Testing DNA with Microtransponders

Abe Abuchowski

Lee Silver

Preventing Genetic Disease

Kary B. Mullis

Dan Conley

How it Works

Vlodek Mandecki Bio

Iceland’s Kari Stefansson and Decode Genetics

Corrections or additions?

DNA Diagnostics’ New Light: A Route 1 firm has an idea, cash, and a challenge

This story by Barbara Figge Fox was published in U.S. 1 Newspaper on January 20, 1999. All rights reserved.

To find the genetic background for a disease is probably

the fastest way to find a cure for that disease, and scientists the

world over are engaged in a fast and furious search to match each

malady with its telltale string of DNA. The first pioneering invention

for gene search, the polymerase chain reaction (PCR), opened the floodgates

for the first tidal wave of gene-sifting, but because the technologies

for the next stages are inefficient, geneticists desperately need

new tools to keep the channels of gene search open.

Wlodek Mandecki, 47, founder of PharmaSeq Inc., aims to supply one

of those gene-sifting and gene-searching technologies. He has invented

an integrated circuit for a microtransponder-based system that

is powered by light and is much smaller and, he says, much faster

than the state of the art DNA diagnostic equipment available now.

He is basking in the glow of receiving a grant that many larger companies

covet but never receive: $2 million from the Advanced Technology Program

(ATP) of the National Institute of Standards and Technology that will

cover his operating expenses for three years.

In spite of gaining this imprimatur, in spite of having a solid patent

position for a technology that could be worth millions, even billions

of dollars, Mandecki faces a daunting challenge. As of today he is

PharmaSeq’s only full-time employee; he went full-time on January

1 and needs to hire scientists and also senior operations and business

people. He has leased 1,500 feet space at 11 Deer Park Drive at Princeton

Corporate Plaza, but his laboratory has yet to be furnished. He has

prototypes, including some made by technicians at Sarnoff Corporation

acting as a subcontractor. Now he needs a second-stage prototype so

he can start testing. His challenge is to quickly develop his microtransponder-based

DNA diagnostic system and grab market share.

But he is confident. "The beauty is, the transponders are so small

that the numbers you can use are huge; you can put 10,000 of them

in a cc of liquid, like a teaspoon," says Mandecki. Competitive

microtransponders are about the size of a Tylenol capsule. In contrast,

he says, PharmaSeq’s microtransponders can be as small as the size

of two human hairs, 250 micrometers on each side.

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Testing DNA with Microtransponders

He predicts that the DNA testing market alone will amount

to $2 billion in five years. "We have the grant that assures steady

growth for three years. I am in an exceptional position, and the technology

is hot," says Mandecki. "I have a lot of opportunities to

get grant money from the government and am taking advantage of that.

PharmaSeq will grow."

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Abe Abuchowski

"Wlodek’s idea is futuristic — it takes a quantum leap. It

is an optical reader, not a chemical reader," says Abe Abuchowski,

founder of Piscataway-based Enzon and a trailblazer for biotech firms

in New Jersey. With his firm New Paradigm Consulting (http://www.npconsulting.com)

he works with PharmaSeq on an as-needed basis. "It goes from a

two-dimensional reader to a three-dimensional reader — a great

stride forward as a scientific tool. The number of analyses that you

can do are astronomical, compared to the others. That is the beauty

of this, its speed and accuracy."

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Lee Silver

Good technology, bad technology, the winner will be what works fastest

and cheapest. "It doesn’t matter whether the technology is one,

two, or three-dimensional as long as it is high throughput, efficient,

and cost effective," says Lee Silver, a nationally prominent geneticist

at Princeton University and author of one of the first books on the

cloning controversy, "Remaking Eden."

"All of these technologies are fantastic," says Silver. "Different

people are competing with different technologies to grab that market.

It is too early to know which one will win the market. Companies want

to spend the least amount of money to get the most information. His

is in the running if he can make it fit the parameters."

Mandecki is only too aware of the competition. "Good technologies

can lose to inferior technologies in the marketplace," he admits,

pointing out how the Beta format for videotapes lost out to the VCR

format because of market share. "People don’t like to retool.

It needs to be so much better that people have no choice but to use

it."

Yet his optimism is buoyed by memories of how one of the first breakthroughs

in gene discovery, the polymerase chain reaction (PCR), took the biotechnology

world by storm. PCR is used to amplify DNA so that scientists can

make billions of copies of a DNA molecule swiftly. It is useful for

finding DNA sequences, to diagnose disease, to detect bacteria or

viruses, and to do DNA fingerprinting. The technology was discovered

in 1985, bought by Hoffman La Roche in 1991 for $300 million, and

is being licensed for thousands of applications. "My team likes

to think that the potential for applications for our product is just

as enormous," says Mandecki.

His microtransponders, he says, could replace current technologies

that are cumbersome. "For many PCR applications I will have a

corresponding transponder application. Microtransponder-based assays

can be used in research, in DNA diagnostics, for drug discovery, for

immunoassays, or for any assay for which the presence or absence of

many molecules or sequences needs to be established," says Mandecki.

Mandecki is also encouraged by the prospect of staving off the tragedies

of genetically-carried diseases. He is fond of recalling the scene

from a recent film, "Gattaca," starring Princeton Junction

native Ethan Hawke as a boy destined by his genes to be a janitor.

In the film’s genetically-engineered world, a man takes a sample of

his fiancee’s hair to a kiosk, and in 30 seconds has a sequence analysis

and the DNA properties of his future wife, "so he can make a rational

decision," says Mandecki.

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Preventing Genetic Disease

He tells the true story of a friend, Christine, who learned that her son

carried the gene for a debilitating and fatal disease, Duchenne muscular

dystrophy, only after her son was four years old. She had to watch

him gradually deteriorate, "spending the next 12 years observing

his gradual death, symptoms that start with difficulties in walking

and end up with the inability to breathe."

"The mission of PharmaSeq Inc. is to develop technology to better

inform potential parents of the consequences due to the genetics of

their offspring," says Mandecki. "This may prevent the tragedy

that Christine and many mothers like her will go through. PharmaSeq’s

goal is to implement affordable methods to detect not only Duchenne

muscular dystrophy but also all other genetic diseases. And this is

just a beginning. The universal technological platform that PharmaSeq

pursues may also be used to detect infectious diseases and to discover

new pharmaceuticals in an efficient and cost effective manner."

The market will be so large that no single company, he says, can serve

all the needs. "We will license the technology but perhaps critical

applications will be developed by PharmaSeq," says Mandecki.

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Kary B. Mullis

If he is dreaming of PCR’s profit margins, Mandecki is planning for

his venture to be very different from PCR in at least one respect:

he will own it. Kary B. Mullis, the scientist who came up with the

idea for PCRs, an idea that would later earn him the Nobel Prize for

chemistry, was working at the time for a company that paid him just

$10,000 for his brainstorm. In contrast, Mandecki planned to first

start his own company, and second, to patent the idea.

To position himself for growth Mandecki has tapped the combined expertise

from the formal and informal networks of scientific and financial

advisors in Central New Jersey. "I am amazed at how well developed

the infrastructure is, the network of the informal interactions in

New Jersey and more specifically in the Princeton area," he says.

Top Of Page
Dan Conley

He worked with the Technology Help Desk ("I can

recommend contacting them to anybody") to find his accountant,

Patrick Alia, of Amper Politziner Mattia. Dan Conley, of Silicon Garden

Angels + Investors, is the "on-call" chief financial officer,

charged with procuring venture leasing, venture lending, and early

stage private equity to leverage the $2 million grant and seed money

obtained from a private party (E-mail: oncallCFO@aol.com).

Mandecki’s Chicago-based pattent attorney is from Brinks Hofer Gilson & Lione,

which is, he says, one of the 15 largest patent law firms in the nation.

His biotech consultant is Abuchowski, one of the early movers and

shakers in New Jersey’s biotech community. He and Abuchowski wrote

the SBIR grant in August, 1997, and it came through in February, 1998.

The ATP grant was written last March and it came through on October

7.

"Abe has a very good feel for the business strategy; he was CEO

for Enzon for 12 years, and he went through all the growth stages,"

says Mandecki. "He provided me with a better understanding of

how the `money people’ think. They don’t necessarily think about how

great the research is, but about how to make the business grow fast

in the shortest time possible; he helped me with the business plan."

As one of the "Best of the Best" presenters at the New Jersey

Entrepreneurial Network meeting on January 6, Mandecki was honored

for receiving the three-year $2 million ATP grant. To put the importance

of that grant in perspective, another ATP winner was Orchid Biocomputer,

the 65-employee Sarnoff Corporation spinoff, with laboratories on

College Road and Deer Park Drive, that offers so much promise in the

field of microfluidic DNA testing and drug discovery. (PharmaSeq is

not related to Seq Inc., the start-up funded by Robert Johnston that

occupies space on Princess Drive.)

"The purpose of the grant is to help technologies that are of

interest to the nation, that could have economic value to the country

in generating jobs," says Abuchowski. "They felt that this

is one of those technologies, and appropriately so. It will make a

major change."

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How it Works

To understand how Mandecki’s light-powered microtransponders work,

remember the last time your dentist gave you a brushing lesson. You

swished a red dye around in your mouth; it adhered to the plaque on

your teeth. You tried to brush the dye away, but you missed some parts,

and when you looked in the mirror you saw where the red dye had stuck

to some crevices.

"The objective of a DNA assay is to find out whether the gene

is a mutant or a normal gene," says Mandecki. The microtransponders

are cube-shaped, light-activated miniature radio-frequency transmitters

about the size of two human hairs. Each has an integrated circuit

that stores, in its electronic memory, information identifying the

sequence of an attached DNA probe.

To begin a DNA assay on PharmaSeq’s microtransponder, the patient’s

DNA is labeled with a fluorescent dye and applied to the surface of

a microtransponder that contains a particular synthetic gene sequence.

Light powers up the electronic circuitry within the microtransponder

and at the same time activates the dye on the surface of the microtransponder.

"DNA `hybridization’ occurs when two DNA molecules of complementary

sequences bind," says Mandecki.

When the patient’s DNA is washed off the surface, the remaining fluorescence

is measured. If any fluorescence remains, that shows a match was made

and that the patient’s DNA contains the particular gene sequence on

the transponder. The DNA has bound to the surface of that transponder.

If no fluorescence remains, the patient’s DNA did not match that transponder’s

gene sequence.

One transponder is used for each sequence or gene mutation but up

to 1,000 or more tests can be done at a time with Pharmaseq’s method.

Each microtransponder will be good for only one gene or mutation

and one test.

Competitive methods include manufacturing DNA arrays

by photolithography process and solid-phase chemical synthesis (being

done at Affymetrix, using Hewlett Packard equipment to read the assay

results), using ink-jet printing (done by Incyte), or what is called

clone spotting using a robotic system (by Hyseq and Incyte).

Mandecki says his assay is novel because it is not indexed by two-dimensional

coordinates but takes place in three dimensions, in the test tube.

"This 3D array is disassembled for the fluorescence measurements

and analyzed as a linear string of solid-phase particles passing through

the flow chamber of the scanner."

Mandecki says he will be able to do faster testing at the same cost

as tests that are currently on the market.

Says geneticist Silver: "They are all just different technologies.

it is impossible to know what will be the most efficient in the long

run. The bottom line is how many genes can you assay at the same time."

"I also want to diversify and go into drug discovery," says

Mandecki. "Microtransponders can be tags for small organic molecules

as well. I believe that the first sales will be for using microtransponders

as tags on small parts, applications for which the barcode is being

used now. The integrated circuit is the same for both biochemical and taggling applications."

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Vlodek Mandecki Bio

Wlodek Mandecki needed to become a geographical bachelor to start

this firm; his family is still in Chicago. Three years ago he rented

a house in Edison and he goes home only every three or four weeks.

"There is a lot of uncertainty in starting a new company,"

he says. "Now that I have the ATP grant I am relocating my family

in Princeton Junction."

A native of Warsaw, he was the only child of an economist and a pharmacist.

He has an undergraduate degree in physics from the University of Warsaw

(Class of 1974) and a PhD from Institute of Biochemistry of the Polish

Academy of Sciences. For his first post doctoral studies, in protein

analyses and sequencing in the medical school at UCLA, he had to leave

his pregnant wife behind and he did not see his son until he was 18

months old. "It was heartbreaking but what can you do? The airfare

to Poland was three months of my salary," he recalls.

Next he worked on how a gene expression is regulated, particularly

on E coli, in the molecular biology department at the University of

Wisconsin at Madison. "At that time DNA sequence analysis was

at the early stages. I was in one of the labs that pioneered sequence

analysis of DNA, with Bill Reznikoff." Then he worked at the University

of Colorado with Marvin Caruthers, whom he calls the "the father

of chemical synthesis of oligonucleotides (DNA)." In Chicago he

worked at Abbott Laboratories, starting as a

group leader and ending up as research manager, working in molecular

biology, genetic analyses, gene expression, protein engineering, protein

evolution. Thirty Abbott diagnostic products are based on his patents.

"Abbott is an exciting place to work," he says. Of the New

Jersey pharmaceuticals, he compares it to Hoffman-La Roche, because

of its diversification into drug discovery, pharmaceuticals, and diagnostics.

He knew he didn’t want to stay in Chicago to found his company, so

he had to leave his family behind. His wife, Wanda, writes Polish

literature textbooks for English-speaking students and teaches on

Saturdays at a Polish high school in Chicago. "She is well recognized

and rewarded; she has made a place for herself," she says. The

oldest son is now 19 and is majoring in business at the University

of Michigan. They have a 16-year-old boy and a 14-year-old girl.

"Not very many start-up biotech companies have succeeded in Chicago,"

he notes, "and New Jersey is one of four major hubs for biotech."

His choice was influenced by an offer to consult in Edison for DGI

Biotechnologies. He had worked on single chain antibodies and protein engineering at Abbott

Labs and continued in this area for DGI. After three years there he

went full-time into his own business as of January 1, 1999.

How he found his lab space is, he says enthusiastically, "one

of those unbelievable stories." Architect Harold Kent was designing

and furnishing the space at the lab where he was doing some consulting.

"I liked what he was doing, and he said he had some space at Deer

Park Drive. Amazingly enough, in two hours I had a facility. He runs

one of the very few centers that care for small business. Not too

many other places would rent 1,500 square feet, with laboratory furniture,

in a very attractive location, next to Wyeth Ayerst, Small Molecule

Therapeutics, and Orchid Biocomputer."

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Iceland’s Kari Stefansson and Decode Genetics

To put Mandecki’s technology in perspective, consider the news coming

from Iceland: a genetic information gathering project with enormous

impact. The country of Iceland has sold the rights to collect information

on its gene pool — famous for being homogeneous and therefore

very attractive to researchers — to Kari Stefansson and his firm

Decode Genetics. He will create a huge electronic database with which

researchers can hunt for the root-gene causes of hundreds of diseases.

The database can be parceled out to other pharmaceutical companies

as well.

Being able to use Iceland’s small gene pool dramatically improves

the odds of zeroing in on a particular gene. Instead of searching

for the particular grain of sand on all of the beaches in the world,

you can narrow your search to just one beach. But current searching

methods are limited to sifting the sand bucket by bucket. Imagine

how much faster it would be to sift truckload by truckload.

Is genetic research the truckload sifter, the fastest way to find

disease cures? Silver, the Princeton geneticist, insists that it is.

"No matter what the biochemists say, they are wrong. At this point

the geneticists have control," says Silver. "From the disease

you find the gene — you find out how it works. Once you understand

how it works properly, you find out how it works in diseased individuals

and that is the paradigm that everybody is using. Already there are

100 diseases being worked on for cures."

Cystic fibrosis is the first success story, Silver says, and he estimates

that 100 diseases are being researched for a genetic cure. "The

market for multiplexing genes is enormous, in the multi billions.

It is the future of medicine."

But all this is very early, almost `pie in the sky’ for PharmaSeq,

which does not yet have a fully working model. "The Eureka moment is

yet to come," admits Abuchowski. "But that will be some moment,

when it happens. If you can tag molecules, you can tag all kinds of

things. It doesn’t take a rocket scientist to realize what the applications

are."

"He probably has an opportunity to sell the technology outright

to one company that could exploit it very quickly and also make a

lot of money," says Abuchowski.

"Don’t make me rich too quickly," says Mandecki.

PharmaSeq Inc., 11 Deer Park Drive, Princeton Corporate

Plaza, Suite 204, Monmouth Junction 08852. Wlodek Mandecki, president

and CEO. 732-355-0100; fax, 732-635-0428. E-mail: mandecki@compuserve.com.

— Barbara Figge Fox


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