S. industrial growth. By common consent, the In-formation Revolution created by the microchip industry has been the mostlife-changing technological revolution since the harnessing of steam power in the18th century and electricity in the 19th century. Imagine medicine today withoutCAT scans, PET scans, or MRIs.

GENES

Now let me tell you about the newest McDonald’s-like transmutation, one that ischanging biomedical science and clinical medicine in ways that will be just as pro-

10 ANNALS NEW YORK ACADEMY OF SCIENCES

found as the way McDonald’s changed the eating habits of the world and microchipschanged the way we devour information.

When I began medical school in 1962, the gene had not yet become a householdword. No one had ever isolated a gene or seen a gene. Genes could not be purifiedor put in a bottle. As medical students, we hardly ever heard about genes or chromo-somes. Genetic diseases were believed to be extremely rare, and medical geneticswas not considered sufficiently important to be taught as a course in the curriculum.Only three of the 100 medical schools in the U.S. had postdoctoral specialty trainingin medical genetics.

The year that I graduated from medical school, 1966, was a turning point in thehistory of genetics. This was the year that the genetic code was completely deci-phered. Six years later, in 1972, the technique of recombinant DNA was discovered.By the early 1980s, scientists had perfected the techniques to clone and sequence in-dividual genes and to study their action in living cells of animals and humans. Today,genes can be cloned, sequenced, weighed, counted, visualized, replicated, altered intest tubes, and shuttled from cell to cell in animals and humans. These phenomenaladvances could never have arisen without two prior decades of what many consid-ered at the time to be esoteric basic research in pure enzymology. This so-called es-oteric research produced the polymerases, ligases, reverse transcriptases, andrestriction endonucleases that are the key reagents used by scientists every day tomanipulate genes.7

Today, manipulating genes is as easy as flipping burgers and surfing the Web. Ev-ery week, the front page of every major newspaper reports the discovery of a newdisease-producing gene or a potentially new gene-based drug. We may soon live ina world where the Golden Arches yield center stage to the Golden Helices.

Our new power to manipulate genes will allow scientists to obtain the completeDNA sequence of the entire human genome—all 100,000 genes that make up theblueprint of you and me. The ultimate aim of the Human Genome Project is to readeach person’s genes like a book and discover which genes make Madonna so sexyand Jim Freedman, the president of Dartmouth College, so smart.

Great scientific discoveries in pure basic research virtually always lead to practi-cal applications that benefit society. The birth of the microchip industry in the 1960swas a direct outgrowth of the discovery of the transistor in 1947 by Bardeen, Brat-tain, and Shockley at Bell Laboratories.4 For the first few years after its discovery,the Bell Laboratory transistor was considered a laboratory curiosity for amplifyingelectrical signals and had no practical utility until Kilby hit upon the idea of integrat-ing multiple transistors on a single chip.

Just as basic research on transistors led to the microchip industry, so basic re-search on genes has led to the creation of the biotechnology industry. The biotech-nology industry began only 20 years ago, but even in this short period, its growth andinfluence, whether measured intellectually or economically, has been extremely im-pressive. Let me give you one striking example.

In 1975, the Rockefeller University, one of the great biomedical research institu-tions in the world, received its first payment for patent royalties in the amount of$500. Twenty years later, in 1995, the Rockefeller University received a payment of$20,000,000 from the biotechnology company Amgen for licensing rights to thegene sequence of a hormone called leptin, which is being used to develop a drug for


FIG

UR

E1.

(Lef

t ) C

over

of

Mar

ch 9

, 198

1 is

sue

of T

ime

mag

azin

e [r

epri

nted

by

perm

issi

on. ©

1981

by

Tim

e-L

ife]

. (R

ight

) C

over

of

Mar

ch 2

,19

92 i

ssue

of

Bus

ines

s W

eek

[rep

rint

ed b

y sp

ecia

l pe

rmis

sion

. ©19

92 b

y M

cGra

w-H

ill

Com

pani

es].


obesity. This phenomenal increase from $500 to $20,000,000 in 20 years is a dra-matic example of how the biotechnology industry is changing the style and practiceof biomedical research in medical schools and research institutions. (The paymentto the Rockefeller University of $500 in 1975 was based on a patent awarded to theNobel Prize-winning immunologist Gerald Edelman, who is also a participant in thissymposium, and who had developed a new method in which antibodies directedagainst cell surface antigens were attached to nylon fibers for use in isolating intactcells.8)

BIOTECHNOLOGY AND SURREALISM

In the remainder of my presentation, I will discuss the biotechnology industry, fo-cusing on its dreams and its realities for medicine in the next century. Much of thesuccess of the biotechnology revolution can be attributed to the industry’s style ofoperation. Biotechnologists have assumed a style that is reminiscent of an earlierrevolution in art called surrealism.9 Like the surrealist artists of the 1930s and 1940s,today’s most creative scientists live and think in a world of fantasy and dreams.

The general public was first introduced to the potential importance of biotechnol-ogy on March 9, 1981, when Time magazine published a lead story entitled “ShapingLife in the Lab.” FIGURE 1 (left) shows the cover of this issue of Time, which fea-tured a picture of Herbert Boyer, the scientific cofounder of Genentech, the first ma-jor biotechnology company. A notable feature of this Time cover is the fact that theengagement of Princess Diana to Prince Charles was apparently deemed less news-worthy than “The Boom in Genetic Engineering” and was thus relegated to the upperright corner of the cover.

In the ensuing decade, many articles on biotechnology were published in all typesof magazines read by the lay public. FIGURE 1 (right) shows a cover from the March2, 1992, issue of Business Week that reflects the excitement and hype that the bio-technology revolution had generated in its first decade of existence. In this surreal-istic cover picture, the genie in the test tube is delivering the golden egg.

Like journalists, many prominent scientists became seduced by the euphoria ofthe biotechnology revolution, and they made a number of bold predictions which arelisted in TABLE 1. These include:

(1) Worldwide Shortage of Paper: Sequencing all 3 × 109 base pairs of DNA thatconstitute the human genome will produce a severe paper shortage, owing to the in-

TABLE 1. Bold predictions by prominent scientists stimulated by the euphoria of thebiotechnology revolution

1. Worldwide shortage of paper

2. Sexual harassment by robots

3. Drugs without side effects

4. Organ replacement with biologically synthesized cells

5. Individual genomes on compact discs (CDs)


crease in computer printouts and proliferation of new journals that will be necessaryto deal with the massive amount of new data.

(2) Sexual Harassment by Robots: The actual work of sequencing the human ge-nome is not done by human beings but by thousands of robotic instruments whosebehavior is programmed by humans.

(3) Drugs without Side Effects: This development will depend on our being ableto identify genetic differences among individuals and to understand how these ge-netic differences predispose different people to metabolize the same drug in differentways. The wonder-drugs of the future will be tailored to the genetic makeup of eachindividual and will be without side effects. Today we all take the same penicillin;

FIGURE 2. René Magritte, 1934. La condition humaine (The Human Condition).© 1997 C. Herscovici, Brussels/Artists Rights Society (ARS), New York.


99% of us do not have a problem, but the remaining 1% suffer severe allergic reac-tions. Doctors today deal in medicines of similarity, while in the future the predictionis that we will have medicines of variation, tailored to our patients’ geneticdifferences.

(4) Organ Replacement with Biologically Synthesized Cells: This developmentwill depend on first understanding the basic science of how an organ like the heartis formed in the embryo and on the ability to use that information to persuade thegenes that work in the developing embryo to work in a test tube. The goal is to createthe new organ, such as a new heart, from the patient’s own genes so that there wouldbe no rejection crisis and no need for toxic immunosuppressant drugs. That is a con-ceivable goal, although I cannot even hazard a guess as to how long it will take toachieve it.

(5) Individual Genomes on Compact Discs: Walter Gilbert, an eminent scientistat Harvard University who received the Nobel Prize in Chemistry in 1982 for discov-ering how to sequence DNA, stated in 1990: “In year 2020–2030 you will be able togo into the drug store, have your DNA sequence read in an hour or so, and given backto you on a compact disc so that you can analyze it.”10 If this turns out to be true,pharmacists are going to play bigger roles in medicine than physicians!

In many of these predictions, the distinction between illusion and reality isblurred, and that is what leads me to suggest that the biotechnology revolution is likethe surrealist revolution in art in which the practitioners—artists or scientists—ex-press their creativity by living and thinking in a world of dreams and fantasy. Thesurrealistic style and spirit of biotechnology is brilliantly captured in many paintingsdone 50 years ago by the famous surrealist artist René Magritte (1898–1967).

FIGURE 2 shows Magritte’s most famous painting, The Human Condition, whichhangs in the National Gallery of Art in Washington. This is a painting within a paint-ing. It exemplifies the essence of surrealism. The distinction between illusion and re-ality is called into question. The tree in the painting hides the real tree behind it,outside the house. This is the way biotechnologists and genomic researchers see theworld: as a painted dream. Is the tree really outside the room? Will we really havedrugs without side effects? Will each of our genomes really be put on a compactdisc? Will we really be able to replace organs with cells produced in the test tube?No one can promise with absolute certainty that any or all these dreams will cometrue, but I can tell (you that a strong start has been made, in large part as a result ofthe biotechnology industry.

TABLE 2. Biotechnology’s successes: 17 drugs approved by FDA

198219851986

198719891990

InsulinGrowth hormoneα-InterferonAnti-OKT3Hepatitis B vaccinetPAErythropoietinγ-Interferon

1991

1991

1993

19941997

G-CSFGM-CSFGlucocerebrosidaseIL-2Factor VIIIDNAseβ-InterferonAnti-IIb/IIIaFactor IX


BIOTECHNOLOGY INDUSTRY IN 1997

At the beginning of 1997, the biotechnology industry consisted of 1,287 compa-nies, of which 23% are publicly owned. It employs 118,000 people; about one-thirdof them are Ph.D. scientists, and virtually none are patient-oriented researchers. Theindustry has a market capitalization of $83 billion, product sales of $11 billion, andresearch and development expenses of $7.9 billion.11 The biotechnology industryrepresents the most rapidly growing new industry in our society, but unlike Mc-Donald’s and the microchip industry, it has not yet shown profits. The net losses ofthe industry as a whole were $4.6 billion last year.

FIGURE 3. René Magritte, 1959. Le château des pyrénées (The Castle in the Sky).© 1997 C. Herscovici, Brussels/Artists Rights Society (ARS), New York.


Together, the 1,287 companies that constitute the biotechnology industry are theequivalent of one big Merck & Co. Merck employs 100,000 people and has productsales of $11 billion; its market capitalization is $50 billion. The difference is thatMerck’s annual profit is of the order of $8 billion.11 One can think of the whole bio-technology industry as one big Merck, without the profits—or even as one Big Macwithout the profits!

To date, the biotechnology industry has developed 17 recombinant protein drugsor vaccines that have been approved by the FDA (TABLE 2). The number-one selleris a hormone called erythropoietin, which raises the number of red-blood cells andthe hemoglobin concentration in the bloodstream. It is given to patients sufferingfrom chronic kidney diseases, especially those undergoing prolonged dialysis. In1996, this drug produced more than a billion dollars in sales, and it is the sixthtop-selling drug of all pharmaceuticals. The four top-selling biotech drugs—eryth-ropoietin, G-CSF, hepatitis B vaccine, and insulin—are among the 20 best-sellingdrugs in the pharmaceutical industry as a whole.11 This is a remarkable achievementfor an industry that is so young.

TABLE 3. Biotech’s “castles in the sky”: the second-generation pipeline for drugdevelopment

New molecules

Soluble TNF receptors—rheumatoid arthritis and other autoimmune disorders

Leptin—obesity

Bone morphogenetic factors—bone fractures

Glial-derived neurotrophic factor—Parkinson’s disease

Thrombopoietin—platelet disorders

Inhibitors of angiogenesis and telomerase—cancer

New concepts

Naked DNA vaccines—AIDS and human papilloma virus

Universal organ transplants—genetically engineered pig livers

Protein pills—oral insulin enveloped in coats of polymethacrylic acid

Intracellular code blockers—antisense DNAs and ribozymes

Combinatorial chemistry—small-molecule drugs

Gene therapy

Cancer

AIDS

Inherited disorders

Genomics

Whole-genome sequencing of human beings and their pathogens—

identification of diagnostic reagents and targets for drugs and vaccines

Proteomics

Characterization of all human proteins expressed in different cell types in normal vs. disease states—identification of diagnostic reagents and targets for drugs


The biotechnology industry currently faces a generational crisis in the sense thatthe “easy targets” that emerged from the first generation of companies (such as in-sulin, growth hormone, tPA, erythropoietin) have all been identified. Identifyingmore-complex targets for treating diseases that involve complicated chemical cas-cades (such as sepsis, degenerative neurologic diseases, skin ulcers) has, to date, to-tally eluded the ingenuity of the best of biotechnologists.

The successful development of a “second generation” of biotechnology drugs re-quires creative breakthroughs, and true to their surrealistic spirit, biotechnologistsare always cooking up new recipes, which the industry calls “drugs in the pipeline”

FIGURE 4. René Magritte, 1928. Tentative de l’impossible (Attempting the Impossi-ble). © 1997 C. Herscovici, Brussels/Artists Rights Society (ARS), New York.


and which Magritte called Castles in the Sky (FIG. 3). A few selected examples ofthese “castles in the sky” are listed in TABLE 3. Even though most of these venturesare risky and unlikely to produce FDA-approved therapies in the next 10 years, it isonly through building “castles in the sky” that new scientific discoveries and bonafide therapies will emerge.

Of the five second-generation initiatives in TABLE 3, gene therapy deserves spe-cial comment inasmuch as it has received so much attention by the news media.More than 200 clinical trials are currently in progress in the U.S. in which the tech-niques of gene therapy are being used to treat patients with cancer, AIDS, and inher-ited diseases. To date, there is no single success story.12 The Achilles heel of genetherapy is the problem of delivering a gene to the right organ in a patient and havingit expressed in a sustained and regulated fashion. This is a formidable challenge andis reminiscent of Magritte’s Attempting the Impossible (FIG. 4). To be successful, thegene therapist must possess the superior powers of the artist who can replace an am-putated arm by simply painting it. As shown in FIGURE 4, the artist succeeds throughhis powers of imagination and his belief in the impossible.

The biotechnology industry has the potential to produce important new medicinesas discussed above and as evidenced by the data in TABLE 1. Some would argue thatthe 20-year-old industry is a big success on the basis of the 17 FDA-approved drugsthat are currently being prescribed to patients. On the other hand, the expense andwastage in producing these drugs is enormous, as revealed in FIGURE 5. On average,one new gene is cloned and characterized each day, one new biotechnology companyis formed each week, but only one new recombinant drug is approved by the FDAeach year. As many as 700 therapeutic products are currently undergoing clinical tri-als by 167 companies.11 But 16 of the last 18 drugs failed in Phase 2/3 studies.

If Magritte, the surrealist, were alive today, he might represent the situationshown in FIGURE 6. The top panel shows a reproduction of Magritte’s famous paint-ing The Betrayal of Images, in which he reminds us that the image of the pipe is notthe same as the pipe itself (Ceci n’est pas une pipe.). The bottom panel shows a mod-

FIGURE 5. The Biotechnology Industry in 1997: From the Surreal to the Real.


FIGURE 6. (Top) René Magritte, 1929. La trahison des images (The Betrayal of Imag-es). Text reads “This is not a pipe.” © 1997. C. Herscovici, Brussels/Artists Rights Society(ARS), New York. (Bottom) A contemporary version of Magritte’s painting adapted to thebiotechnology industry. Text reads “This is not a drug.”


ern version that reminds us that a gene sequence is not a drug (Ceci n’est pas un mé-dicament.).

Cloning a gene is only the first step in producing a drug. The DNA sequence ofthe cloned gene must be converted into a protein function in order for drug develop-ment to occur. Moving from the gene sequence to a drug may take 10 to 15 years ifthe function of the protein encoded by the gene is known. This process may take 20to 30 years if nothing is known about the function of the encoded protein.

Fortunately, there is one way to speed the drug discovery process, as illustratedin Magritte’s painting Clairvoyance (FIG. 7). Here, Magritte teaches us how to createdrugs from the DNA sequence. The artist, Magritte himself, is looking at an egg, buthe is painting the bird that is implicit in the egg. Such prescience is exactly what sci-entists of the future will need to learn to do: look at a DNA sequence, deduce thefunction of the protein, and produce a drug. The scientist of the future must functionmore and more like an artist, who looks at some amorphous, ill-defined, abstractphenomenon of nature and creates an object of beauty. A major challenge of basicresearchers is to learn how to move quickly from the DNA sequence to protein func-

FIGURE 7. René Magritte, 1936. La Clairvoyance (Clairvoyance). © 1997 C. Hers-covici, Brussels/Artists Rights Society (ARS), New York.


tion and ultimately to a drug.An equally important challenge is the need for clinicalinvestigators to acquire the scholarship and the analytical insight that will allowthem to point the biotechnology companies in the right direction in selecting theright recombinant molecule for the right disease.13 In his closing lecture at this bi-centennial symposium, Michael Brown will discuss this particular role of the physi-cian-scientist in more detail.14

Let us assume that scientists of the future acquire “clairvoyance” á la Magritteand learn how to look at DNA sequences and discover the functions of the 100,000proteins encoded in the human genome. We will then be in a position to answer, forthe first time, the central questions in biology, such as: How does an adult humandevelop from a simple egg? How do our brains work? How do humans differ fromone another? Which specific gene variations and which specific environmental fac-tors predispose different individuals to different diseases?

What will medicine be like in 2097, when Dartmouth Medical School celebratesits 300th anniversary? I will make one prediction that I am absolutely certain will betrue: Expect the unexpected. All we need is two or three new McDonald’s-like trans-mutations comparable in impact to the microchip and the gene and, who knows? Per-haps the surreality of the biotechnology industry of today will become the reality ofthe clinical medicine of tomorrow.

REFERENCES

1. DRUCKER, S. March 10, 1996. Who is the best restaurateur in America? The New YorkTimes Magazine. 45–47.

2. McDonald’s Fact Sheet. 1997. McDonald’s Corp. Riverside, IL.3. KROC, R. 1987. Grinding it Out: The Making of McDonald’s. 1–218. St. Martin’s

Paperbacks. Chicago, IL.4. RIORDAN, M. & L.HUDDESON. 1997. Crystal Fire: The Birth of the Information Age.

W.W. Norton & Co. New York. 5. REID, T.R. 1986. Tracing the roots of the microchip. Computerworld 20: 52–65.6. MOORE, G.E. 1996. Intel—Memories and the microprocessor. In The Power of Bold-

ness: Ten Master Builders of American Industry Tell Their Story. E. Blout, Ed. 77–101. Joseph Henry Press. Washington, DC.

7. KORNBERG, A. 1989. For the Love of Enzymes: The Odyssey of a Biochemist.: 269–296. Harvard University Press. Cambridge, MA.

8. Personal communication from William H. Griesar, Vice President and General Coun-sel, The Rockefeller University.

9. WILSON, S. 1991. Surrealist Painting. 1–128. Phaidon Press Limited. London.10. Personal communication from Walter Gilbert, Harvard University.11. LEE, K.B., JR. & G.S. BURRILL. 1996. Biotech 97 Alignment—The Eleventh Industry

Annual Report. 1-78. Ernst and Young LLP. Palo Alto, CA.12. VERMA, I.M. & N. SONIA. 1997. Gene therapy—promises, problems and prospects.

Nature 389: 239–242.13. GOLDSTEIN, J.L. & M.S. BROWN. 1997. The clinical investigator: bewitched, both-

ered, and bewildered—but still beloved. J. Clin. Invest. 99: 2803–2812.14. BROWN, M.S. The making of a physician–scientist: 2000. Ann. N.Y. Acad. Sci. This

issue.

burgers, chips, and genes

Documents